This is a multi-center, open-label, randomized, Phase 1b/2 trial to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in subjects with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. This study has 2:1 randomization (Tepotinib/Gefitinib arm versus Chemotherapy arm).
Name: Tepotinib
Name: Gefitinib
Name: Pemetrexed
Name: Cisplatin
Name: Carboplatin
Description: PFS (assessed by investigator/site radiologist) time is defined as the time (in months) from randomization to either the first disease progression (PD) per RECIST Version 1.1 or death in T790M negative, MET+ subjects due to any cause within 84 days of either randomization or last tumor assessment. If no progression or death is observed, or if death without previously documented PD is observed after more than 84 days of last tumor assessment without progression, the PFS time will be censored on the date of last tumor assessment/date of randomization, whatever occurs later.
Measure: Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment Time: Up to 8 monthsDescription: PFS time is defined as the time (in months) from randomization either the first observation of PD (as assessed by the independent review committee) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment.
Measure: Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments Time: Time from randomization to the date of death or up to 8 months whichever occur firstDescription: PFS time is defined as the time (in months) from the first administration of the trial treatment to either the first observation of documented PD per RECIST Version 1.1 or occurrence of death due to any cause within 84 days of either the first administration of the trial treatment or the last tumor assessment.
Measure: Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment Time: Time from first administration of trial treatment to the date of death or up to 8 months whichever occur firstDescription: OS time is defined as the time (in months) from randomization/the first administration of the trial treatment to the date of death in the randomized part of Phase 2/the single-arm cohort of Phase 2
Measure: Overall Survival (OS) Time Time: Time from randomization to the date of death or up to 10 months whichever occur firstDescription: Objective response is defined as complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the trial treatment to the first observation of PD.
Measure: Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria Time: Every 6 weeks until Week 72 and every 12 weeks after Week 72 until radiologically documented progressive disease, death, end of trial, or starting a new treatment, whichever occurs first (assessed up to 3.5 years)Description: Disease control is defined as CR, PR, or stable disease (SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the trial treatment to the first observation of PD. In the case of SD, measurements must have met the SD criteria at least once after entry at a minimum interval of 42 days after randomization/the first administration of the trial treatment;
Measure: Percentage of subjects with disease control according to RECIST version 1.1 criteria Time: Time Frame: Every 6 weeks until Week 72 and every 12 weeks after Week 72 until radiologically documented progressive disease, death, end of trial, or starting a new treatment, whichever occurs first (assessed up to 3.5 years)Allocation: Randomized
Parallel Assignment
There is one SNP
Tepotinib With Gefitinib in Subjects With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) This is a multi-center, open-label, randomized, Phase 1b/2 trial to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in subjects with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. --- T790M ---
PFS (assessed by investigator/site radiologist) time is defined as the time (in months) from randomization to either the first disease progression (PD) per RECIST Version 1.1 or death in T790M negative, MET+ subjects due to any cause within 84 days of either randomization or last tumor assessment. --- T790M ---
Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M ---
Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M --- --- T790M ---
Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M --- --- T790M --- --- T790M ---