Adenocarcinoma, Adenocarcinoma, Papillary, Bronchial Neoplasms, Carcinoma, Carcinoma, Bronchogenic, Carcinoma, Neuroendocrine, Carcinoma, Non-Small-Cell Lung, Colonic Diseases, Colonic Neoplasms, Colorectal Neoplasms, Digestive System Disease, Digestive System Neoplasm, Endocrine Gland Neoplasm, Endocrine System Diseases, Gastrointestinal Disease, Gastrointestinal Neoplasms, Head and Neck Neoplasms, Intestinal Disease, Intestinal Neoplasms, Lung Diseases, Lung Neoplasm, Medullary Thyroid Cancer, Neoplasms, Neoplasms by Histologic Type, Neoplasms by Site, Neoplasms, Germ Cell and Embryonal, Neoplasms, Glandular and Epithelial, Neoplasms, Nerve Tissue, Neuroectodermal Tumors, Neuroendocrine Tumors, Respiratory Tract Disease, Respiratory Tract Neoplasms, RET-altered Colon Cancer, RET-altered Non Small Cell Lung Cancer, RET-altered Papillary Thyroid Cancer, RET-altered Solid Tumors, Thoracic Neoplasms, Thyroid Cancer, Papillary, Thyroid Diseases, Thyroid Neoplasm
Conditions
Keywords
RET Lung, RET Thyroid, RET fusion, RET alteration, RET mutation, RET positive, RET inhibitor, RET altered, RET rearrangement, RET NSCLC, RET medullary thyroid cancer, RET-rearranged NSCLC, RET-rearranged thyroid, M918T, TRIM33-RET, RET fusion lung cancer, RET fusion thyroid cancer, lung cancer mutation, BLU 667, RET tyrosine kinase, RET gene mutation, RET kinase, RET MTC, advanced lung cancer, advanced non small cell lung cancer, metastatic lung cancer, KIF5B-RET, CCDC6-RET, NCOA4-RET, advance solid tumor, V804L, V804M, thyroid cancer RET inhibitor, lung cancer RET inhibitor, RET PTC, rearranged during transfection, RET-PTC1, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET
Brief summary
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in participants with medullary thyroid cancer (MTC), RET-altered NSCLC and other RET-altered solid tumors.
Detailed description
The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part (Phase 2). Both parts will enroll participants with advanced non-resectable NSCLC, advanced non-resectable thyroid cancer and other advanced solid tumors that have progressed following standard systemic therapy, have not adequately responded to standard systemic therapy, or the participants must be intolerant to or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.
Interventions
pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants
Sponsors
Study design
Intervention model description
Phase 1 (Complete): * Advanced MTC, NSCLC or other solid tumor * 30-600mg (PO QD or BID) Phase 2 (400mg QD): * Group 1: RET fusion NSCLC previously treated with a platinum chemotherapy * Group 2: RET fusion NSCLC not previously treated for metastatic disease * Group 3: MTC previously treated with cabozantinib and/or vandetanib * Group 4: MTC not previously treated with cabozantinib or vandetanib * Group 5: Other solid tumors with a RET fusion not eligible for any of the other groups and previously treated with SOC or have no acceptable SOC for their tumor type as determined by the investigator * Group 6: Any solid tumor with a RET alteration (fusion or mutation) previously treated with a selective RET Inhibitor * Group 7: Other solid tumors with a RET mutation previously treated with SOC * Group 8: RET fusion NSCLC previously treated with a platinum chemotherapy (China only) * Group 9: MTC not previously treated with systemic therapy for advanced or metastatic disease (China only)
Eligibility
Inclusion criteria
Key Inclusion Criteria: * Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor. * All participants treated at doses \> 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood. * Diagnosis during dose expansion (Phase 2) - All participants (with the exception of participants with MTC enrolled in Groups 3, 4, and 9) must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below. * Group 1 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy. * Group 2 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy, including those who have not had any systemic therapy. Prior platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if the last dose of platinum was 4 months or more before the first dose of study drug. * Group 3 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib. * Group 4 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib and/or vandetanib. * Group 5 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received standard of care (SOC) appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate), and must not have been eligible for any of the other groups. * Group 6 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective tyrosine kinase inhibitor (TKI) that inhibits RET * Group 7 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups * Group 8 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum based chemotherapy (China only). * Group 9 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit, and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only). * Participants must have non-resectable disease. * Dose expansion (Phase 2): Participants in all groups (except Group 7) must have measurable disease per RECIST v1.1 (or RANO, criteria if appropriate for tumor type). * Participants agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Phase 2, Group 6, participants are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue. * Participants has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. Key
Exclusion criteria
* Participant's cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1 or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation. * Participants had any of the following within 14 days prior to the first dose of study drug: 1. Platelet count \< 75 × 10\^9/L. 2. Absolute neutrophil count \< 1.0 × 10\^9/L. 3. Hemoglobin \< 9.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug. 4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 × the upper limit of normal (ULN) if no hepatic metastases are present; \> 5 × ULN if hepatic metastases are present. 5. Total bilirubin \> 1.5 × ULN; \> 3 × ULN with direct bilirubin \> 1.5 × ULN in presence of Gilbert's disease. 6. Estimated (Cockcroft-Gault formula) or measured creatinine clearance \< 40 mL/min. 7. Total serum phosphorus \> 5.5 mg/dL * QT interval corrected using Fridericia's formula (QTcF) \> 470 msec or history of prolonged QT syndrome or Torsades de pointes, or familial history of prolonged QT syndrome. * Clinically significant, uncontrolled, cardiovascular disease. * Central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms. * Clinically symptomatic interstitial lung disease or interstitial pneumonitis including radiation pneumonitis * Participants in Groups 1-5 and 7 (Phase 2) previously treated with a selective RET inhibitor * Participant had a major surgical procedure within 14 days of the first dose of study drug * Participant had a history of another primary malignancy that had been diagnosed or required therapy within the a year prior to the study * Pregnant or breastfeeding female participants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib | Up to approximately 30.8 months | MTD was defined as the highest tolerated dose of pralsetinib without causing dose limiting toxicities (DLTs). DLT was defined as any Grade ≥3 adverse event (AE) occurring during Cycle 1 during Phase 1 (dose escalation) that is not clearly caused by something other than pralsetinib. RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase. |
| Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | From Cycle 1 Day 1 up to 30 days after the final dose of study drug (up to approximately 6.7 years) | An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. |
| Phase 2: Overall Response Rate (ORR) | Up to approximately 79.8 months | ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) for at least two assessments with at least 28 days apart and no disease progression (PD) in between. Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), were presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in both MTC and differentiated TC (DTC). These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3. |
| Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR, or stable disease (SD) which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). |
| Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). |
| Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in both MTC and DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). |
| Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). |
| Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). |
| Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in both MTC and DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). |
| Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5), CCDC6, NCOA4). RET genotypes were determined by local testing &/or central analysis of circulating tumor deoxyribonucleic acid (ctDNA). DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR=disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to \<10 mm. PR=at least a 30% decrease in SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study. DOR was analyzed using the Kaplan-Meier (KM) method. |
| Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR= disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to \<10 mm. PR=at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the Kaplan-Meier (KM) method. |
| Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR= disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to \<10 mm. PR=at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the KM method. |
| Phase 2: DOR | Up to approximately 79.8 months | DOR was defined as the time from first documented response (CR/PR) to the date of first documented PD or death due to any cause, whichever occurs first. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DOR was analyzed using the KM methods. |
| Phase 2: CBR | Up to approximately 79.8 months | CBR was defined as the percentage of participants with CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). CBR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented. |
| Phase 2: DCR | Up to approximately 79.8 months | DCR was defined as the percentage of participants with a confirmed CR/PR, or SD, per RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DCR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented. |
| Phase 2: Progression-free Survival (PFS) | Up to approximately 7 years | PFS was defined as the time from the first dose of pralsetinib to the date of first documented PD or death due to any cause, whichever occurred first. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). PFS was analyzed using KM methods. |
| Phase 2: Overall Survival (OS) | Up to approximately 7 years | OS was defined as the time from the first dose of pralsetinib to the date of death due to any causes. |
| Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants | Up to approximately 79.8 months | ORR=percentage of participants with CR or PR for at least 2 assessments with at least 28 days apart & no PD in between. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/or cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR =at least a 30% decrease in the SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in the absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or the identification of new CNS/brain lesion. PD=either at least 20% increase in the SOD of target CNS/brain lesion, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of any CNS/brain lesion identified as RECIST 1.1 nontarget lesions at baseline, or the identification of new CNS/brain lesion. |
| Phase 1: Time to Maximum Plasma Concentration (Tmax) | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants | Up to approximately 79.8 months | DOR=time from first documented CR/PR to the date of first documented PD/death due to any cause, whichever occurs first. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/ cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR=at least a 30% decrease in SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or identification of new CNS/brain lesion. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion. DOR was analyzed using the KM methods. |
| Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants | Up to approximately 79.8 months | CBR=percentage of participants with CR/PR/SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in 1 cycle) from first dose date. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/ cerebellum identified at baseline&disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR=at least a 30% decrease in SOD of any CNS/brain lesion, identified as target lesions at baseline & if in absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or identification of new CNS/brain lesion. SD=neither sufficient shrinkage for PR nor sufficient increase for PD for target/non-target CNS/brain lesion, taking as reference smallest SOD while on study. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion. |
| Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants | Up to approximately 79.8 months | DCR=percentage of participants with a confirmed CR/PR, or SD. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/or cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR =at least a 30% decrease in the SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in the absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or the identification of new CNS/brain lesion. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target/non-target CNS/brain lesion, taking as reference the smallest SOD while on study. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion. |
| Phase 1: Maximum Plasma Concentration (Cmax) | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | The maximum values for Tlast slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 24 hours postdose on Day 1 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Apparent Volume of Distribution (Vz/F) | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Terminal Elimination Half-Life (t½) | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | The maximum values for t1/2 slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Apparent Oral Clearance (CL/F) | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Accumulation Ratio for Cmax (RCmax) | 24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 1: Accumulation Ratio for AUC (RAUC) | 24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days) | Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM. |
| Phase 2: Cmax | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | — |
| Phase 2: Tmax | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | — |
| Phase 2: Tlast | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | The maximum values for Tlast slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. |
| Phase 2: AUC0-24 | 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | — |
| Phase 2: C24hr | 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | — |
| Phase 2: t½ | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | The maximum values for t1/2 slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. |
| Phase 1: ORR | Up to approximately 28 months | ORR was defined as the percentage of participants with a confirmed CR or PR for at least two assessments with at least 28 days apart and no PD in between. Per RECIST v1.1, CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), was presented. |
| Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | Baseline, Week 4 | The dose dependent change in a mitogen-activated protein kinases (MAPK) pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker DUSP6 levels was explored. |
| Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | Baseline, Week 4 | The dose dependent change in a MAPK pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker SPRY4 levels was explored. |
| Phase 2: CL/F | Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days) | — |
| Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., Kinesin family member 5B (KIF5B), coiled-coil domain containing 6 (CCDC6), nuclear receptor coactivator 4 (NCOA4)). RET genotypes were determined by local testing and/or central analysis of circulating tumor deoxyribonucleic acid (ctDNA). ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3. |
| Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | Up to approximately 79.8 months | Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3. |
Countries
Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
A total of 590 participants with rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), RET mutation-positive medullary thyroid cancer (also known as RET-mutant MTC), RET fusion-positive thyroid cancer (TC) and other advanced solid tumors took part in the study at 74 investigative sites across 13 countries from 17 March 2017 to 21 March 2024. The study was divided into two parts: Phase 1 (Dose Escalation) and Phase 2 (Dose Expansion).
