Clinical trial NCT04139317: Safety and Efficacy of Capmatinib (INC280) Plus Pembrolizumab vs Pembrolizumab Alone in NSCLC With PD-L1≥ 50%
Official title: 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%
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer (NSCLC)
Keywords: capmatinib
pembrolizumab
NSCLC
PD-L1
EGFR
ALK
MET,
squamous
non-squamous
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-10-25
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1
timeFrame: Up to 1.3 years
Secondary outcomes:
measure: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1
timeFrame: Up to 1.3 years
measure: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1
timeFrame: Up to 1.3 years
measure: Time to Response (TTR) by Investigator Assessment as Per RECIST 1.1
timeFrame: Up to 1.3 years
measure: Duration of Response (DOR) by Investigator Assessment as Per RECIST 1.1
timeFrame: Up to 1.3 years
measure: Overall Survival (OS)
timeFrame: Up to 2.1 years
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study treatment to 30 days after last dose, up to 2.1 years
measure: Maximum Observed Plasma Concentration (Cmax) of Capmatinib
timeFrame: 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.
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib
timeFrame: 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.
measure: Trough Serum Concentration (Ctrough) of Pembrolizumab
timeFrame: 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.
measure: Number of Participants With Anti-pembrolizumab Antibodies
timeFrame: Baseline (pre-dose), up to 8 months
Other outcomes:
Locations:
city: Wollongong
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: North Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Shepparton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Yvoir
country: Belgium
facility: Novartis Investigative Site
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Ostrava Vitkovice
country: Czechia
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Shatin New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Delhi
country: India
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Aviano
country: Italy
facility: Novartis Investigative Site
state: PN
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kuching
country: Malaysia
facility: Novartis Investigative Site
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Amersfoort
country: Netherlands
facility: Novartis Investigative Site
city: Breda
country: Netherlands
facility: Novartis Investigative Site
city: Zwolle
country: Netherlands
facility: Novartis Investigative Site
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Changhua
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
Study officials:
References: