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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03940703
Recruitment Status : Active, not recruiting
First Posted : May 7, 2019
Results First Posted : June 4, 2024
Last Update Posted : June 4, 2024
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
This study was to 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).

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: Tepotinib Drug: Osimertinib Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 140 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 19, 2019
Actual Primary Completion Date : May 11, 2023
Estimated Study Completion Date : May 27, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Tepotinib and Osimertinib
Participants received a single oral dose of Tepotinib 500 milligrams (mg) followed by Omisertinib 80 mg once daily until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal.
Drug: Tepotinib
Participants were administered with Tepotinib orally once daily at a dose of 500 mg.

Drug: Osimertinib
Participants received Osimertinib at a dose of 80 mg orally once daily.
Other Name: Tagrisso®

Experimental: Tepotinib Mono-therapy
Participants received a single oral dose of Tepotinib 500 mg until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal.
Drug: Tepotinib
Participants were administered with Tepotinib orally once daily at a dose of 500 mg.




Primary Outcome Measures :
  1. Combined Therapy (Tepotinib+Osimertinib): 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) [ Time Frame: Up to Day 21 of Cycle 1 (each Cycle is of 21 days) ]
    DLTs are defined as any of the following toxicities and judged by the Investigator and/or the Sponsor to be not attributable to the disease or disease-related processes under investigation: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (>=) 3 febrile neutropenia; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade >= 3 nausea/vomiting and/or diarrhea that has not improved within 72 hours despite adequate and optimal treatment; Any other Grade >= 3 non-hematological AE, except alopecia or Grade 3 nauseas/vomiting and/or diarrhea that has improved within 72 hours with optimal treatment.

  2. Combined Therapy: Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Per Independent Review Committee in Participants With MET Amplification Determined Centrally by Fluorescence in Situ Hybridization(FISH) [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.


Secondary Outcome Measures :
  1. Combined Therapy: Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Per Independent Review Committee in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  2. Monotherapy (Tepotinib): Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1 as Per Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  3. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.

  4. Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Related TEAEs [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    The laboratory measurements included hematology, biochemistry, coagulation and urinalysis. Number of participants with clinically significant abnormalities in laboratory values reported as treatment related TEAEs were reported. Clinical significance was decided by investigator.

  5. Number of Participants With Markedly Abnormal Vital Sign Measurements [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Vital signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse rate (PR), respiratory rate (RR) body weight (BW) and body temperature (BT). Markedly abnormal value (MAV) criteria for vital signs: SBP and DBP: maximal on treatment (TR) increase or decrease greater than (>) 40 millimeter of mercury (mmHg); PR: maximal on TR increase or decrease >40 beats per minute (bpm); RR: maximal on TR increase or decrease >10 breaths per minute (breaths/minute), BW: maximum on TR increase or decrease >=10% and BT: maximal on TR increase greater than or equal to (>=)2 degree Celsius. Number of participants who met the MAV criteria for vital signs at least once post dose were reported.

  6. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    ECOG performance status measured to assess participant's performance status on a scale of 0 to 5, where 0 = Fully active, able to carry on all pre-disease activities without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; 3 = Capable of only limited self-care, confined to bed/chair for more than 50 percent of waking hours; 4 = Completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5 = dead. ECOG performance status was reported in terms of number of participants with shifts in score from baseline value vs worst post-baseline value (that is [i.e.] highest score).

  7. Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Findings [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Electrocardiograms (ECG) was obtained after the participant has been in a semi-supine position for at least 5 min. ECG parameters included heart rate, PQ/PR duration, QRS and QT duration, QT Interval. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported.

  8. Combined Therapy: Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1 Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  9. Combined Therapy (Tepotinib + Osimertinib): Number of Participants With Confirmed Complete Response (CR) Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Confirmed CR was defined as the disappearance of all evidence of target and non-target lesions.

  10. Combined Therapy (Tepotinib + Osimertinib): Number of Participants With Confirmed Complete Response (CR) Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Confirmed CR was defined as the disappearance of all evidence of target and non-target lesions.