Pre-assignment details
For Phase I, The number of participants in each arm within the participant flow reflects the arms they were originally assigned to, whereas numbers reported in the pharmacokinetics outcome measure (OM) represent the number based on actual treatment received by the participants. 1 participant assigned to the 200/100 mg arm received the 100/100 mg treatment. Hence, was counted under the 100/100 mg arm in the PK-evaluable population.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Pralsetinib 30 mg Participants received pralsetinib 30 milligrams (mg) orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 2 |
| Phase I: Pralsetinib 60 mg Participants received pralsetinib 60 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 6 |
| Phase I: Pralsetinib 100 mg Participants received pralsetinib 100 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 5 |
| Phase I: Pralsetinib 200 mg Participants received pralsetinib 200 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 13 |
| Phase I: Pralsetinib 300 mg Participants received pralsetinib 300 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 11 |
| Phase I: Pralsetinib 400 mg Participants received pralsetinib 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 12 |
| Phase I: Pralsetinib 600 mg Participants received pralsetinib 600 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. | 4 |
| Phase I: Pralsetinib 100/100 mg Participants received pralsetinib 100 mg, orally, twice a day (BID) until discontinuation due to toxicity, disease progression, or other reasons. | 5 |
| Phase I: Pralsetinib 200/100 mg Participants received pralsetinib 200 mg in the morning and then 100 mg in the evening orally until discontinuation due to toxicity, disease progression, or other reasons. | 4 |
| Phase II: Pralsetinib 400 mg Participants with advanced NSCLC, advanced non-resectable TC and other advanced non-resectable solid tumors with various rearranged during transfection (RET)-alterations were enrolled in this arm to receive pralsetinib, 400 mg, QD until discontinuation due to toxicity, disease progression, or other reasons. | 528 |
| Total | 590 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 6 |
| Overall Study | Death | 1 | 4 | 2 | 2 | 5 | 2 | 1 | 4 | 3 | 240 |
| Overall Study | Initiation of Another Therapy | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 16 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 0 | 1 | 1 | 5 | 2 | 0 | 1 | 0 | 0 | 30 |
| Overall Study | Reason Not Specified | 0 | 1 | 0 | 4 | 3 | 6 | 2 | 0 | 1 | 181 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 2 | 1 | 3 | 0 | 0 | 0 | 52 |
Baseline characteristics
| Characteristic | Phase I: Pralsetinib 30 mg | Phase I: Pralsetinib 60 mg | Phase I: Pralsetinib 100 mg | Phase I: Pralsetinib 200 mg | Phase I: Pralsetinib 300 mg | Phase I: Pralsetinib 400 mg | Phase I: Pralsetinib 600 mg | Phase I: Pralsetinib 100/100 mg | Phase I: Pralsetinib 200/100 mg | Phase II: Pralsetinib 400 mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 54.5 years STANDARD_DEVIATION 9.2 | 49.5 years STANDARD_DEVIATION 18 | 51.2 years STANDARD_DEVIATION 13.2 | 53.8 years STANDARD_DEVIATION 13.6 | 60.6 years STANDARD_DEVIATION 11 | 49.2 years STANDARD_DEVIATION 17.8 | 59.5 years STANDARD_DEVIATION 9.1 | 63.0 years STANDARD_DEVIATION 11.09 | 61.8 years STANDARD_DEVIATION 18.25 | 57.7 years STANDARD_DEVIATION 12.6 | 57.5 years STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 19 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 4 Participants | 4 Participants | 12 Participants | 11 Participants | 9 Participants | 4 Participants | 3 Participants | 4 Participants | 465 Participants | 516 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 44 Participants | 46 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 203 Participants | 209 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 32 Participants | 39 Participants |
| Race/Ethnicity, Customized White | 0 Participants | 3 Participants | 2 Participants | 11 Participants | 11 Participants | 9 Participants | 4 Participants | 3 Participants | 4 Participants | 284 Participants | 331 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 257 Participants | 283 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 1 Participants | 8 Participants | 7 Participants | 9 Participants | 1 Participants | 4 Participants | 2 Participants | 271 Participants | 307 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 37 | 245 / 540 | 7 / 9 | 268 / 590 |
| other Total, other adverse events | 36 / 37 | 536 / 540 | 9 / 9 | 585 / 590 |
| serious Total, serious adverse events | 26 / 37 | 381 / 540 | 7 / 9 | 416 / 590 |
Outcome results
Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs)
An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Time frame: From Cycle 1 Day 1 up to 30 days after the final dose of study drug (up to approximately 6.7 years)
Population: Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels. As pre-specified in the SAP, safety data was to be analyzed and reported as per the pre-planned grouped dose level II (SAP section 3.6.5.2). Hence, per dose safety data is not presented for this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | AEs | 37 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | SAEs | 26 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | SAEs | 381 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | AEs | 540 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | AEs | 9 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | SAEs | 7 percentage of participants |
| Pralsetinib All Doses | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | AEs | 590 percentage of participants |
| Pralsetinib All Doses | Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) | SAEs | 416 percentage of participants |
Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib
MTD was defined as the highest tolerated dose of pralsetinib without causing dose limiting toxicities (DLTs). DLT was defined as any Grade ≥3 adverse event (AE) occurring during Cycle 1 during Phase 1 (dose escalation) that is not clearly caused by something other than pralsetinib. RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase.
Time frame: Up to approximately 30.8 months
Population: Dose-determining population included all participants in the dose-escalation part who have received ≥75% (21 days) of the study drug and completed safety evaluations through Cycle 1 Day 28 or experienced a DLT.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib | MTD | 400 mg |
| Phase 1: All Participants QD | Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib | RP2D | 400 mg |
Phase 2: Overall Response Rate (ORR)
ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) for at least two assessments with at least 28 days apart and no disease progression (PD) in between. Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), were presented.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who had measurable (target) disease per RECIST v1.1 at baseline according to blinded central review (BICR) and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are also included in Phase 2 efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Overall Response Rate (ORR) | 63.1 percentage of participants |
| Pralsetinib 400 mg QD | Phase 2: Overall Response Rate (ORR) | 73.9 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 2: Overall Response Rate (ORR) | 78.3 percentage of participants |
| Pralsetinib All Doses | Phase 2: Overall Response Rate (ORR) | 56.7 percentage of participants |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 2: Overall Response Rate (ORR) | 77.8 percentage of participants |
| RET-fusion Positive TC | Phase 2: Overall Response Rate (ORR) | 85.2 percentage of participants |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 2: Overall Response Rate (ORR) | 46.4 percentage of participants |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 2: Overall Response Rate (ORR) | 19.0 percentage of participants |
| RET-mutation Positive Tumors Other Than MTC | Phase 2: Overall Response Rate (ORR) | 7.7 percentage of participants |
Phase 1: Accumulation Ratio for AUC (RAUC)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: 24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Accumulation Ratio for AUC (RAUC) | 1.43 ratio | — |
| Pralsetinib 400 mg QD | Phase 1: Accumulation Ratio for AUC (RAUC) | 1.47 ratio | Geometric Coefficient of Variation 11.1 |
| Pralsetinib BID Dosing Schedule | Phase 1: Accumulation Ratio for AUC (RAUC) | 3.22 ratio | — |
| Pralsetinib All Doses | Phase 1: Accumulation Ratio for AUC (RAUC) | 1.31 ratio | Geometric Coefficient of Variation 147 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Accumulation Ratio for AUC (RAUC) | 2.33 ratio | Geometric Coefficient of Variation 11.4 |
| RET-fusion Positive TC | Phase 1: Accumulation Ratio for AUC (RAUC) | 2.75 ratio | Geometric Coefficient of Variation 70.9 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Accumulation Ratio for AUC (RAUC) | 2.48 ratio | — |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Accumulation Ratio for AUC (RAUC) | 4.28 ratio | — |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Accumulation Ratio for AUC (RAUC) | 1.21 ratio | — |
Phase 1: Accumulation Ratio for Cmax (RCmax)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: 24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.04 ratio | — |
