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

A Randomized, Open Label, Multicenter Phase II Study Evaluating the Efficacy and Safety of Capmatinib (INC280) Plus Pembrolizumab Versus Pembrolizumab Alone as First Line Treatment for Locally Advanced or Metastatic Non-small Cell Lung Cancer With PD-L1≥ 50%

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.

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Drug: Capmatinib; Biological: Pembrolizumab

Detailed Description

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: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Wollongong, New South Wales, Australia, 2500
      • Novartis Investigative Site
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Novartis Investigative Site
  • Victoria
    • Shepparton, Victoria, Australia, 3630
      • Novartis Investigative Site
• Belgium
  • Yvoir, Belgium, 5530
    • Novartis Investigative Site
• Canada
  • Quebec, Canada, GIV 4G5
    • Novartis Investigative Site
• Czechia
  • Ostrava Vitkovice, Czechia, 703 84
    • Novartis Investigative Site
• France
  • Lille, France, 59000
    • Novartis Investigative Site
  • Strasbourg Cedex, France, 67091
    • Novartis Investigative Site
  • Toulouse, France, 31400
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 14165
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 11526
    • Novartis Investigative Site
  • Thessaloniki, Greece, 57001
    • Novartis Investigative Site
• Hong Kong
  • Shatin New Territories, Hong Kong
    • Novartis Investigative Site
• India
  • Delhi, India, 110 085
    • Novartis Investigative Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 401107
      • Novartis Investigative Site
  • West Bengal
    • Kolkata, West Bengal, India, 700160
      • Novartis Investigative Site
• Italy
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • PN
    • Aviano, PN, Italy, 33081
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 466 8560
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama-city, Kanagawa, Japan, 236 0051
      • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
• Netherlands
  • Amersfoort, Netherlands, 3813 TZ
    • Novartis Investigative Site
  • Breda, Netherlands, 4819 EV
    • Novartis Investigative Site
  • Zwolle, Netherlands, 8025 AB
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Catalunya
    • Badalona, Catalunya, Spain, 08916
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
• Taiwan
  • Changhua, Taiwan, 50006
    • Novartis Investigative Site
  • Taichung, Taiwan, 40705
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Capmatinib 400mg BID + pembrolizumab 200mg Q3W; Capmatinib (INC280) 400 mg orally twice daily (BID) in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W)	Drug: Capmatinib; INC280 tablets were administered orally at 400 mg on a continuous twice daily (BID) dosing schedule, from Day 1 until Day 21 of each 21-day cycle.; Other Names: INC280; Biological: Pembrolizumab; Pembrolizumab was administered by intravenous infusion at 200 mg once every 3 weeks (Q3W).; Other Names: MK-3475; Keytruda®
Active Comparator: Pembrolizumab 200mg Q3W; Pembrolizumab 200 mg intravenously every 3 weeks (Q3W)	Biological: Pembrolizumab; Pembrolizumab was administered by intravenous infusion at 200 mg once every 3 weeks (Q3W).; Other Names: MK-3475; Keytruda®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 1.3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	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.	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.	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.	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.	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.	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.	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.	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.	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	Baseline (pre-dose), up to 8 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2020
• Primary Completion (Actual): January 14, 2022
• Study Completion (Actual): February 7, 2023

Study Registration Dates

• First Submitted: October 14, 2019
• First Submitted That Met QC Criteria: October 23, 2019
• First Posted (Actual): October 25, 2019

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; EGFR; PD-L1; capmatinib; pembrolizumab; ALK; squamous; non-squamous; MET,
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: CINC280I12201; 2019-002660-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No