  11. Combined Therapy (Tepotinib + Osimertinib): Duration of Response Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 42 months ]
    DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  12. Combined Therapy (Tepotinib + Osimertinib): Duration of Response Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 42 months ]
    DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  13. Combined Therapy (Tepotinib + Osimertinib): Disease Control Rate Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Disease control rate is defined as the percentage of participants with objective resposne (complete resposne [CR] or partial resposne [PR] or stable disease [SD]). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  14. Combined Therapy (Tepotinib + Osimertinib): Disease Control Rate Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Disease control rate is defined as the percentage of participants with objective resposne (complete resposne [CR] or partial resposne [PR] or stable disease [SD]). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  15. Combined Therapy (Tepotinib + Osimertinib): Progression-Free Survival (PFS) According to RECIST Version1.1 as Assessed by the Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed approximately up to 42 months ]
    PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause within 126 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  16. Combined Therapy (Tepotinib + Osimertinib): Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Assessed by the Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed approximately up to 42 months ]
    PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause within 126 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  17. Combined Therapy (Tepotinib + Osimertinib): Overall Survival in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment to the date of death, assessed approximately up to 42 months ]
    Overall survival is defined as the time from first administration of study treatment to the date of death.

  18. Combined Therapy: Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Assessed by Investigator in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  19. Combined Therapy (Tepotinib + Osimertinib): Number of Participants With Confirmed Complete Response (CR) Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Confirmed CR was defined as the disappearance of all evidence of target and non-target lesions.

  20. Combined Therapy (Tepotinib + Osimertinib): Number of Participants With Confirmed Complete Response (CR) Assessed by Investigator in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Confirmed CR was defined as the disappearance of all evidence of target and non-target lesions.

  21. Combined Therapy (Tepotinib + Osimertinib): Duration of Response Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 42 months ]
    DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  22. Combined Therapy (Tepotinib + Osimertinib): Duration of Response Assessed by Investigator in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 42 months ]
    DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  23. Combined Therapy (Tepotinib + Osimertinib): Disease Control Rate Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Disease control rate is defined as the percentage of participants with objective resposne (complete resposne [CR] or partial resposne [PR] or stable disease [SD]). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  24. Combined Therapy (Tepotinib + Osimertinib): Disease Control Rate Assessed by Investigator in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Disease control rate is defined as the percentage of participants with objective resposne (complete resposne [CR] or partial resposne [PR] or stable disease [SD]). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  25. Combined Therapy (Tepotinib + Osimertinib): Progression-Free Survival (PFS) According to RECIST Version1.1 as Per Independent Review Committee in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed approximately up to 42 months ]
    PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause within 126 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  26. Combined Therapy ((Tepotinib + Osimertinib): Progression-Free Survival (PFS) According to RECIST Version1.1 as Assessed by the Investigator in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed approximately up to 42 months ]
    PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause within 126 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  27. Combined Therapy (Tepotinib + Osimertinib): Overall Survival in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing [ Time Frame: Time from first administration of study treatment to the date of death, assessed approximately up to 42 months ]
    Overall survival is defined as the time from first administration of study treatment to the date of death.

  28. Monotherapy (Tepotinib): Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Per Investigator in Participants With MET Amplification Determined Centrally by Fluorescence in Situ Hybridization(FISH) [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  29. Monotherapy (Tepotinib): Number of Participants With Confirmed Complete Response (CR) Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Confirmed CR was defined as the disappearance of all evidence of target and non-target lesions.

  30. Monotherapy (Tepotinib): Number of Participants With Confirmed Complete Response (CR) Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Confirmed CR was defined as the disappearance of all evidence of target and non-target lesions.