| Pralsetinib 400 mg QD | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.25 ratio | Geometric Coefficient of Variation 27.6 |
| Pralsetinib BID Dosing Schedule | Phase 1: Accumulation Ratio for Cmax (RCmax) | 3.20 ratio | Geometric Coefficient of Variation 114 |
| Pralsetinib All Doses | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.17 ratio | Geometric Coefficient of Variation 110 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.87 ratio | Geometric Coefficient of Variation 40.5 |
| RET-fusion Positive TC | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.62 ratio | Geometric Coefficient of Variation 102 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Accumulation Ratio for Cmax (RCmax) | 2.97 ratio | — |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.91 ratio | Geometric Coefficient of Variation 40.7 |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Accumulation Ratio for Cmax (RCmax) | 1.41 ratio | — |
Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in both MTC and DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status | CCDC6 | 82.4 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status | NCOA4 | 100 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status | Other | 75.0 percentage of participants |
| Unknown | Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status | KIF5B | — percentage of participants |
Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 78.0 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 76.9 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 100 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 86.0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 96.0 percentage of participants |
Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status
Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR, or stable disease (SD) which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 76.0 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 76.9 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 53.8 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | NCOA4 | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 75.0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 88.2 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 63.6 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 81.6 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 84.2 percentage of participants |
Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in both MTC and DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status | CCDC6 | 94.1 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status | NCOA4 | 100 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Unknown | Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status | KIF5B | — percentage of participants |
Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 95.1 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 92.3 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 100 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 90.7 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 96.0 percentage of participants |
Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status
Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 88.0 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 93.4 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 84.6 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | NCOA4 | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 50.0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 94.1 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 88.2 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 89.5 percentage of participants |
Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR= disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to \<10 mm. PR=at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the KM method.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR \& sufficient evidence of a RET alteration. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants who had a response of CR/PR were analyzed in this outcome measure. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status | CCDC6 | NA months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status | NCOA4 | 15.2 months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status | Other | NA months |
Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR= disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to \<10 mm. PR=at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the Kaplan-Meier (KM) method.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR \& sufficient evidence of a RET alteration. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants who had a response of CR/PR were analyzed in this outcome measure. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 21.8 months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | Other | NA months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 29.5 months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 18.4 months |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 36.8 months |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 51.8 months |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status | Other | NA months |
Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status
Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5), CCDC6, NCOA4). RET genotypes were determined by local testing &/or central analysis of circulating tumor deoxyribonucleic acid (ctDNA). DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR=disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to \<10 mm. PR=at least a 30% decrease in SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study. DOR was analyzed using the Kaplan-Meier (KM) method.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR \& sufficient evidence of a RET alteration. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants who had a response of CR/PR were analyzed in this outcome measure. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | KIF5B | 15.1 months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | NCOA4 | 12.9 months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | Other | 35.2 months |
| Phase 1: All Participants QD | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | CCDC6 | 46.7 months |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | CCDC6 | 29.6 months |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | KIF5B | 21.5 months |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | CCDC6 | NA months |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | KIF5B | 9.2 months |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status | Other | 41.2 months |
Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status
Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., Kinesin family member 5B (KIF5B), coiled-coil domain containing 6 (CCDC6), nuclear receptor coactivator 4 (NCOA4)). RET genotypes were determined by local testing and/or central analysis of circulating tumor deoxyribonucleic acid (ctDNA). ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 68.0 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 63.7 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 46.2 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | NCOA4 | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 75.0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 82.4 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | Other | 63.6 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | KIF5B | 78.9 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status | CCDC6 | 84.2 percentage of participants |
Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in both MTC and differentiated TC (DTC). These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status | CCDC6 | 82.4 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status | NCOA4 | 100 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status | Other | 75.0 percentage of participants |
| Unknown | Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status | KIF5B | — percentage of participants |
Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status
Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Number analyzed is the number of participants with the specified mutation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 53.7 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 46.2 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 100 percentage of participants |
| Phase 1: All Participants QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | Other | 100 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | Other | 66.7 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | M918T | 74.4 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | V804X | 0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status | Cysteine Rich Domain | 88.0 percentage of participants |
Phase 1: Apparent Oral Clearance (CL/F)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 4.26 liters per hour (L/hr) | — |
| Phase 1: All Participants QD | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 14.0 liters per hour (L/hr) | — |
| Pralsetinib 400 mg QD | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 14.7 liters per hour (L/hr) | Geometric Coefficient of Variation 42.3 |
| Pralsetinib 400 mg QD | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 11.3 liters per hour (L/hr) | Geometric Coefficient of Variation 51.2 |
| Pralsetinib BID Dosing Schedule | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 20.6 liters per hour (L/hr) | Geometric Coefficient of Variation 48.1 |
| Pralsetinib BID Dosing Schedule | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 12.0 liters per hour (L/hr) | Geometric Coefficient of Variation 38.9 |
| Pralsetinib All Doses | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 27.3 liters per hour (L/hr) | Geometric Coefficient of Variation 60.3 |
| Pralsetinib All Doses | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 31.4 liters per hour (L/hr) | Geometric Coefficient of Variation 97.8 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 23.3 liters per hour (L/hr) | Geometric Coefficient of Variation 40.2 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 13.2 liters per hour (L/hr) | Geometric Coefficient of Variation 33 |
| RET-fusion Positive TC | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 15.2 liters per hour (L/hr) | Geometric Coefficient of Variation 88.1 |
| RET-fusion Positive TC | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 11.1 liters per hour (L/hr) | Geometric Coefficient of Variation 72.2 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 1 | 11.6 liters per hour (L/hr) | Geometric Coefficient of Variation 81.3 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Apparent Oral Clearance (CL/F) | Cycle 1 Day 15 | 8.57 liters per hour (L/hr) | — |
Phase 1: Apparent Volume of Distribution (Vz/F)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 96.1 liters | — |
| Phase 1: All Participants QD | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 355 liters | — |
| Pralsetinib 400 mg QD | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 230 liters | Geometric Coefficient of Variation 37.1 |
| Pralsetinib 400 mg QD | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 171 liters | Geometric Coefficient of Variation 176 |
| Pralsetinib BID Dosing Schedule | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 458 liters | Geometric Coefficient of Variation 125 |
| Pralsetinib BID Dosing Schedule | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 232 liters | Geometric Coefficient of Variation 43.7 |
| Pralsetinib All Doses | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 499 liters | Geometric Coefficient of Variation 50.8 |
| Pralsetinib All Doses | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 622 liters | Geometric Coefficient of Variation 67.3 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 543 liters | Geometric Coefficient of Variation 82.6 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 367 liters | Geometric Coefficient of Variation 86.6 |
| RET-fusion Positive TC | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 430 liters | Geometric Coefficient of Variation 62.6 |
| RET-fusion Positive TC | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 418 liters | Geometric Coefficient of Variation 19.9 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 350 liters | Geometric Coefficient of Variation 115 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 15 | 181 liters | — |
Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: 24 hours postdose on Day 1 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 4450 hours*nanograms/milliliter (hours*ng/ml) | — |
| Pralsetinib 400 mg QD | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 3620 hours*nanograms/milliliter (hours*ng/ml) | Geometric Coefficient of Variation 50.8 |
| Pralsetinib BID Dosing Schedule | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 3010 hours*nanograms/milliliter (hours*ng/ml) | Geometric Coefficient of Variation 84.8 |
| Pralsetinib All Doses | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 5260 hours*nanograms/milliliter (hours*ng/ml) | Geometric Coefficient of Variation 46.2 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 8470 hours*nanograms/milliliter (hours*ng/ml) | Geometric Coefficient of Variation 54.5 |
| RET-fusion Positive TC | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 14700 hours*nanograms/milliliter (hours*ng/ml) | Geometric Coefficient of Variation 60.3 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) | 27700 hours*nanograms/milliliter (hours*ng/ml) | Geometric Coefficient of Variation 94.1 |
Phase 1: Maximum Plasma Concentration (Cmax)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: Pharmacokinetic (PK)-evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 346 nanograms per milliliters (ng/mL) | — |
| Phase 1: All Participants QD | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 130 nanograms per milliliters (ng/mL) | — |
| Pralsetinib 400 mg QD | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 335 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 52.8 |
| Pralsetinib 400 mg QD | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 420 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 56.9 |
| Pralsetinib BID Dosing Schedule | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 198 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 99.8 |
| Pralsetinib BID Dosing Schedule | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 586 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 47.8 |
| Pralsetinib All Doses | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 459 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 52.3 |
| Pralsetinib All Doses | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 525 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 72.5 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 688 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 53.3 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 1390 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 35.3 |
| RET-fusion Positive TC | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 1930 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 66.7 |
| RET-fusion Positive TC | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 1210 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 85.3 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 4330 nanograms per milliliters (ng/mL) | — |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 1820 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 63.8 |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 569 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 42 |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 1080 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 43.8 |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1 | 715 nanograms per milliliters (ng/mL) | Geometric Coefficient of Variation 64.1 |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Maximum Plasma Concentration (Cmax) | Cycle 1 Day 15 | 1780 nanograms per milliliters (ng/mL) | — |
Phase 1: ORR
ORR was defined as the percentage of participants with a confirmed CR or PR for at least two assessments with at least 28 days apart and no PD in between. Per RECIST v1.1, CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), was presented.
Time frame: Up to approximately 28 months
Population: Efficacy population included all participants who have been exposed to at least one dose of the study drug on or prior to 11 July 2019.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 1: ORR | 0 percentage of participants |
| Pralsetinib 400 mg QD | Phase 1: ORR | 50.0 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 1: ORR | 40.0 percentage of participants |
| Pralsetinib All Doses | Phase 1: ORR | 38.5 percentage of participants |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: ORR | 45.5 percentage of participants |
| RET-fusion Positive TC | Phase 1: ORR | 41.7 percentage of participants |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: ORR | 25.0 percentage of participants |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: ORR | 80.0 percentage of participants |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: ORR | 75.0 percentage of participants |
Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6)
The dose dependent change in a mitogen-activated protein kinases (MAPK) pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker DUSP6 levels was explored.
Time frame: Baseline, Week 4
Population: Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | 0 percent change | Standard Deviation 0 |
| Pralsetinib 400 mg QD | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | 54.26 percent change | Standard Deviation 88.318 |
| Pralsetinib BID Dosing Schedule | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | 0 percent change | Standard Deviation 0 |
| Pralsetinib All Doses | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | -20.27 percent change | Standard Deviation 42.971 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | -74.87 percent change | Standard Deviation 15.707 |
| RET-fusion Positive TC | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | -13.32 percent change | Standard Deviation 82.394 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | 0 percent change | Standard Deviation 0 |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | -81.57 percent change | Standard Deviation 3.057 |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) | -61.96 percent change | Standard Deviation 39.141 |
Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4)
The dose dependent change in a MAPK pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker SPRY4 levels was explored.
Time frame: Baseline, Week 4
Population: Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | 0 percent change | Standard Deviation 0 |
| Pralsetinib 400 mg QD | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | 210.16 percent change | Standard Deviation 309.468 |
| Pralsetinib BID Dosing Schedule | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | 0 percent change | Standard Deviation 0 |
| Pralsetinib All Doses | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | -34.98 percent change | Standard Deviation 29.569 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | -69.00 percent change | Standard Deviation 28.731 |
| RET-fusion Positive TC | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | -3.26 percent change | Standard Deviation 99.349 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | 0 percent change | Standard Deviation 0 |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | -75.65 percent change | Standard Deviation 10.944 |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) | 124.93 percent change | Standard Deviation 311.21 |
Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 110 ng/mL | — |
| Phase 1: All Participants QD | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 55.9 ng/mL | — |
| Pralsetinib 400 mg QD | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 69.2 ng/mL | Geometric Coefficient of Variation 81 |
| Pralsetinib 400 mg QD | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 94.2 ng/mL | Geometric Coefficient of Variation 123 |
| Pralsetinib BID Dosing Schedule | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 175 ng/mL | Geometric Coefficient of Variation 31.3 |
| Pralsetinib BID Dosing Schedule | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 65.8 ng/mL | Geometric Coefficient of Variation 59.6 |
| Pralsetinib All Doses | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 104 ng/mL | Geometric Coefficient of Variation 76.6 |
| Pralsetinib All Doses | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 137 ng/mL | Geometric Coefficient of Variation 132 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 221 ng/mL | Geometric Coefficient of Variation 64.2 |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 713 ng/mL | Geometric Coefficient of Variation 42.2 |
| RET-fusion Positive TC | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 376 ng/mL | Geometric Coefficient of Variation 74.1 |
| RET-fusion Positive TC | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 977 ng/mL | Geometric Coefficient of Variation 107 |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 15 | 1950 ng/mL | — |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) | Cycle 1 Day 1 | 715 ng/mL | Geometric Coefficient of Variation 75.9 |
Phase 1: Terminal Elimination Half-Life (t½)
The maximum values for t1/2 slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 16.3 hours |
| Phase 1: All Participants QD | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 17.6 hours |
| Pralsetinib 400 mg QD | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 9.87 hours |
| Pralsetinib 400 mg QD | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 8.10 hours |
| Pralsetinib BID Dosing Schedule | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 13.4 hours |
| Pralsetinib BID Dosing Schedule | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 14.3 hours |
| Pralsetinib All Doses | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 13.2 hours |
| Pralsetinib All Doses | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 12.6 hours |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 12.2 hours |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 20.4 hours |
| RET-fusion Positive TC | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 16.5 hours |
| RET-fusion Positive TC | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 20.9 hours |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 15 | 13.0 hours |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 19.7 hours |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Terminal Elimination Half-Life (t½) | Cycle 1 Day 1 | 10.7 hours |
Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast)
The maximum values for Tlast slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 24.0 hours |
| Phase 1: All Participants QD | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 23.8 hours |
| Pralsetinib 400 mg QD | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 24.0 hours |
| Pralsetinib 400 mg QD | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 24.1 hours |
| Pralsetinib BID Dosing Schedule | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 24.0 hours |
| Pralsetinib BID Dosing Schedule | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 24.3 hours |
| Pralsetinib All Doses | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 24.0 hours |
| Pralsetinib All Doses | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 24.0 hours |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 23.8 hours |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 24.0 hours |
| RET-fusion Positive TC | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 24.0 hours |
| RET-fusion Positive TC | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 23.8 hours |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 24.1 hours |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 23.9 hours |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 12.5 hours |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 12.2 hours |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 1 | 12.3 hours |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) | Cycle 1 Day 15 | 12.5 hours |
Phase 1: Time to Maximum Plasma Concentration (Tmax)
Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 3.04 hour |
| Phase 1: All Participants QD | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 1.87 hour |
| Pralsetinib 400 mg QD | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.04 hour |
| Pralsetinib 400 mg QD | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 2.00 hour |
| Pralsetinib BID Dosing Schedule | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.03 hour |
| Pralsetinib BID Dosing Schedule | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 3.97 hour |
| Pralsetinib All Doses | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.07 hour |
| Pralsetinib All Doses | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 2.97 hour |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.02 hour |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 2.23 hour |
| RET-fusion Positive TC | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 3.03 hour |
| RET-fusion Positive TC | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 3.00 hour |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 6.00 hour |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.00 hour |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 12.5 hour |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 2.00 hour |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 12.0 hour |
| RET-mutation Positive Tumors Other Than MTC | Phase 1: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 4.03 hour |
Phase 2: AUC0-24
Time frame: 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: AUC0-24 | Cycle 1 Day 1 | 20400 hours*ng/mL | Geometric Coefficient of Variation 64.2 |
| Phase 1: All Participants QD | Phase 2: AUC0-24 | Cycle 1 Day 15 | 40100 hours*ng/mL | Geometric Coefficient of Variation 59.5 |
| Pralsetinib 400 mg QD | Phase 2: AUC0-24 | Cycle 1 Day 15 | 33900 hours*ng/mL | Geometric Coefficient of Variation 27.4 |
| Pralsetinib 400 mg QD | Phase 2: AUC0-24 | Cycle 1 Day 1 | 17400 hours*ng/mL | Geometric Coefficient of Variation 152 |
| Pralsetinib BID Dosing Schedule | Phase 2: AUC0-24 | Cycle 1 Day 1 | 103000 hours*ng/mL | — |
| Pralsetinib BID Dosing Schedule | Phase 2: AUC0-24 | Cycle 1 Day 15 | 91100 hours*ng/mL | Geometric Coefficient of Variation 46.8 |
| Pralsetinib All Doses | Phase 2: AUC0-24 | Cycle 1 Day 1 | 18400 hours*ng/mL | Geometric Coefficient of Variation 69.8 |
| Pralsetinib All Doses | Phase 2: AUC0-24 | Cycle 1 Day 15 | 32000 hours*ng/mL | Geometric Coefficient of Variation 90.8 |
Phase 2: C24hr
Time frame: 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: C24hr | Cycle 1 Day 1 | 540 ng/mL | Geometric Coefficient of Variation 75.4 |
| Phase 1: All Participants QD | Phase 2: C24hr | Cycle 1 Day 15 | 1150 ng/mL | Geometric Coefficient of Variation 69 |
| Pralsetinib 400 mg QD | Phase 2: C24hr | Cycle 1 Day 15 | 797 ng/mL | Geometric Coefficient of Variation 42.8 |
| Pralsetinib 400 mg QD | Phase 2: C24hr | Cycle 1 Day 1 | 519 ng/mL | Geometric Coefficient of Variation 197 |
| Pralsetinib BID Dosing Schedule | Phase 2: C24hr | Cycle 1 Day 1 | 1020 ng/mL | Geometric Coefficient of Variation 225 |
| Pralsetinib BID Dosing Schedule | Phase 2: C24hr | Cycle 1 Day 15 | 1400 ng/mL | Geometric Coefficient of Variation 207 |
| Pralsetinib All Doses | Phase 2: C24hr | Cycle 1 Day 1 | 415 ng/mL | Geometric Coefficient of Variation 140 |
