Tepotinib Phase II in NSCLC Harboring MET Alterations (VISION)

• ClinicalTrials.gov Identifier: NCT02864992
• Recruitment Status: Active, not recruiting
• First Posted: August 12, 2016
• Results First Posted: June 9, 2023
• Last Update Posted: June 9, 2023
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Tracking Information

• First Submitted Date: July 29, 2016
• First Posted Date: August 12, 2016
• Results First Submitted Date: May 15, 2023
• Results First Posted Date: June 9, 2023
• Last Update Posted Date: June 9, 2023
• Actual Study Start Date: September 13, 2016
• Actual Primary Completion Date: May 16, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2023)

• Part 1: Cohort A: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Review Committee (IRC) [ Time Frame: Time from first treatment up to data cutoff (approximately Month 66) ]
  Objective response will be determined according to RECIST 1.1 and as per IRC. Objective response was defined as number 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.
• Part 1: Cohort B: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Assessed by Independent Review Committee (IRC) [ Time Frame: Time from first treatment up to data cutoff (approximately Month 66) ]
  Objective response will be determined according to RECIST 1.1 and as per IRC. Objective response was defined as number 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.
• Part 2: Cohort C: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Assessed by Independent Review Committee (IRC) [ Time Frame: Time from first treatment up to data cutoff (approximately Month 66) ]
  Objective response will be determined according to RECIST 1.1 and as per IRC. Objective response was defined as number 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.

Original Primary Outcome Measures (submitted: August 9, 2016)

Objective response as assessed by independent review committee [ Time Frame: Baseline up to 20 months ]

Objective response will be determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as adjudicated by an Independent review committee. Objective response is defined as either a confirmed complete response (CR) or partial response (PR) from first administration of trial 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 is 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.

Current Secondary Outcome Measures (submitted: May 15, 2023)

• Part 1 & 2: Cohort A + B + C: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Duration of Response (DOR) Assessed by Investigator [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Objective Disease Control Rate Assessed by IRC [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Objective Disease Control Rate Assessed by Investigator [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Progression-free Survival by IRC Assessment [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B +C: Progression-free Survival by Investigator Assessment [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Overall Survival (OS) [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B +C: Number of Participants With Markedly Abnormal Clinical Laboratory Tests [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Number of Participants With Markedly Abnormal Vital Signs and Physical Examination [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Number of Participants With Clinically Significant Change From Baseline in 12-Lead Electrocardiogram (ECG) [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Change From Baseline in Euro Quality of Life Questionnaire With 5 Questions Alternatives (EQ5D-5L) Summary Score [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]
• Part 1 & 2: Cohort A + B + C: Quality of Life (QoL) Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [ Time Frame: Time from first treatment up to end of study (approximately Month 101) ]

Original Secondary Outcome Measures (submitted: August 9, 2016)

• Objective response assessed as per Investigator [ Time Frame: Baseline up to 20 months ]
  Objective response will be determined according to RECIST 1.1 and as per investigator's discretion. Objective response is defined as either a confirmed complete response (CR) or partial response (PR) from first administration of trial treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is 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.
• Duration of response as assessed by independent review committee [ Time Frame: Baseline until PD/ death within 84 days of last tumor assessment; assessed up to 20 months ]
  Duration of response according to RECIST 1.1 and as adjudicated by an Independent review committee is the time from when the CR/PR (whichever is first) criteria are first met until progression of disease (PD) or death due to any cause within 84 days of the last tumor assessment, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is 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.
• Duration of response as assessed by investigator [ Time Frame: Baseline until PD/ death within 84 days of last tumor assessment; assessed up to 20 months ]
  Duration of response according to RECIST 1.1 and as per investigator's discretion is the time from when the CR/PR (whichever is first) criteria are first met until progression of disease (PD) or death due to any cause within 84 days of the last tumor assessment, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is 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.
• Objective disease control as assessed by independent review committee [ Time Frame: Baseline up to 20 months ]
  Objective disease control will be determined according to RECIST 1.1 and as adjudicated by an Independent review committee. Objective disease control is defined as either a confirmed CR or PR, or stable disease (SD) lasting at least 12 weeks (84 days) as assessed by independent review committee. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is 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.
• Objective disease control as assessed by investigator [ Time Frame: Baseline up to 20 months ]
  Objective disease control will be determined according to RECIST 1.1 and as per investigator's discretion. Objective disease control is defined as either a confirmed CR or PR, or stable disease (SD) lasting at least 12 weeks (84 days) as assessed by investigator. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is 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.
• Progression free survival as assessed by independent review committee [ Time Frame: Baseline until PD or death within 84 days of last tumor assessment; assessed up to 20 months ]
  Progression free survival as assessed by independent review committee is defined as the time (in months) from the first administration of trial treatment to the date of the first documentation of PD (based on independent review) or death due to any cause within 84 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Progression free survival as assessed by investigator [ Time Frame: Baseline until PD or death within 84 days of last tumor assessment; assessed up to 20 months ]
  Progression free survival as assessed by investigator is defined as the time (in months) from the first administration of trial treatment to the date of the first documentation of PD (as assessed by investigator) or death due to any cause within 84 days of the last tumor assessment, whichever occurs first. PD is defined as at least a 20 % increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Overall survival [ Time Frame: Baseline until death, assessed up to 20 months ]
  Overall survival is defined as the time (in months) from first trial treatment administration to the date of death.
• Occurrence of Treatment emergent adverse event (TEAEs) and deaths [ Time Frame: From the first dose of study drug administration until 33 days after the last dose of study drug administration, assessed up to 20 Months ]
  This outcome measure will be presented as the percentage of subjects with any (serious) adverse event (AE). Percentages are calculated using total number of subjects per treatment cohort as the denominator.
• Percentage of subjects with of markedly abnormal clinical laboratory tests (hematology and coagulation, biochemistry and urinalysis), vital signs, Electrocardiogram (ECG), and Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: Baseline up to 20 months ]
  This outcome measure will be presented as the percentage of subjects with markedly abnormal vital sign measurements. Percentages are calculated using total number of subjects per treatment cohort as the denominator. Abnormalities in Systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, body temperature as a part of vital signs; electrocardiogram (ECG) wave, body weight, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), and clinical laboratory tests (hematology and coagulation, biochemistry and urinalysis) will be assessed.
• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [ Time Frame: Baseline up to 20 months ]
• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) [ Time Frame: Baseline up to 20 months ]
• EuroQol Five Dimension Five Level Scale (EQ5D5L [ Time Frame: Baseline up to 20 months ]
• Maximum Plasma concentration (Cmax) of drug [ Time Frame: pre-dose, at 1.5 hours post-dose and at 4 hours post-dose on Cycle 1, Day 1 and on Cycle 2, Day 1 ]
• Trough plasma concentration (Ctrough) of drug [ Time Frame: pre-dose, at 1.5 hours post-dose and at 4 hours post-dose on Cycle 1, Day 1 and on Cycle 2, Day 1 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tepotinib Phase II in NSCLC Harboring MET Alterations (VISION)
• Official Title: A Phase II Single-arm Trial to Investigate Tepotinib in Advanced (Locally Advanced or Metastatic) Non-small Cell Lung Cancer With METex14 Skipping Alterations or MET Amplification (VISION)
• Brief Summary: This study looked at how effective the study drug (tepotinib) was at stopping the growth and spread of lung cancer. This study also measures a number of other things including safety of the study drug and the side effects, how body processes the study drug, or how the study drug affects your quality of life. The study also has an optional pharmacogenetic research part. Pharmacogenetic research is an important way to try to understand the role of genetics in human disease and how genes impact the effectiveness of drugs, because differences in genes can change the way a person responds to a particular drug.
• Detailed Description: The study included 3 cohorts with one primary endpoint (Objective Response Rate). Enrollment number and completion data is changed by new cohorts.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced (Stage IIIB/IV) Non-small Cell Lung Cancer (NSCLC) With MET Exon 14 (METex14) Skipping Alterations or MET Amplification
• Lung Adenocarcinoma Stage IIIB/IV

Intervention

Drug: Tepotinib

Subjects will receive 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent.

Study Arms

• Part 1: Cohort A: METex14 Skipping Alterations
  Participants received 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent.
  Intervention: Drug: Tepotinib
• Part 1: Cohort B: MET Amplification
  Participants received 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent.
  Intervention: Drug: Tepotinib
• Part 2: Cohort C: Confirmatory Part for METex14 Skipping Alterations
  Participants received 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent.
  Intervention: Drug: Tepotinib

Publications *

• Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC, Mazieres J, Viteri S, Senellart H, Van Meerbeeck J, Raskin J, Reinmuth N, Conte P, Kowalski D, Cho BC, Patel JD, Horn L, Griesinger F, Han JY, Kim YC, Chang GC, Tsai CL, Yang JC, Chen YM, Smit EF, van der Wekken AJ, Kato T, Juraeva D, Stroh C, Bruns R, Straub J, Johne A, Scheele J, Heymach JV, Le X. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med. 2020 Sep 3;383(10):931-943. doi: 10.1056/NEJMoa2004407. Epub 2020 May 29.
• Xiong W, Hietala SF, Nyberg J, Papasouliotis O, Johne A, Berghoff K, Goteti K, Dong J, Girard P, Venkatakrishnan K, Strotmann R. Exposure-response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations. Cancer Chemother Pharmacol. 2022 Jul;90(1):53-69. doi: 10.1007/s00280-022-04441-3. Epub 2022 Jun 30.
• Xiong W, Papasouliotis O, Jonsson EN, Strotmann R, Girard P. Population pharmacokinetic analysis of tepotinib, an oral MET kinase inhibitor, including data from the VISION study. Cancer Chemother Pharmacol. 2022 May;89(5):655-669. doi: 10.1007/s00280-022-04423-5. Epub 2022 Apr 6.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 9, 2021): 337
• Original Estimated Enrollment (submitted: August 9, 2016): 60
• Estimated Study Completion Date: February 20, 2025
• Actual Primary Completion Date: May 16, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Signed, written informed consent by participant or legal representative prior to any trial-specific screening procedure
• Male or female, greater than or equal to (>=) 18 years of age (or have reached the age of majority according to local laws and regulations)
• Measurable disease confirmed by an independent review committee (IRC) in accordance with RECIST version 1.1
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
• A female participant was eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential OR
• A woman of childbearing potential who agrees to use a highly effective contraception
• A male participant must agree to use and to have their female partners of childbearing potential to use a highly effective contraception
• Histologically or cytologically confirmed advanced (locally advanced or metastatic) NSCLC (all types including squamous and sarcomatoid)
• Treatment naïve participant in first-line or pretreated participant with no more than 2 lines of prior therapy
• Participants with MET alterations, namely METex14 skipping alterations in plasma and/or tissue as determined by the central laboratory or by an assay with appropriate regulatory status

Exclusion Criteria:

• Participants with characterized Epidermal Growth Factor Receptor (EGFR) activating mutations that predict sensitivity to anti-EGFR-therapy
• Participants with characterized Anaplastic Lymphoma Kinase (ALK) rearrangements that predict sensitivity to anti-ALK therapy
• Participants with symptomatic brain metastases who are neurologically unstable
• Any unresolved toxicity Grade 2 or more according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) from previous anticancer therapy
• Need for transfusion within 14 days prior to the first dose of trial treatment
• Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment;
• Participants who have brain metastasis as the only measurable lesion
• Inadequate hematological, liver, renal, cardiac function
• Prior treatment with other agents targeting the Hepatocyte Growth Factor c(HGF/c) -Met pathway
• Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg)
• Past or current history of neoplasm other than Non-small Cell Lung Cancer (NSCLC), except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years
• Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the test product
• Major surgery within 28 days prior to Day 1 of trial treatment
• Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C virus
• Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with trial participation at the discretion of Investigators
• Known hypersensitivity to any of the trial treatment ingredients
• Legal incapacity or limited legal capacity
• Any other reason that, in the opinion of the Principal Investigator, precludes the participant from participating in the trial
• Participation in another clinical trial within the past 30 days

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, China, France, Germany, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Spain, Switzerland, Taiwan, United States

Administrative Information

• NCT Number: NCT02864992
• Other Study ID Numbers: MS200095-0022; 2015-005696-24 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports 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 bit.ly/IPD21
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• 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

• Current Responsible Party: EMD Serono ( EMD Serono Research & Development Institute, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: EMD Serono Research & Development Institute, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; EMD Serono Research & Development Institute, Inc, a business of Merck KGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: May 2023