Study of Capmatinib Efficacy in Comparison With Docetaxel in Previously Treated Participants With Non-small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutation

Phase 3

Completed

• Conditions: Carcinoma, Non-Small-Cell Lung
• Interventions: Drug: Capmatinib; Drug: Docetaxel

• Registration Number: NCT04427072
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

The purpose of the study is to learn whether the study drug (capmatinib) helps to control lung cancer better compared to a single agent chemotherapy (docetaxel) and whether it is safe when given to patients suffering from a particular type of lung cancer. This type of cancer is called non-small cell lung cancer (NSCLC) with certain specific genetic alterations (called mutations) of a gene called MET, within a specific part of the gene called exon 14.

Detailed Description

Approximately 90 patients with advanced or metastatic lung cancer, with these specific mutations in the MET gene but without changes in their epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes, will be enrolled in this study. Participants will be randomly assigned to get either capmatinib or docetaxel in a 2 to 1 ratio. The randomization will be stratified by prior lines of systemic therapy received for advanced/metastatic disease (one line vs. two lines).

During treatment, visits will be scheduled every 21 days.

For all participants, the respective treatment (either with capmatinib or docetaxel) may be continued beyond initial disease progression as per RECIST 1.1 (as assessed by the investigator and confirmed by BIRC) if, in the judgment of the investigator, there is evidence of clinical benefit, and the participant wishes to continue on the study treatment. After treatment discontinuation, all participants will be followed for safety evaluations during the safety follow-up period, and the participant's status will be collected every 12 weeks as part of the survival follow-up.

Participants randomized to docetaxel treatment will be eligible to crossover to receive capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease and after meeting the eligibility criteria prior to crossover.

Study Timeline

• Study First Submitted: 2020-06-09
• Study First Submitted QC: 2020-06-09
• Study First Posted: 2020-06-11
• Study Start: 2020-09-25
• Primary Completion: 2023-02-15
• Study Completion: 2023-11-06
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-16
• Last Update Posted: 2024-07-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

• Stage IIIB/IIIC (not amenable to surgery, radiation or multi modality therapy) or IV NSCLC (according to Version 8 of the American Joint Committee on Cancer (AJCC) Staging Manual) at the time of study entry.

• Histologically or cytologically confirmed diagnosis of NSCLC that is:

  1. EGFR wt. Assessed as part of participant's standard of care by a validated test for EGFR mutations as per local guidelines. The EGFR wt status (for EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution mutations.
  2. AND ALK rearrangement negative. Assessed as part of participant's standard of care by a validated test.
  3. AND has METΔex14 mutation as determined by Novartis-designated central laboratory or by locally performed, tissue-based test, validated according to local regulation, from a Clinical Laboratory Improvement Amendments (CLIA)-certified US laboratory or an accredited local laboratory outside of the US. The positive METΔex14 mutation result as determined per local test must be documented in the participant's source documents and in the CRF prior to entering main screening.

• Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (archival tumor block or slides, or a newly obtained tumor sample) with quality and quantity sufficient to allow assessment of METΔex14 mutation status (as defined in the study [laboratory manual]). This pertains to all participants, including those who have a METΔex14 mutation result from a local test. Tumor samples must contain at least 10% tumor content.

  6. Participants must have progressed on one or two prior lines of

• Progressed on one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB/IIIC [not candidates for surgery, radiation or multi modality therapy] or IV NSCLC) and must be docetaxel naïve and candidates for single agent chemotherapy (docetaxel). Treatment failure is defined as documented disease progression or intolerance to treatment., however participants must have progressed on or after the last therapy before study entry.

• At least one measurable lesion as defined by RECIST 1.1

• Adequate organ function

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

• Participants must have a life expectancy of at least 3 months.

Key

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Exclusion Criteria

• Prior treatment with any MET inhibitor or HGF-targeting therapy.
• Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
• Participants with known druggable molecular alterations (such as ROS1and RET rearrangement, BRAF mutation, KRAS mutation, NTRK fusion, etc.) which might be a candidate for alternative targeted therapies.
• Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
• Substance abuse, active infection or other severe, acute, or chronic medical or psychotic conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation

Other protocol-defined inclusion/exclusion criteria may apply.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Capmatinib	Capmatinib	400mg of capmatinib tablets, administered orally twice daily
Docetaxel	Docetaxel	Docetaxel 75 mg/m2 solution administered by intravenous infusion on Day 1 of every 21-day cycle

