RET-fusion Non Small Cell Lung Cancer, Lung Neoplasm, Carcinoma, Non-Small-Cell Lung, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms by Site, Neoplasms, Lung Diseases, Respiratory Tract Disease, Carcinoma, Bronchogenic, Bronchial Diseases, Head and Neck Neoplasms, Adenocarcinoma, Carcinoma, Neoplasms by Histologic Type, Neoplasms, Germ Cell and Embryonal, Neoplasms, Nerve Tissue
Conditions
Keywords
Advanced Non-Small Cell Lung Cancer, RET Lung, RET Mutation, RET Alteration, RET Positive, RET Inhibitor, RET Altered, RET Rearrangement, RET NSCLC, RET-Rearranged NSCLC, RET Fusion, RET Fusion Lung Cancer, M918T, TRIM33-RET, Lung Cancer Mutation, BLU 667, Pralsetinib, RET Tyrosine Kinase, RET Gene Mutation, RET Kinase, Advanced Lung Cancer, Metastatic Lung Cancer, KIF5B-RET, CCDC6-RET
Brief summary
This is an international, randomized, open-label, Phase 3 study designed to evaluate whether the potent and selective RET inhibitor, pralsetinib, improves outcomes when compared to a platinum chemotherapy-based regimen chosen by the Investigator from a list of standard of care treatments, as measured primarily by progression free survival (PFS), for participants with RET fusion-positive metastatic NSCLC who have not previously received systemic anticancer therapy for metastatic disease.
Interventions
DRUGPralsetinib
Administered orally
DRUGCarboplatin
Administered IV
DRUGCisplatin
Administered IV
DRUGPemetrexed
Administered IV
DRUGPembrolizumab
Administered IV
DRUGGemcitabine
Administered IV
DRUGPaclitaxel
Administered IV
DRUGNab-Paclitaxel
Administered IV
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has pathologically confirmed, definitively diagnosed, locally advanced (not able to be treated with surgery or radiotherapy) or metastatic NSCLC and has not been treated with systemic anticancer therapy for metastatic disease. * Participant must have a documented RET-fusion * Participant has measurable disease based on RECIST 1.1 as determined by the local site Investigator/radiology assessment. * Participant has an ECOG Performance Status of 0 or 1. * Participant should not have received any prior anticancer therapy for metastatic disease. * Participants can have received previous anticancer therapy (except a selective RET inhibitor) in the neoadjuvant or adjuvant setting but must have experienced an interval of at least ≥ 6 months from completion of therapy to recurrence. * Participants that received previous immune checkpoint inhibitors in the adjuvant or consolidation following chemoradiation are not allowed to receive pembrolizumab if randomized in Arm B * Participant is an appropriate candidate for and agrees to receive 1 of the Investigator choice platinum-based chemotherapy regimens if randomized to Arm B. * For women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception. * For men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom and agree to refrain from donating sperm.
Exclusion criteria
* Participant's tumor has any additional known primary driver alterations other than RET, such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF. Investigators should discuss enrollment with Sponsor designee regarding co-mutations. * Participant previously received treatment with a selective RET inhibitor. * Participant received radiotherapy or radiosurgery to any site within 14 days before randomization or more than 30 Gy of radiotherapy to the lung in the 6 months before randomization. * Participant with a history of pneumonitis within the last 12 months. * Participant has CNS metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a participant requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks before Cycle 1 Day 1. * Participant has had a history of another primary malignancy that has been diagnosed or required therapy within the past 3 years prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arm A vs Arm B: Treatment Period: Progression-free Survival (PFS) | Up to approximately 50 months | PFS was defined as the time from randomization to the date of first documented PD as determined by the investigator with the use of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints, including baseline. In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of at least 5 millimeters (mm). Kaplan-Meier (K-M) method was used to estimate median PFS. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arm A vs Arm B: Objective Response Rate (ORR) | Up to approximately 50 months | ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator with the use of RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in 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. 95% CI for rates were constructed using the Clopper-Pearson method. Percentages have been rounded off. |
| Arm A vs Arm B: Overall Survival (OS) | From randomization to death (up to approximately 50 months) | OS was defined as the time from randomization to death from any cause. K-M method was used to estimate median OS. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to approximately 50 months | An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. 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/birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. |
| Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Baseline up to 50 months | ECOG is a 6-point scale (0-5) used to assess participants functional status, where, 0= Fully active, able to carry on all pre-disease performance without restriction; 1= restricted in physically strenuous activity but ambulatory \& able to carry out work of a light or sedentary nature, e.g., light housework, office work; 2= ambulatory \& capable of all self-care but unable to carry out any work activities. Up \& about more than 50% of waking hours; 3= capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5= dead. |
| Arm A vs Arm B: Duration of Response (DOR) | Up to approximately 50 months | DOR was defined as the time from the first occurrence of a documented objective response (OR) to PD or death from any cause, whichever occurred first, as determined by the investigator with the use of RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in 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 the SOD of target lesions, taking as reference the smallest SOD at prior timepoints, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. K-M method was used to estimate median DOR. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| Arm A vs Arm B: Clinical Benefit Rate (CBR) | Up to approximately 50 months | CBR was defined as the percentage of participants who experienced the best response of stable disease (SD) with a minimum duration of 6 months, a CR, or a PR, as assessed by investigator with use of RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as the disappearance of all target lesions or any pathological lymph nodes must have reduction in 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 the SOD of target lesions, taking as reference the smallest SOD at prior timepoints, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 95% CI for rates were constructed using the Clopper-Pearson method. Percentages are rounded off. |
| Arm A vs Arm B: Disease Control Rate (DCR) | Up to approximately 50 months | DCR was defined as the percentage of participants who experienced the best response of CR, or PR, or SD, as assessed by investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as the disappearance of all target lesions or any pathological lymph nodes must have reduction in 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 the SOD of target lesions, taking as reference the smallest SOD at prior timepoints, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 95% CI for rates were constructed using the Clopper-Pearson method. Percentages are rounded off. |
Countries
Argentina, Australia, Belgium, Brazil, Costa Rica, France, Germany, Ireland, Italy, Japan, Mexico, Netherlands, Norway, Panama, Poland, Portugal, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 223 participants with rearranged during transfection (RET) fusion-positive metastatic non-small cell lung cancer (NSCLC) took part in the study at 74 investigative sites across 22 countries from 24 July 2020 to 27 January 2025. The study consists of a treatment period and a crossover period.
Pre-assignment details
Participants in treatment period were randomized in 1:1 ratio to receive standard of care (SOC) platinum containing anticancer treatment regimens (Arm A) or pralsetinib (Arm B). Participants with disease progression (PD) in Arm A had the option to crossover & receive pralsetinib (Arm C), which was later discontinued as of Protocol Version 5. 11 randomized participants did not receive any study treatment and were excluded from safety analysis.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 16 Participants |
| Race/Ethnicity, Customized Asian | 21 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 5 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants |
| Race/Ethnicity, Customized White | 133 Participants |
| Sex: Female, Male Female | 117 Participants |
| Sex: Female, Male Male | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 27 / 113 | 33 / 110 | 8 / 38 |
| other Total, other adverse events | 103 / 104 | 106 / 108 | 38 / 38 |
| serious Total, serious adverse events | 38 / 104 | 67 / 108 | 22 / 38 |
Outcome results
None listed