  31. Monotherapy (Tepotinib): Duration of Response Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 42 months ]
    DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  32. Monotherapy (Tepotinib): Duration of Response Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 42 months ]
    DOR was defined for participants with objective response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  33. Monotherapy (Tepotinib): Disease Control Rate Assessed by Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Disease control rate is defined as the percentage of participants with objective resposne (complete resposne [CR] or partial resposne [PR] or stable disease [SD]). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  34. Monotherapy (Tepotinib): Disease Control Rate Assessed by Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment up to data cutoff (approximately assessed up to 42 months) ]
    Disease control rate is defined as the percentage of participants with objective resposne (complete resposne [CR] or partial resposne [PR] or stable disease [SD]). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  35. Monotherapy (Tepotinib): Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Assessed by the Independent Review Committee in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed approximately up to 42 months ]
    PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause within 126 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  36. Monotherapy (Tepotinib): Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as Assessed by the Investigator in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Time from first administration of study treatment to the date of the first documentation of PD or death due to any cause, assessed approximately up to 42 months ]
    PFS was defined as the time is defined as the time from first administration of study treatment to the date of the first documentation of PD or death due to any cause within 126 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  37. Combined Therapy (Tepotinib + Osimertinib): Change From Baseline in European Quality Of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) at Safety Follow-up (42 Months) [ Time Frame: Baseline, safety follow-up (assessed up to 42 months) ]
    The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L profile defines health in terms of mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each dimension has five levels: 1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, and 5: extreme problems. The responses were used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 was the worst health you can imagine and 100 was the best health you can imagine.

  38. Combined Therapy (Tepotinib + Osimertinib): Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status) at Safety Follow-up (42 Months) [ Time Frame: Baseline, safety follow-up (up to 42 months) ]
    EORTC QLQ-C30 was a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact). The EORTC QLQ-C30 GHS/QoL score ranged from 0 to 100; High score indicated better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.

  39. Combined Therapy (Tepotinib + Osimertinib): Change From Baseline in Health-Related Quality of Life as Assessed by Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) at Safety Follow-up (42 Months) [ Time Frame: Baseline, safety follow-up (up to 42 months) ]
    NSCLC-SAQ was a question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 5 domains: cough, pain, dyspnea, fatigue, and appetite. The NSCLC-SAQ score ranged from 0 to 20; High score indicated more severe NSCLC-related symptomatology. mains: cough, pain, dyspnea, fatigue, and appetite.

  40. Combined Therapy (Tepotinib + Osimertinib): Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of Tepotinib and Its Metabolites (MSC2571109A, MSC2571107A), Osimertinib and Its Metabolite AZD5104 [ Time Frame: 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) ] ]
    Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.

  41. Combined Therapy (Tepotinib + Osimertinib): Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Its Metabolites (MSC2571109A, MSC2571107A), Osimertinib and Its Metabolite AZD5104 [ Time Frame: 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) ] ]
    Cmax was obtained directly from the concentration versus time curve.

  42. Combined Therapy (Tepotinib + Osimertinib): Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tepotinib and Its Metabolites (MSC2571109A, MSC2571107A), Osimertinib and Its Metabolite AZD5104 [ Time Frame: 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) ] ]
    Tmax was obtained directly from the concentration versus time curve.

  43. Combined Therapy (Tepotinib + Osimertinib): Apparent Total Body Clearance (CL/f) of Tepotinib and Its Metabolites (MSC2571109A, MSC2571107A), Osimertinib and Its Metabolite AZD5104 [ Time Frame: 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) ] ]
    CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

  44. Combined Therapy (Tepotinib + Osimertinib): Apparent Volume Of Distribution (Vz/F) of of Tepotinib and Its Metabolites (MSC2571109A, MSC2571107A), Osimertinib and Its Metabolite AZD5104 [ Time Frame: 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) ] ]
    Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

  45. 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) [ Time Frame: From Day 1 of Cycle 3 up to end of treatment (14 days after last dose, approximately assessed up to 35.6 months) (each Cycle is for 21 days) ]
    Percentage of participants with resistant mutations of the EGFR gene or other pathways as assessed in ctDNA were reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03940703


Locations
Show Show 179 study locations
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
  Study Documents (Full-Text)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol  [PDF] May 4, 2021
Statistical Analysis Plan  [PDF] April 4, 2023

Additional Information:
Publications:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT03940703    
Other Study ID Numbers: MS200095_0031
2019-001538-33 ( EudraCT Number )
First Posted: May 7, 2019    Key Record Dates
Results First Posted: June 4, 2024
Last Update Posted: June 4, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
URL: http://bit.ly/IPD21

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Tepotinib
Osimertinib
Non-Small Cell Lung Cancer
INSIGHT 2
MET amplified
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Tepotinib
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents