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
Conditions
Keywords
lung, neoplasm, cancer, tumor, adenocarcinoma, MET exon 14, METex14, pulmonary, stage III, stage IV, c-Met, cMET, NSCLC, advanced non-small cell lung cancer, MET amplification, non-small cell lung cancer
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.
Interventions
DRUGTepotinib
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.
Sponsors
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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. |
Secondary
| Measure | Time frame |
|---|---|
| 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 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 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 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 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 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 from first treatment up to end of study (approximately Month 101) |
| Part 1 & 2: Cohort A + B + C: Overall Survival (OS) | 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 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 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 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 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 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 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 from first treatment up to end of study (approximately Month 101) |
Countries
Austria, Belgium, China, France, Germany, Israel, Italy, Japan, Netherlands, Poland, South Korea, Spain, Switzerland, Taiwan, United States
Contacts
STUDY_DIRECTORMedical Responsible
EMD Serono Research & Development Institute, Inc, a business of Merck KGaA, Darmstadt, Germany
Participant flow
Pre-assignment details
For Cohort A: A total of 168 participants were screened of which 152 participants were enrolled to receive the study drug. For Cohort B: A total of 32 participants were screened of which 24 participants were enrolled to receive the study drug. For Cohort C: A total of 175 participants were screened of which 161 participants were enrolled to receive the study drug.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 152 |
| 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. | 24 |
| 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. | 161 |
| Total | 337 |
Baseline characteristics
| Characteristic | Part 1: Cohort A: METex14 Skipping Alterations | Part 1: Cohort B: MET Amplification | Part 2: Cohort C: Confirmatory Part for METex14 Skipping Alterations | Total |
|---|---|---|---|---|
| Age, Continuous | 73.0 years STANDARD_DEVIATION 8.97 | 62.3 years STANDARD_DEVIATION 9.17 | 71.5 years STANDARD_DEVIATION 9.24 | 71.5 years STANDARD_DEVIATION 9.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 148 Participants | 23 Participants | 157 Participants | 328 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 38 Participants | 07 Participants | 68 Participants | 113 Participants |
| Race (NIH/OMB) Black or African American | 01 Participants | 0 Participants | 02 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 05 Participants | 0 Participants | 04 Participants | 9 Participants |
| Race (NIH/OMB) White | 108 Participants | 17 Participants | 87 Participants | 212 Participants |
| Sex: Female, Male Female | 73 Participants | 3 Participants | 86 Participants | 162 Participants |
| Sex: Female, Male Male | 79 Participants | 21 Participants | 75 Participants | 175 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 200 / 337 |
| other Total, other adverse events | 331 / 337 |
| serious Total, serious adverse events | 169 / 337 |
Outcome results
Primary
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)
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.
Time frame: Time from first treatment up to data cutoff (approximately Month 66)
Population: Safty Analysis Set included all participants in Cohort A who were administered at least 1 dose of tepotinib, including participants with METex14 skipping alterations not confirmed by a validated central laboratory assay.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A: METex14 Skipping Alterations | 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) | 46.7 percentage of participants |
Primary
Part 1: Cohort B: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Assessed by Independent Review Committee (IRC)
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.
Time frame: Time from first treatment up to data cutoff (approximately Month 66)
Population: Safety Analysis Set included all participants in Cohort B who were administered at least 1 dose of tepotinib, including participants with a MET Amplification.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A: METex14 Skipping Alterations | Part 1: Cohort B: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Assessed by Independent Review Committee (IRC) | 41.7 percentage of participants |
Primary
Part 2: Cohort C: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Assessed by Independent Review Committee (IRC)
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.
Time frame: Time from first treatment up to data cutoff (approximately Month 66)
Population: Safety analysis set included all participants in Cohort C who were administered at least 1 dose of tepotinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A: METex14 Skipping Alterations | Part 2: Cohort C: Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Assessed by Independent Review Committee (IRC) | 54.7 percentage of participants |
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
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)
Secondary
Part 1 & 2: Cohort A + B + C: Overall Survival (OS)
Time frame: Time from first treatment up to end of study (approximately Month 101)
Secondary
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)
Secondary
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)
Secondary
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)