A Study of Tepotinib Plus Osimertinib in Osimertinib Relapsed MET Amplified NSCLC (INSIGHT 2)

Study Overview
=================
Brief Summary
-----------------
This study will assess the antitumor activity, safety, tolerability, and pharmacokinetics (PK) of the Mesenchymal-epithelial Transition Factor (MET) inhibitor tepotinib combined with the 3rd generation EGFR inhibitor osimertinib in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Official Title
-----------------
A Phase II, Two-arm Study to Investigate Tepotinib Combined With Osimertinib in MET Amplified, Advanced or Metastatic NSCLC Harboring Activating EGFR Mutations and Having Acquired Resistance to Prior Osimertinib Therapy (INSIGHT 2)

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Tepotinib
* Drug: Osimertinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) histology (confirmed by either histology or cytology) with documented activating Epidermal Growth Factor Receptor (EGFR) mutation Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a minimum life expectancy of 12 weeks Acquired resistance on previous first-line osimertinib. Participants must meet both of the following 2 criteria: Radiological documentation of disease progression on first-line osimertinib Objective clinical benefit documented during previous osimertinib therapy, defined by either partial or complete radiological response, or durable stable disease (SD) (SD should last greater than (>) 6 months after initiation of osimertinib Have received only first-line osimertinib as a prior line of therapy in the non curative advanced or metastatic NSCLC setting MET amplification as determined by either FISH testing (central or local) on tumor tissue (TBx) or central blood-based next generation sequencing (LBx). Tumor and blood samples must be collected following progression on prior first-line osimertinib at Prescreening Submission of tumor tissue and blood sample obtained after progression on first-line osimertinib, is mandatory for all patients for MET amplification testing Submission of tumor tissue during Prescreening or Screening is mandatory for patients with tumor tissue tested by local FISH, to confirm MET amplification status. Central confirmation is not mandated prior to the start of study treatment Other protocol defined inclusion criteria could apply Exclusion Criteria: Spinal cord compression or brain metastasis unless asymptomatic, stable or not requiring steroids for at least 2 weeks prior to start of study intervention Any unresolved toxicity Grade 2 or more according to National cancer institute common terminology criteria for adverse events( NCI-CTCAE) version 5, from previous anticancer therapy with the exception of alopecia Inadequate hematological, liver and renal function Impaired cardiac function History of interstitial lung disease(ILD) or interstitial pneumonitis including radiation pneumonitis that required steroid treatment Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 millimeter of mercury (mmHg) Contraindication to the administration of osimertinib Other protocol defined exclusion criteria could apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tepotinib and Osimertinib<br>Participants will receive a combination of tepotinib and osimertinib. The combination will be applied in cycles of 21 days until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal. | Drug: Tepotinib<br>* Participants will be administered Tepotinib orally once daily at an initial dose of 500 milligram (mg). A safety monitoring committee (SMC) may decide to confirm or adapt the dose.<br>Drug: Osimertinib<br>* Participants will receive Osimertinib at a dose of 80 mg orally once daily.<br>* Other names: Tagrisso®;|
| Experimental: Tepotinib Mono-therapy<br>Participants will receive once daily dose of tepotinib. The mono therapy will be applied in cycles of 21 days until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal. | Drug: Tepotinib<br>* Participants will be administered Tepotinib orally once daily at an initial dose of 500 milligram (mg). A safety monitoring committee (SMC) may decide to confirm or adapt the dose.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version (NCI-CTCAE v 5.0) |  | Up to Day 21 of Cycle 1 (each Cycle is of 21 days) | 
| Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as per Independent Review Committee for Combined Therapy in Participants With MET Amplification Determined Centrally by Fluorescence in situ Hybridization(FISH) | Participants are identified as having an objective response if they achieve either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progression disease (PD) according to determined according to RECIST 1.1 as adjudicated by the IRC. CR: Complete Response defined as disappearance of all target and non target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to less than (<) 10 mm. Partial response defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 38 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response According to RECIST Version 1.1 as per IRC for Combined Therapy in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing | Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to determined according to RECIST 1.1 as adjudicated by the IRC. CR: Complete Response defined as disappearance of all target and non target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to less than (<) 10 mm. Partial response defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Objective Response According to RECIST Version 1.1 as per IRC for Tepotinib Monotherapy in Participants With MET Amplification Determined Centrally by FISH | Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to determined according to RECIST 1.1 as adjudicated by the IRC. CR: Complete Response defined as disappearance of all target and non target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to less than (<) 10 mm. Partial response defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Number of Participants With Adverse Events (AEs) and Treatment-Related Adverse Events According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and Deaths |  | Baseline up to 30 days after the last dose of study treatment | 
| Percentage of Participants With Abnormal greater Than or Equal to (>=) Grade 3 Laboratory Findings |  | Baseline up to 30 days after the last dose of study treatment | 
| Percentage of Participants With Abnormal Vital Signs, Electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) Performance Status | Percentage of participants with abnormalities in vital signs; clinically significant electrocardiograms (ECGs), change in body weight and change in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) will be analyzed. | Baseline up to 30 days after the last dose of study treatment | 
| Objective Response According to RECIST Version 1.1 Assessed by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH | Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to RECIST 1.1 as adjudicated by the Investigator. CR: CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Confirmed Complete Response Assessed by IRC and by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH | Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. Participants will be assessed who have confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD. Participants are identified as having a confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Duration of Response Assessed by Independent Review Committee (IRC) and by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH | Duration of response is the time from when the CR/PR (whichever is first) criteria are first met until PD or death due to any cause of the last tumor assessment, whichever occurs first. | Approximately 42 months | 
| Percentage of Participants With Disease Control Assessed by IRC and by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH | Participants are identified as having objective disease control if they achieve either a confirmed CR or PR (confirmation needs to take place after the tumor assessments initially indicating CR or PR), or stable disease (SD). | Approximately 42 months | 
| Progression-Free Survival Assessed by the IRC and Investigator for Combined Therapy According to RECIST v1.1 in Participants with MET Amplification Determined Centrally by FISH | Progression free survival is defined as the time (in months) from first administration of study treatment to the date of the first documentation of PD or death due to any cause of the last tumor assessment, whichever occurs first. | Approximately 42 months | 
| Overall Survival for Combined Therapy in Participants With MET Amplification Determined Centrally by FISH | Overall survival is defined as the time (in months) from first administration of study treatment to the date of death. | Approximately 42 months | 
| Objective Response Assessed by Investigator According to RECIST v1.1 for Tepotinib Monotherapy in Participants with MET Amplification Determined Centrally by FISH | Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to RECIST 1.1 as adjudicated by the Investigator. CR: CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Confirmed Complete Response Assessed by IRC and by Investigator for Tepotinib Monotherapy in Participants With MET Amplification Determined Centrally by FISH | Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. Participants will be assessed who have confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD. Participants are identified as having a confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD. | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Duration of Response Assessed by IRC and by Investigator for Tepotinib Monotherapy in Participants with MET Amplification Determined Centrally by FISH | Duration of response is the time from when the CR/PR (whichever is first) criteria are first met until PD or death due to any cause of the last tumor assessment, whichever occurs first. | Approximately 42 months | 
| Percentage of Participants With Disease Control Assessed by IRC and Investigator for Tepotinib Monotherapy in Participants with MET Amplification Determined Centrally by FISH | Participants are identified as having objective disease control if they achieve either a confirmed CR or PR (confirmation needs to take place after the tumor assessments initially indicating CR or PR), or stable disease (SD). | Approximately 42 months | 
| Progression-Free Survival Assessed by the IRC and Investigator for Tepotinib Monotherapy According to RECIST v1.1 in Participants with MET Amplification Determined Centrally by FISH | Progression free survival is defined as the time (in months) from first administration of study treatment to the date of the first documentation of PD or death due to any cause of the last tumor assessment, whichever occurs first. | Approximately 42 months | 
| Health-Related Quality of Life as Assessed by EuroQol Five Dimension Five Level (EQ-5D-5L) Scale Score in Combination Therapy |  | Approximately 42 months | 
| Health-Related Quality of Life as assessed by European Organisation For Research And Treatment of Cancer Quality of Life Questionnaire Core 3D (EORTC-QLQ-C30) in Combination Therapy |  | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Health-Related Quality of Life as assessed by Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) in Combination Therapy |  | Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months) | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib and Osimertinib and Their Metabolities |  | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days) | 
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Osimertinib and Their Metabolities |  | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days) | 
| Time to Reach Maximum Observed Plasma Concentration (tmax) of Tepotinib and Osimertinib and Their Metabolities |  | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days) | 
| Apparent Total Body Clearance (CL/f) of Tepotinib and Osimertinib and Their Metabolities | The apparent total body clearance of study intervention following extravascular administration, taking into account the fraction of dose absorbed. CL/f = Dose p.o. /AUC0-infinity (AUC0-inf). | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days) | 
| Apparent Volume Of Distribution (Vz/F) of Tepotinib and Osimertinib and Their Metabolities | The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z). | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days) | 
| Percentage of Participants With resistant Mutations of the Epidermal Growth Factor Receptor (EGFR) gene or other pathways as Assessed in Circulating Tumor Deoxyribonucleic Acid (ctDNA |  | From Day 1 of Cycle 3 up to end of treatment (14 days after last dose) (each Cycle is for 21 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tepotinib, Osimertinib, Non-Small Cell Lung Cancer, INSIGHT 2, MET amplified