Safety and Efficacy of Capmatinib (INC280) Plus Pembrolizumab vs Pembrolizumab Alone in NSCLC With PD-L1≥ 50%

Phase 2TerminatedNCT04139317

Novartis Pharmaceuticals76 enrolled

Overview

The purpose was to evaluate the efficacy and safety of the combination of capmatinib with pembrolizumab compared to pembrolizumab alone as first-line treatment for subjects with locally advanced or metastatic NSCLC who have PD-L1 expression ≥ 50% and have no EGFR mutation or ALK rearrangement. Capmatinib has demonstrated immunomodulatory activities when combined with an anti-PD1 antibody in preclinical tumor models irrespective of MET dysregulation. The combination of capmatinib with checkpoint inhibitors has been established to be tolerable and could provide additional clinical benefit to the subjects.

This was a randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of capmatinib plus pembrolizumab in comparison to pembrolizumab alone as first line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) expression ≥ 50%, mesenchymal epithelial transition (MET) unselected, epidermal growth factor receptor (EGFR) wild type and anaplastic lymphoma kinase (ALK) negative. All eligible subjects were randomized to one of the treatment arms in a 2:1 (capmatinib plus pembrolizumab: pembrolizumab alone) ratio. Participants in both treatment arms were to receive up to 35 cycles (approximately 24 months) of study treatment. The study enrollment was halted on 21-Jan-2021 per sponsor's decision. The enrollment halt decision was based on lack of tolerability observed in the capmatinib plus pembrolizumab arm. Immediately following the enrollment halt, the below procedural changes were performed: * Capmatinib treatment was discontinued in subjects on the combination arm. All ongoing subjects were allowed to continue receiving pembrolizumab single agent treatment as per investigator's discretion until unacceptable toxicity, or disease progression, or up to 35 cycles of treatment, whichever occurred first. * Termination of capmatinib pharmacokinetics (PK) sample collection. * Termination of pembrolizumab PK/immunogenicity (IG) sample collection. After the enrollment halt, the study protocol was amended (amendment 03) and the collection of efficacy data was stopped. As pembrolizumab is a registered and commercialized treatment for the study indication, the efficacy and safety assessments were to be performed as per each institution's standard of care and no longer captured in the electronic Case Report Form (eCRF) (except reporting of adverse events). Additionally, as single-agent pembrolizumab is a well-established standard treatment for the study indication, the requirement for post-treatment disease progression follow-up and survival follow-up were removed.

Study Type

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically confirmed and documented locally advanced stage III (not candidates for surgical resection or definitive chemo-radiation) or stage IV (metastatic) NSCLC (per AJCC/IASLC v.8) for treatment in the first-line setting * Histologically or cytologically confirmed diagnosis of NSCLC that is both EGFR wild type status and ALK- negative rearrangement statu * Have an archival tumor sample or newly obtained tumor biopsy with high PD-L1 expression (TPS ≥ 50%) * ECOG performance status score ≤ 1 * Have at least 1 measurable lesion by RECIST 1.1 * Have adequate organ function Exclusion Criteria: * Prior treatment with a MET inhibitor or HGF-targeting therapy * Prior immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) * Have untreated symptomatic central nervous system (CNS) metastases * Clinically significant, uncontrolled heart diseases * Prior palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment

Locations (36)

Novartis Investigative Site

Wollongong, New South Wales, Australia

Novartis Investigative Site

North Adelaide, South Australia, Australia

Novartis Investigative Site

Shepparton, Victoria, Australia

Novartis Investigative Site

Yvoir, Belgium

Novartis Investigative Site

Québec, Quebec, Canada

Outcomes

Primary Outcomes

Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1

PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. Tumor response was based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment, the start of a subsequent anti-neoplastic therapy (if any) or the date of sponsor's decision to discontinue capmatinib (applicable only to subjects on the combination arm). Due to the discontinuation of one of the investigational drugs (capmatinib) in all subjects in the combination arm, PFS was censored on the 21-Jan-2021 or the last adequate tumor assessment prior to that date for the capmatinib plus pembrolizumab arm. PFS was analyzed using Kaplan-Meier estimates.

Time frame: Up to 1.3 years

Secondary Outcomes

Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1

Tumor response was based on local investigator assessment as RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR). For the capmatinib plus pembrolizumab arm, 21-Jan-2021 or any last adequate tumor assessment prior to that date was considered as the end of evaluation period for BOR. 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 1.3 years

Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1

Tumor response was based on local investigator assessment per RECIST v1.1. DCR is defined as the percentage of participants with a BOR of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). For the capmatinib plus pembrolizumab arm, 21-Jan-2021 or any last adequate tumor assessment prior to that date was considered as the end of evaluation period for BOR. 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; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).

Time frame: Up to 1.3 years

Time to Response (TTR) by Investigator Assessment as Per RECIST 1.1

TTR is defined as the time from the date of randomization to the first documented response of either complete response or partial response, which must be subsequently confirmed (although initial date of response is used, not date of confirmation). TTR was analyzed using the Kaplan-Meier method as defined in the statistical analysis plan.

Time frame: Up to 1.3 years

Duration of Response (DOR) by Investigator Assessment as Per RECIST 1.1

DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. DOR was analyzed using the Kaplan-Meier method as defined in the statistical analysis plan.

Time frame: Up to 1.3 years

Overall Survival (OS)

OS is defined as the time from the date of randomization to the date of death due to any cause. The requirement for survival follow-up period was removed following the discontinuation of one of the investigational drugs (capmatinib) in all subjects in the combination arm and the implementation of Protocol Amendment 03. OS was analyzed using the Kaplan-Meier method as defined in the statistical analysis plan.

Time frame: Up to 2.1 years

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.

Time frame: From first dose of study treatment to 30 days after last dose, up to 2.1 years

Maximum Observed Plasma Concentration (Cmax) of Capmatinib

Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

Time frame: pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.

Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib

PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.

Time frame: pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib

PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Time frame: pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.

Trough Serum Concentration (Ctrough) of Pembrolizumab

PK parameters were calculated based on pembrolizumab serum concentrations by using non-compartmental methods. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.

Time frame: pre-dose on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 6 Day 1 and Cycle 12 Day 1. The duration of one cycle was 21 days.

Number of Participants With Anti-pembrolizumab Antibodies

Immunogenicity (IG) was evaluated in serum samples. The assay to quantify and assess the IG was a validated homogeneous enzyme-linked immunosorbent assay (ELISA). * ADA-negative at baseline: ADA-negative sample at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples * ADA-positive post-baseline: patient with at least 1 ADA-positive sample post baseline

Time frame: Baseline (pre-dose), up to 8 months

Safety and Efficacy of Capmatinib (INC280) Plus Pembrolizumab vs Pembrolizumab Alone in NSCLC With PD-L1≥ 50%

Overview

Conditions

Interventions

Eligibility

Locations (36)

Outcomes

Primary Outcomes

Secondary Outcomes