Nonsquamous Non-small Cell Lung Cancer, EGFR L858R, EGFR Exon 19 Deletion
Conditions
Keywords
Nonsquamous Non-small Cell Lung Cancer, EGFR L858R, EGFR exon 19 deletion, Patritumab deruxtecan, HER3-DXd, U3-1402
Brief summary
Disease progression is typical for patients with epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). Standard platinum-based chemotherapy offers limited efficacy and an unfavorable safety profile.There is an urgent need for more effective and tolerable therapies for patients with EGFRm NSCLC who have exhausted available targeted therapies. Clinical evidence suggest that patritumab deruxtecan constitutes a promising investigational therapy for patients with EGFRm NSCLC.
Detailed description
Patritumab deruxtecan (HER3-DXd, U3-1402) is an antibody-drug conjugate (ADC) comprising an anti-HER3 mAb linked to a topoisomerase I inhibitor that is in clinical development for patients with NSCLC, metastatic breast cancer, and colorectal cancer. The primary objective of the current study is to compare the efficacy of patritumab deruxtecan versus platinum-based chemotherapy, as measured by progression-free survival (PFS) and the key secondary endpoint of overall survival (OS), in participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) after failure of third-generation (eg, osimertinib, lazertinib, aumolertinib, alflutinib) EGFR TKI therapy.
Interventions
Intravenous administration, 5.6 mg/kg every 3 weeks (q3W)
Intravenous, pemetrexed 500 mg/m\^2 plus either cisplatin (75 mg/m\^2) or carboplatin (target area under the plasma concentration time curve of 5 \[AUC5\] by using the Calvert formula) q3W
Sponsors
Merck Sharp & Dohme LLC
Daiichi Sankyo
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
1. Is a male or female subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old). 2. Has histologically or cytologically documented metastatic or locally advanced non-squamous NSCLC not amenable to curative surgery or radiation. 3. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R at diagnosis or thereafter. 4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third -generation EGFR TKI 5. May have received either neoadjuvant and/or adjuvant treatment if progression to metastatic or locally advanced disease occurred at least 12 months after the last dose of such therapy and subsequently experienced disease progression on or after third-generation EGFR TKI treatment administered in the metastatic or locally advanced setting. 6. Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI). 7. Has documentation of radiographic disease progression while receiving or after receiving a third generation EGFR TKI for metastatic or locally advanced disease. 8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment. 9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue. 10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening. 11. Has adequate bone marrow reserve and organ function based on local laboratory evaluation within 14 days prior to randomization: * Platelet count: ≥100,000/mm\^3 or ≥100 × 10\^9/L within 14 days prior to the assessment of platelet count during the Screening Period * Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L within 14 days prior to the assessment of absolute neutrophil count during the Screening Period * Hemoglobin (Hgb): ≥9.0 g/dL within 14 days prior to the assessment of hemoglobin during the Screening Period * Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using the Cockcroft-Gault equation or measured CrCl * Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): AST/ALT ≤3× Upper limit of normal (ULN) * Total bilirubin (TBL): TBL ≤1.5 × ULN * Serum albumin: ≥2.5 g/dL * Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT): ≤1.5 × ULN, except for participants receiving coumarin-derivative anticoagulants or other similar anticoagulant therapy who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
Exclusion criteria
1. Has any previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy, or squamous NSCLC histology 2. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during Screening 3. Has clinically severe respiratory compromise (based on the Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to the following: * Any underlying pulmonary disorder, restrictive lung disease, or pleural effusion * Any autoimmune, connective tissue, or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of Screening * OR prior complete pneumonectomy 4. Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to randomization 5. Has any history of or evidence of current leptomeningeal disease 6. Has evidence of clinically active spinal cord compression or brain metastases, defined as being symptomatic and untreated, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms 7. Any prior treatment with any agent including an antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I, human epidermal growth factor receptor 3 (HER3) antibody, and any systemic therapies (other than EGFR TKIs) in the metastatic/locally advanced setting, including chemotherapy or any other systemic therapy in combination with an EGFR TKI 8. Has history of other active malignancy within 3 years prior to randomization, except for adequately resected nonmelanoma skin cancer, adequately treated intraepithelial carcinoma of the cervix, and any other curatively treated in situ disease 9. Has uncontrolled or significant cardiovascular disease prior to randomization 10. Has active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of active viral infection within 28 days of randomization 11. Has a known human immunodeficiency virus (HIV) infection that is not well controlled 12. Has clinically significant corneal disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) Based on RECIST v1.1 | Baseline up to approximately 49 months | Progression-free survival (PFS) is defined as the time from the date of randomization to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by Investigator Review Based on RECIST v1.1 | Baseline up to approximately 49 months | Progression-free survival (PFS) is defined as the time from the date of randomization to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause. |