Primary Outcome Measures

Name	Time	Method
Progression free survival (PFS) per blinded independent review committee (BIRC) using RECIST v1.1	From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months	Progression free survival is defined as the time from the date of randomization to the date of the first documented progression assessed by BIRC according to RECIST 1.1, or death due to any cause

Secondary Outcome Measures

Name	Time	Method
Overall response (ORR) per RECIST 1.1 by investigator	Up to approximately 21 months	Percentage of participants with confirmed BOR of CR or PR, assessed by local review according to RECIST 1.1.
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13)	Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days.	EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. The five domains of the questionnaire include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain is score based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms.; Change from baseline in EORTC QLQ-LC13 scores will be assessed
Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire	Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days.	EQ-5D-5L is a standardized measure to assess the overall health-related quality of life in patients. The EQ-5D-5L consists of 2 parts- the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: from 1 (no problems) to 5 (extreme problems). The EQ VAS is a self-perceived health score assessed using a visual analogue scale that ranges from 0 (the worst imaginable health) to 100 (the best imaginable health), with higher scores indicating higher health utility.; Change from baseline in EQ-5D-5L scores will be assessed
Time to symptom deterioration for chest pain, cough and dyspnea assessed using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13)	Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment. Each cycle duration is 21 days.	EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. The five domains of the questionnaire include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain is score based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms.; Time to symptom deterioration for chest pain, cough and dyspnea will be assessed
Time to response (TTR) per RECIST 1.1 by BIRC	From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months	Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by BIRC according to RECIST 1.1.
Disease Control Rate (DCR) per RECIST 1.1 by BIRC	Up to approximately 21 months	Percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) assessed by BIRC according to RECIST 1.1
Overall intracranial response rate (OIRR)	Up to approximately 21 months	Percentage of participants with confirmed best overall intracranial response (BOIR) of CR or partial response (PR), as assessed by BIRC review per RANO-BM criteria.
Progression free survival (PFS) per investigator using RECIST v1.1	From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months	Time from the date of randomization to the date of the first documented progression assessed by local review according to RECIST 1.1, or death due to any cause
Duration of intracranial response (DOIR)	From date of first documented intracranial response (CR or PR) to first documented intracranial progression, assessed up to approximately 21 months	Time from date of first documented intracranial response (CR or PR) to first documented intracranial progression per RANO-BM assessed by BIRC or date of death due to underlying cause of cancer.
Plasma capmatinib concentration	Cycle (C) 1 Day (D) 15 pre-dose, 1 and 4 hours post-dose, C3 D1 pre-dose. Each cycle duration is 21 days.	Plasma concentrations of capmatinib. Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Time to response (TTR) per RECIST 1.1 by investigator	From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months	Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by local review according to RECIST 1.1.
Duration of response (DOR) per RECIST 1.1 by BIRC	From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months	Time from the date of first documented response (CR or PR) to the first documented progression by BIRC per RECIST 1.1 or death due to any cause.
Disease Control Rate (DCR) per RECIST 1.1 by investigator	Up to approximately 21 months	Percentage of participants with a BOR of confirmed CR, PR and SD assessed by local review according to RECIST 1.1
Overall survival (OS)	From randomization to death due to any cause, assessed up to approximately 42 months	OS is defined as the time from the date of randomization to the date of death due to any cause.
Time to intracranial response (TTIR)	From date of randomization to first documented intracranial response of either CR or PR, assessed up to approximately 21 months	Time from date of randomization to first documented intracranial response of either CR or PR, per RANO-BM criteria and assessed by BIRC, which must be subsequently confirmed.
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30	Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days.	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. The questionnaire is composed of both multi-item scales and single-item measures based on the participants experience over the past week. These include five domains (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/HRQoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.; Change from baseline in EORTC QLQ-C30 scores will be assessed
Time to deterioration for global health status /QoL assessed using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30	Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment. Each cycle duration is 21 days.	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. The questionnaire is composed of both multi-item scales and single-item measures based on the participants experience over the past week. These include five domains (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/HRQoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.; Time to deterioration in QoL from EORTC-QLQ-C30 will be assessed.
Overall response (ORR) per RECIST 1.1 by BIRC	Up to approximately 21 months	Percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR), assessed by BIRC according to RECIST 1.1.
Duration of response (DOR) per RECIST 1.1 by investigator	From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months	Time from the date of first documented response (CR or PR) to the first documented progression by local review per RECIST 1.1 or death due to any cause.
Intracranial disease control rate (IDCR)	Up to approximately 21 months	Percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) (or non-CR/non-PD) per RANO-BM, assessed by BIRC.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇪🇸 Madrid, Spain