| Pralsetinib All Doses | Phase 2: C24hr | Cycle 1 Day 15 | 1050 ng/mL | Geometric Coefficient of Variation 94 |
Phase 2: CBR
CBR was defined as the percentage of participants with CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). CBR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: CBR | 74.6 percentage of participants |
| Pralsetinib 400 mg QD | Phase 2: CBR | 78.3 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 2: CBR | 80.2 percentage of participants |
| Pralsetinib All Doses | Phase 2: CBR | 80.0 percentage of participants |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 2: CBR | 90.3 percentage of participants |
| RET-fusion Positive TC | Phase 2: CBR | 85.2 percentage of participants |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 2: CBR | 60.7 percentage of participants |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 2: CBR | 28.6 percentage of participants |
| RET-mutation Positive Tumors Other Than MTC | Phase 2: CBR | 23.1 percentage of participants |
Phase 2: CL/F
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: CL/F | Cycle 1 Day 1 | 13.4 liters per hour (L/hour) | Geometric Coefficient of Variation 56.8 |
| Phase 1: All Participants QD | Phase 2: CL/F | Cycle 1 Day 15 | 9.91 liters per hour (L/hour) | Geometric Coefficient of Variation 58.9 |
| Pralsetinib 400 mg QD | Phase 2: CL/F | Cycle 1 Day 15 | 7.49 liters per hour (L/hour) | Geometric Coefficient of Variation 64.4 |
| Pralsetinib 400 mg QD | Phase 2: CL/F | Cycle 1 Day 1 | 12.7 liters per hour (L/hour) | Geometric Coefficient of Variation 347 |
| Pralsetinib BID Dosing Schedule | Phase 2: CL/F | Cycle 1 Day 1 | 2.00 liters per hour (L/hour) | — |
| Pralsetinib BID Dosing Schedule | Phase 2: CL/F | Cycle 1 Day 15 | 2.92 liters per hour (L/hour) | — |
| Pralsetinib All Doses | Phase 2: CL/F | Cycle 1 Day 1 | 16.1 liters per hour (L/hour) | Geometric Coefficient of Variation 43.3 |
| Pralsetinib All Doses | Phase 2: CL/F | Cycle 1 Day 15 | 1.39 liters per hour (L/hour) | Geometric Coefficient of Variation 1220 |
Phase 2: Cmax
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: Cmax | Cycle 1 Day 1 | 1680 ng/mL | Geometric Coefficient of Variation 69.4 |
| Phase 1: All Participants QD | Phase 2: Cmax | Cycle 1 Day 15 | 2840 ng/mL | Geometric Coefficient of Variation 50.7 |
| Pralsetinib 400 mg QD | Phase 2: Cmax | Cycle 1 Day 15 | 2200 ng/mL | Geometric Coefficient of Variation 36.7 |
| Pralsetinib 400 mg QD | Phase 2: Cmax | Cycle 1 Day 1 | 1380 ng/mL | Geometric Coefficient of Variation 65.4 |
| Pralsetinib BID Dosing Schedule | Phase 2: Cmax | Cycle 1 Day 1 | 2450 ng/mL | Geometric Coefficient of Variation 164 |
| Pralsetinib BID Dosing Schedule | Phase 2: Cmax | Cycle 1 Day 15 | 3440 ng/mL | Geometric Coefficient of Variation 93.9 |
| Pralsetinib All Doses | Phase 2: Cmax | Cycle 1 Day 1 | 1770 ng/mL | Geometric Coefficient of Variation 87.2 |
| Pralsetinib All Doses | Phase 2: Cmax | Cycle 1 Day 15 | 2430 ng/mL | Geometric Coefficient of Variation 55.3 |
Phase 2: DCR
DCR was defined as the percentage of participants with a confirmed CR/PR, or SD, per RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DCR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: DCR | 91.5 percentage of participants |
| Pralsetinib 400 mg QD | Phase 2: DCR | 91.3 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 2: DCR | 89.6 percentage of participants |
| Pralsetinib All Doses | Phase 2: DCR | 95.0 percentage of participants |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 2: DCR | 93.1 percentage of participants |
| RET-fusion Positive TC | Phase 2: DCR | 96.3 percentage of participants |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 2: DCR | 75.0 percentage of participants |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 2: DCR | 42.9 percentage of participants |
| RET-mutation Positive Tumors Other Than MTC | Phase 2: DCR | 69.2 percentage of participants |
Phase 2: DOR
DOR was defined as the time from first documented response (CR/PR) to the date of first documented PD or death due to any cause, whichever occurs first. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DOR was analyzed using the KM methods.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR \& sufficient evidence of a RET alteration. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants who had a response of CR/PR were analyzed in this OM.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: DOR | 31.8 months |
| Pralsetinib 400 mg QD | Phase 2: DOR | 22.6 months |
| Pralsetinib BID Dosing Schedule | Phase 2: DOR | 13.4 months |
| Pralsetinib All Doses | Phase 2: DOR | 21.7 months |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 2: DOR | 51.8 months |
| RET-fusion Positive TC | Phase 2: DOR | NA months |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 2: DOR | 11.1 months |
| RET-altered Solid Tumors Previously Treated With RET Inhibitor | Phase 2: DOR | NA months |
| RET-mutation Positive Tumors Other Than MTC | Phase 2: DOR | 5.5 months |
Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants
CBR=percentage of participants with CR/PR/SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in 1 cycle) from first dose date. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/ cerebellum identified at baseline&disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR=at least a 30% decrease in SOD of any CNS/brain lesion, identified as target lesions at baseline & if in absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or identification of new CNS/brain lesion. SD=neither sufficient shrinkage for PR nor sufficient increase for PD for target/non-target CNS/brain lesion, taking as reference smallest SOD while on study. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As specified in the SAP, CBR was to be assessed in RET-fusion CNS metastases sub-population (participants with CNS metastases) only. Hence only NSCLC arms are presented here. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants | 61.5 percentage of participants |
| Pralsetinib 400 mg QD | Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants | 100 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants | 0 percentage of participants |
Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants
DCR=percentage of participants with a confirmed CR/PR, or SD. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/or cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR =at least a 30% decrease in the SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in the absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or the identification of new CNS/brain lesion. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target/non-target CNS/brain lesion, taking as reference the smallest SOD while on study. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As specified in the SAP, DCR was to be assessed in RET-fusion CNS metastases sub-population (participants with CNS metastases) only. Hence only NSCLC arms are presented here. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants | 76.9 percentage of participants |
| Pralsetinib 400 mg QD | Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants | 100 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants | 0 percentage of participants |
Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants
DOR=time from first documented CR/PR to the date of first documented PD/death due to any cause, whichever occurs first. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/ cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR=at least a 30% decrease in SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or identification of new CNS/brain lesion. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion. DOR was analyzed using the KM methods.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population=participants in efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR\&sufficient evidence of a RET alteration. As specified in SAP, DOR was to be assessed in RET-fusion CNS metastases sub-population only. Hence only NSCLC arms are presented here. Participants with a CR/PR were assessed for this OM. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants | 28.3 months |
| Pralsetinib 400 mg QD | Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants | 11.3 months |
Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants
ORR=percentage of participants with CR or PR for at least 2 assessments with at least 28 days apart & no PD in between. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/or cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR =at least a 30% decrease in the SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in the absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or the identification of new CNS/brain lesion. PD=either at least 20% increase in the SOD of target CNS/brain lesion, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of any CNS/brain lesion identified as RECIST 1.1 nontarget lesions at baseline, or the identification of new CNS/brain lesion.
Time frame: Up to approximately 79.8 months
Population: RET-altered measurable disease population included participants in the efficacy population who have measurable (target) disease per RECIST v1.1, at baseline according to BICR and sufficient evidence of a RET alteration. As specified in the SAP, ORR was to be assessed in RET-fusion CNS metastases sub-population (participants with CNS metastases) only. Hence only NSCLC arms are presented here. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants | 53.8 percentage of participants |
| Pralsetinib 400 mg QD | Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants | 100 percentage of participants |
| Pralsetinib BID Dosing Schedule | Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants | 0 percentage of participants |
Phase 2: Overall Survival (OS)
OS was defined as the time from the first dose of pralsetinib to the date of death due to any causes.
Time frame: Up to approximately 7 years
Population: Efficacy population included all participants who have been exposed to at least one dose of the study drug at the RP2D. As pre-specified in the SAP, OS was to be assessed in participants with RET-fusion positive NSCLC, RET-mutation MTC, RET-fusion TC, and RET-fusion solid tumors other than NSCLC and TC. Hence, only the data for these arms is presented here.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Overall Survival (OS) | 39.7 months |
| Pralsetinib 400 mg QD | Phase 2: Overall Survival (OS) | 46.0 months |
| Pralsetinib BID Dosing Schedule | Phase 2: Overall Survival (OS) | 50.1 months |
| Pralsetinib All Doses | Phase 2: Overall Survival (OS) | 42.2 months |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 2: Overall Survival (OS) | NA months |
| RET-fusion Positive TC | Phase 2: Overall Survival (OS) | NA months |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 2: Overall Survival (OS) | 10.3 months |
Phase 2: Progression-free Survival (PFS)
PFS was defined as the time from the first dose of pralsetinib to the date of first documented PD or death due to any cause, whichever occurred first. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). PFS was analyzed using KM methods.
Time frame: Up to approximately 7 years
Population: Efficacy population included all participants who have been exposed to at least one dose of the study drug at the RP2D. As pre-specified in the SAP, PFS was to be assessed in participants with RET-fusion positive NSCLC, RET-mutation MTC, RET-fusion TC, and RET-fusion solid tumors other than NSCLC and TC. Hence, only the data for these arms is presented here. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: All Participants QD | Phase 2: Progression-free Survival (PFS) | 16.4 months |
| Pralsetinib 400 mg QD | Phase 2: Progression-free Survival (PFS) | 13.0 months |
| Pralsetinib BID Dosing Schedule | Phase 2: Progression-free Survival (PFS) | 12.1 months |
| Pralsetinib All Doses | Phase 2: Progression-free Survival (PFS) | 24.9 months |
| RET-mutation MTC With No Prior Cabozantinib or Vandetanib Treatment | Phase 2: Progression-free Survival (PFS) | 55.3 months |
| RET-fusion Positive TC | Phase 2: Progression-free Survival (PFS) | NA months |
| RET-fusion Positive Solid Tumors Other Than NSCLC and TC | Phase 2: Progression-free Survival (PFS) | 7.0 months |
Phase 2: t½
The maximum values for t1/2 slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: t½ | Cycle 1 Day 1 | 13.4 hours | Geometric Coefficient of Variation 44.1 |
| Phase 1: All Participants QD | Phase 2: t½ | Cycle 1 Day 15 | 17.9 hours | Geometric Coefficient of Variation 58.8 |
| Pralsetinib 400 mg QD | Phase 2: t½ | Cycle 1 Day 15 | 16.5 hours | Geometric Coefficient of Variation 44.6 |
| Pralsetinib 400 mg QD | Phase 2: t½ | Cycle 1 Day 1 | 18.4 hours | Geometric Coefficient of Variation 98.8 |
| Pralsetinib BID Dosing Schedule | Phase 2: t½ | Cycle 1 Day 1 | 20.8 hours | — |
| Pralsetinib BID Dosing Schedule | Phase 2: t½ | Cycle 1 Day 15 | 25.8 hours | — |
| Pralsetinib All Doses | Phase 2: t½ | Cycle 1 Day 1 | 11.0 hours | Geometric Coefficient of Variation 55.8 |
| Pralsetinib All Doses | Phase 2: t½ | Cycle 1 Day 15 | 63.0 hours | Geometric Coefficient of Variation 882 |
Phase 2: Tlast
The maximum values for Tlast slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol.
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: Tlast | Cycle 1 Day 1 | 23.9 hours |
| Phase 1: All Participants QD | Phase 2: Tlast | Cycle 1 Day 15 | 23.8 hours |
| Pralsetinib 400 mg QD | Phase 2: Tlast | Cycle 1 Day 15 | 23.70 hours |
| Pralsetinib 400 mg QD | Phase 2: Tlast | Cycle 1 Day 1 | 8.00 hours |
| Pralsetinib BID Dosing Schedule | Phase 2: Tlast | Cycle 1 Day 1 | 23.10 hours |
| Pralsetinib BID Dosing Schedule | Phase 2: Tlast | Cycle 1 Day 15 | 24.00 hours |
| Pralsetinib All Doses | Phase 2: Tlast | Cycle 1 Day 1 | 8.05 hours |
| Pralsetinib All Doses | Phase 2: Tlast | Cycle 1 Day 15 | 24.00 hours |
Phase 2: Tmax
Time frame: Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Population: PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants QD | Phase 2: Tmax | Cycle 1 Day 1 | 4.00 hours |
| Phase 1: All Participants QD | Phase 2: Tmax | Cycle 1 Day 15 | 4.00 hours |
| Pralsetinib 400 mg QD | Phase 2: Tmax | Cycle 1 Day 15 | 5.00 hours |
| Pralsetinib 400 mg QD | Phase 2: Tmax | Cycle 1 Day 1 | 3.90 hours |
| Pralsetinib BID Dosing Schedule | Phase 2: Tmax | Cycle 1 Day 1 | 4.0 hours |
| Pralsetinib BID Dosing Schedule | Phase 2: Tmax | Cycle 1 Day 15 | 4.00 hours |
| Pralsetinib All Doses | Phase 2: Tmax | Cycle 1 Day 1 | 2.05 hours |
| Pralsetinib All Doses | Phase 2: Tmax | Cycle 1 Day 15 | 3.05 hours |