| Progression-free Survival (PFS) as Assessed by Local Standard Clinical Practice | Baseline up to approximately 49 months | Progression-free survival (PFS) by local standard clinical practice is defined as the time from date of randomization to the documented progression on the first new anticancer therapy (if administered) or death due to any cause, whichever occurred first. |
| Objective Response Rate (ORR) as Assessed by BICR and Investigator Review Based on RECIST v1.1 | Baseline up to approximately 49 months | Objective response rate (ORR) is defined as the proportion of participants who have a confirmed best overall response (BOR) of complete response (CR) or partial response (PR). |
| Duration of Response (DoR) as Assessed by BICR and Investigator Review Based on RECIST v1.1 | Baseline up to approximately 49 months | Duration of response (DoR) is defined as the time from the first documentation of objective response (CR or PR) to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause. |
| Clinical Benefit Rate (CBR) as Assessed by BICR and Investigator Review Based on RECIST v1.1 | Baseline up to approximately 49 months | Clinical benefit rate (CBR) will be assessed by BICR and Investigator based on RECIST v1.1. CBR is defined as the proportion of participants who have a confirmed BOR of CR, PR, or stable disease (SD) that lasts for at least 180 days. |
| Disease Control Rate (DCR) as Assessed by BICR and Investigator Review Based on RECIST v1.1 | Baseline up to approximately 49 months | Disease control rate (DCR) is defined as the proportion of participants who have a confirmed BOR of CR, PR, or SD. |
| Time to Response (TTR) as Assessed by BICR and Investigator Review Based on RECIST v1.1 | Baseline up to approximately 49 months | Time to response (TTR) is defined as the time from the date of randomization to the date of the first documentation of response (CR or PR) that is subsequently confirmed. |
| Intracranial PFS as Assessed by BICR | Baseline up to approximately 49 months | Intracranial PFS is defined as the time from the date of randomization to the earlier of the dates of the first documented radiographic intracranial disease progression or death, whichever comes first, as assessed by BICR per CNS-RECIST, in participants with CNS lesion(s) at baseline by BICR per CNS-RECIST. |
| Overall Survival (OS) | Baseline up to approximately 49 months | Overall survival (OS) is defined as the time from the date of randomization to the date of death due to any cause. |
| Mean Change from Baseline in Patient's Global Impression of Change | Baseline up to approximately 49 months | The PGI-C is a 7-point scale depicting a participant's rating of overall improvement. |
| Mean Change from Baseline in Patient's Global Impression of Severity | Baseline up to approximately 49 months | The PGI-S is a one-item questionnaire that contains six response options. |
| Mean Change from Baseline in Patient's Global Impression of Treatment Tolerability | Baseline up to approximately 49 months | The PGI-TT will capture the patient's overall impression of treatment tolerability. |
| Mean Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) | Baseline up to approximately 49 months | The EORTC-QLQ-C30 will assess the patient's overall quality of life (QoL). |
| Mean Change from Baseline in EuroQol Questionnaire-5 dimensions-5 levels (EQ-5D-5L) | Baseline up to approximately 49 months | The EQ-5D-5L is a standardized instrument that will be used for measuring generic health status required for health technology assessments. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline up to approximately 49 months | TEAEs will be graded by using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. |
| Percentage of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) | Baseline up to approximately 49 months | The immunogenicity of patritumab deruxtecan will be confirmed by assessing the anti-drug antibodies. |
| Percentage of Participants Who Have Treatment-emergent ADA | Baseline up to approximately 49 months | The immunogenicity of patritumab deruxtecan will be confirmed by assessing the anti-drug antibodies. |
| Mean Change from Baseline in Non-small Cell Lung Cancer - Symptom Assessment Questionnaire | Baseline up to approximately 49 months | The NSCLC-SAQ will assess disease-related symptom change in patients with NSCLC. |
Countries
Australia, Austria, Belgium, Canada, China, France, Germany, Hong Kong, Italy, Japan, Netherlands, Norway, Poland, Portugal, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Outcome results
None listed