The purpose of the study was to learn whether the study treatment (capmatinib), which already shows efficacy and safety in non-Chinese patients, could help Chinese patients with controlling their lung cancer in a safe way. Participants had a type of lung cancer called non-small cell lung lancer (NSCLC), with a specific alteration in a part of their DNA (called mutation) of the MET gene, within a specific part of this gene called exon 14. Participants who had advanced (or metastatic) non-small cell lung cancer with specific mutations in the MET gene but without mutations in the EGFR or ALK genes, who were aged 18 years or older were enrolled in this study. The study drug, capmatinib (also known as INC280), is an oral drug that is called a 'targeted' medicine, which means it targets particular processes that may not be working properly in cancer cells (called dysregulation). The dysregulation of the MET signaling in cancer cells of patients with NSCLC is believed to make the cancer worse. Capmatinib has been shown to selectively block the effects of the MET gene and therefore may help in keeping the disease under control, stopping cancer cells from growing.
This was an open-label, multicenter two-cohort phase II study. Chinese adult participants with EGFR wild-type (wt) (EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative, advanced (stage IIIB, IIIC or IV) NSCLC disease harboring MET exon 14-skipping (METΔex14) mutations as determined by a Novartis central molecular laboratory were treated in this study. Cohort 1 included treatment naive participants and Cohort 2 participants who failed one or two prior lines of therapy in the advanced stage (stage IIIB, IIIC or IV). Each participant received 400 mg capmatinib tablet twice daily (BID) until either the disease worsened or there were other reasons to discontinue the drug. After treatment discontinuation, participants were followed for safety up to 30 days after the last dose of study drug. In addition to the 30-day safety follow-up, participants who discontinued treatment without documented progressive disease (PD) continued efficacy assessments and patient-reported outcomes (PROs) collection during the post-treatment follow-up until documented progression. After the post-treatment follow-up phase, the participant's survival status was collected as part of the survival follow-up phase. The primary endpoint was the overall response rate (ORR) by cohort as per the blinded independent review committee (BIRC) review. ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
400 mg of capmatinib tablets, administered orally twice daily
Novartis Investigative Site
Xiamen, Fujian, China
Novartis Investigative Site
Foshan, Guangdong, China
Novartis Investigative Site
Guangzhou, Guangdong, China
Novartis Investigative Site
Guangzhou, Guangdong, China
Novartis Investigative Site
Guangzhou, Guangdong, China
Novartis Investigative Site
Harbin, Heilongjiang, China
Novartis Investigative Site
Zhengzhou, Henan, China
Novartis Investigative Site
Wuhan, Hubei, China
Novartis Investigative Site
Shenyang, Liaoning, China
Novartis Investigative Site
Jinan, Shandong, China
...and 7 more locations
Overall Response Rate (ORR) Per RECIST v1.1 by BIRC Assessment
Tumor response was assessed by a blinded independent review committee (BIRC) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. The primary efficacy endpoint ORR was estimated and the exact 95% confidence interval (CI) was provided by cohort.
Time frame: Up to approximately 125 weeks
Duration Of Response (DOR) Per RECIST v1.1 by BIRC Assessment
DOR only applies to patients whose best overall response is complete response (CR) or partial response (PR) based on BIRC assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response of CR or PR to the date of first documented progression or death due to any cause. If a patient did not have an event, DOR was censored as defined in the statistical analysis plan. DOR was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Overall Response Rate (ORR) Per RECIST v1.1 by Investigator Assessment
Tumor response was assessed by the investigator based on RECIST v1.1. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Duration Of Response (DOR) Per RECIST v1.1 by Investigator Assessment
DOR only applies to patients whose best overall response is complete response (CR) or partial response (PR) based on investigator assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response of CR or PR to the date of first documented progression or death due to any cause. If a patient did not have an event, DOR was censored as defined in the statistical analysis plan. DOR was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Time To Response (TTR) Per RECIST v1.1 by BIRC and Investigator Assessment
TTR is defined as the time from the start date of study drug to the first documented response of either CR or PR, which must be subsequently confirmed. If a patient did not have an event, TTR was censored as defined in the statistical analysis plan. Tumor response was assessed by BIRC and by the investigator based on RECIST v1.1. TTR was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Disease Control Rate (DCR) Per RECIST v1.1 by BIRC and Investigator Assessment
DCR is the percentage of patients with a best overall response of CR, PR or stable disease (SD), based on BIRC review and local investigator assessment per RECIST v1.1.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Progression-Free Survival (PFS) Per RECIST v1.1 by BIRC and Investigator Assessment
PFS is defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) or death due to any cause. If a patient did not have an event, PFS was censored as defined in the statistical analysis plan. Tumor response was assessed by BIRC and by the investigator based on RECIST v1.1. PFS was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 193 weeks (median 37.6 weeks)
Overall Survival (OS)
OS is defined as the time from the start date of study drug to the date of death due to any cause. If a patient did not have an event, OS was censored as defined in the statistical analysis plan. OS was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 193 weeks (median 37.6 weeks)
Overall Intracranial Response Rate (OIRR) Per RANO-BM Criteria by BIRC Assessment
OIRR was calculated based on response assessments in the brain for participants having measurable or non-measurable brain metastases at baseline. OIRR is defined as the percentage of participants with a confirmed best overall intracranial response of CR or PR from the start of treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria as assessed by BIRC review.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Intracranial Disease Control Rate (IDCR) Per RANO-BM Criteria by BIRC Assessment
IDCR is defined as the percentage of participants with a confirmed best overall intracranial response of CR or PR or SD (or non-CR/non-PD) per RANO-BM criteria as assessed by BIRC review.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Time To Intracranial Response (TTIR) Per RANO-BM Criteria by BIRC Assessment
TTIR is defined as the time from the start date of study drug to the date of the first documented intracranial response of either CR or PR per RANO-BM criteria as assessed by the BIRC review, which must be subsequently confirmed. If a patient did not have an event, TTIR was censored as defined in the statistical analysis plan. TTIR was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
Duration Of Intracranial Response (DOIR) Per RANO-BM Criteria by BIRC Assessment
DOIR only applies to participants whose confirmed best overall intracranial response is CR or PR per RANO-BM criteria as assessed by the BIRC review. DOIR is defined as the time from the date of first documented intracranial response of either CR or PR to the date of the first documented intracranial progression per RANO-BM criteria as assessed by BIRC review or date of death due to any cause. If a patient did not have an event, DOIR was censored as defined in the statistical analysis plan. DOIR was estimated using the Kaplan-Meier method.
Time frame: Up to approximately 189 weeks (median 33.6 weeks)
ORR Per RECIST v1.1 by BIRC and Investigator Assessment for Patients by MET Mutation Status in ctDNA
At Cycle 1 Day 1 (C1D1, pre-dose), blood samples were collected to investigate the association between Mesenchymal Epithelial Transition (MET) mutation status in baseline circulating tumor DNA (ctDNA) and capmatinib efficacy. These blood samples were tested for MET exon 14 (METex14) skipping mutations and classified as mutant or non-mutant. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). Tumor response was assessed by BIRC and by the investigator based on RECIST v1.1.
Time frame: Baseline, up to approximately 189 weeks (median 33.6 weeks)
DOR Per RECIST v1.1 by BIRC Assessment for Patients by MET Mutation Status in ctDNA
At Cycle 1 Day 1 (C1D1, pre-dose), blood samples were collected to investigate the association between MET mutation status in baseline ctDNA and capmatinib efficacy. These blood samples were tested for METex14 skipping mutations and classified as mutant or non-mutant. DOR only applies to patients whose best overall response is CR or PR based on BIRC assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response of CR or PR to the date of first documented progression or death due to any cause. If a patient did not have an event, DOR was censored as defined in the statistical analysis plan. DOR was estimated using the Kaplan-Meier method.
Time frame: Baseline, up to approximately 189 weeks (median 33.6 weeks)
DOR Per RECIST v1.1 by Investigator Assessment for Patients by MET Mutation Status in ctDNA
At Cycle 1 Day 1 (C1D1, pre-dose), blood samples were collected to investigate the association between MET mutation status in baseline ctDNA and capmatinib efficacy. These blood samples were tested for METex14 skipping mutations and classified as mutant or non-mutant. DOR only applies to patients whose best overall response is CR or PR based on investigator assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response of CR or PR to the date of first documented progression or death due to any cause. If a patient did not have an event, DOR was censored as defined in the statistical analysis plan. DOR was estimated using the Kaplan-Meier method.
Time frame: Baseline, up to approximately 189 weeks (median 33.6 weeks)
PFS Per RECIST v1.1 by BIRC and Investigator Assessment for Patients by MET Mutation Status in ctDNA
At Cycle 1 Day 1 (C1D1, pre-dose), blood samples were collected to investigate the association between MET mutation status in baseline ctDNA and capmatinib efficacy. These blood samples were tested for METex14 skipping mutations and classified as mutant or non-mutant. PFS is defined as the time from the start date of study drug to the date of the first radiologically documented PD or death due to any cause. If a patient did not have an event, PFS was censored as defined in the statistical analysis plan. Tumor response was assessed by BIRC and by the investigator based on RECIST v1.1. PFS was estimated using the Kaplan-Meier method.
Time frame: Baseline, up to approximately 189 weeks (median 33.6 weeks)
Capmatinib Plasma Concentrations at Steady-state
Plasma capmatinib concentrations at steady state were quantified using a validated liquid chromatography tandem-mass spectrometry assay. Concentrations below the lower limit of quantification were treated as zero in the calculations. Pre-dose concentrations correspond to Ctrough, defined as the lowest plasma drug concentration observed immediately before the next dose.
Time frame: Cycle 2 Day 1 (C2D1): Pre-dose, 1 hour (±0.5 hours) and 4 hours (±1 hour). Cycle 3 Day 1 (C3D1): Pre-dose. Each cycle duration is 21 days.
Number of Participants With AEs and SAEs During the On-treatment Period
Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes in physical exams, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. The on-treatment period is defined from the day of first administration of study drug up to 30 days after the date of the last actual administration of study drug.
Time frame: Up to approximately 193 weeks (median 37.6 weeks)
Change From Baseline in EORTC QLQ-C30: Global Health Status/Quality of Life (QoL) Scale
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items and is composed of both multi-item scales and single-item measures. These include 1 global health status/quality of life (QoL) scale, 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All scales and single-item measures are scored from 0 to 100. This record summarizes the values of the global health status/QoL scale (0 to 100), where higher scores indicate better health/QoL. Therefore, a positive change from baseline is favorable.
Time frame: Baseline (before first dose), Cycle 3 Day 1 (Week 7) and then every 6 weeks until Cycle 65 Day 1 (Week 193). Each cycle duration is 21 days.
Change From Baseline in EORTC QLQ-LC13: Dyspnea Scale
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer Module 13 (EORTC QLQ-LC13) is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The 13 items of the LC13 include 1 multi-item scale (dyspnea) and 9 single items (coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, and pain in other parts). Each item uses a 4-point Likert scale (1=not at all, 4=very much). Scores for both the dyspnea scale and single items are transformed to a 0-100 scale. This record summarizes the values of the dyspnea scale (0 to 100), where higher scores indicate greater symptom burden. Therefore, a negative change from baseline is a favorable outcome.
Time frame: Baseline (before first dose), Cycle 3 Day 1 (Week 7) and then every 6 weeks until Cycle 65 Day 1 (Week 193). Each cycle duration is 21 days.
Change From Baseline in EQ-5D-5L: EQ VAS
The EuroQol 5-Dimension 5-Level (EQ-5D-5L) is a standardized, generic instrument to measure health-related quality of life (HRQoL). It consists of two components: a descriptive system and a visual analogue scale. The descriptive system includes five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each rated on five levels of severity (1=no problems, 5=extreme problems). The EuroQol visual analogue scale (EQ VAS) is a 0-100 scale for self-rated overall health, where 0 represents the worst imaginable health and 100 the best imaginable health. This record summarizes the values of the EQ VAS (0 to 100), where higher scores indicate better health. Therefore, a positive change from baseline is favorable.
Time frame: Baseline (before first dose), Cycle 3 Day 1 (Week 7) and then every 6 weeks until Cycle 65 Day 1 (Week 193). Each cycle duration is 21 days.
Change From Baseline in NCCN FACT-FBrSI: Total Composite Score
The National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy - Brain Symptom Index (NCCN FACT-FBrSI) was used to assess changes in symptoms potentially associated with brain metastases in this study. The NCCN FACT-FBrSI contains 24 items with a 7-day recall period and includes the following subscales: Disease-related symptoms - physical (12 items), Disease-related symptoms - emotional (5 items), Treatment side effects (5 items) and Function/well-being (2 items). Each item uses a 5-point Likert-type scale (0 = Not at all; 4 = Very much). Negatively worded items are reverse scored so that higher scores consistently indicate better symptom status and well-being. The total composite score is the sum of all 24 items and ranges from 0 to 96, with higher scores indicating better symptom status and well-being. An increase in the total composite score from baseline indicates a favorable outcome, while a decrease indicates an unfavorable outcome.
Time frame: Baseline (before first dose), Cycle 3 Day 1 (Week 7) and then every 6 weeks until Cycle 65 Day 1 (Week 193). Each cycle duration is 21 days.
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