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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 of efficacy and safety of capmatinib in combination with pembrolizumab versus pembrolizumab alone in subjects with non-small cell lung cancer with PD-L1>= 50%

76

A total of 51 subjects in the capmatinib plus pembrolizumab arm and 25 subjects in the pembrolizumab arm were randomized and treated. The demographic and baseline characteristics were well balanced between the treatment arms, except a higher number in the capmatinib plus pembrolizumab arm compared to the pembrolizumab arm of Asian subjects (43.1% vs 32.0%). The median age of subjects was 66.0 years with more male subjects (67.1%). Overall, 53.9% of subjects were White.

A total of 76 participants were randomized as in a ratio of 2:1 to the capmatinib plus pembrolizumab arm and the pembrolizumab arm.Ten subjects in the capmatinib plus pembrolizumab arm and 7 subjects in the pembrolizumab arm had completed study treatment. 41 subjects in the capmatinib plus pembrolizumab arm and 18 subjects in the pembrolizumab arm had discontinued study treatment. The main reason for discontinuation of study treatment were progressive disease (19 subjects), AE (10 subjects) and death (6 subjects) in the capmatinib plus pembrolizumab arm and progressive disease (9 subjects), death (4 subjects) , AE (2 subjects) and subject decision (2 subjects) in the pembrolizumab arm.

A total of 49 subjects (96.08%) in the capmatinib plus pembrolizumab arm and all 25 subjects in the pembrolizumab arm had at least one AE across all grades. The incidences of treatment-related AEs (88.2% vs 72%), SAEs (35.3% vs 4%), AEs leading to discontinuation (33.3% vs 8%) and AEs leading to dose reduction/interruption (47.1% vs 8%) were higher in the capmatinib plus pembrolizumab arm compared to the pembrolizumab arm. In the capmatinib plus pembrolizumab arm, with the exception of pyrexia in 4 subjects (7.8%), pericardial effusion, pneumonia, sepsis in 3 subjects each (5.9%) and bronchitis and acute kidney injury in 2 subjects each (3.9%), all other SAEs were reported in a subject each. Pneumonia, dyspnoea and chronic obstructive pulmonary disease were the only SAEs reported in more than 1 subject (2 subjects each; 8.0%) in the pembrolizumab arm.

Per primary analysis, the median PFS was 5.2 months in the capmatinib plus pembrolizumab arm and 5.1 months, in the pembrolizumab arm.

In the capmatinib plus pembrolizumab arm, ORR was 9.8% and DCR was 37.3%. In the pembrolizumab arm, ORR was 40% and DCR was 60.0%. Median OS and TTR were not reached for either arm. Following the administration of 400 mg BID capmatinib in combination with 200 mg Q3W pembrolizumab on cycle 2 day 1, the geometric mean (geo CV%) AUClast and Cmax of capmatinib were 4210 (232.8%) hr*ng/mL and 2730 (155.9%) ng/mL, respectively. Capmatinib concentrations reached peak around 1.33 hrs (median Tmax) on cycle 2 day 1. The prevalence of ADA-positive sample of pembrolizumab were similar in both treatment arms and was 14.3% (6 of 42 subjects) in the capmatinib plus pembrolizumab arm, 10.0% (2 of 20 subjects) in the pembrolizumab arm.

The Analysis for PFS was not performed and no statistical comparison was made between the 2 treatment arms due to insufficient number of participants with events. The combination treatment was associated with higher rates of SAEs and AEs leading to study treatment dose adjustments/interruptions and/or treatment discontinuation compared to pembrolizumab alone.The study enrollment was halted on 21-Jan-2021 per sponsor's decision based on lack of tolerability observed in the capmatinib plus pembrolizumab arm.

Yes

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 expert 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 is currently available according to the process described on www.clinicalstudydatarequest.com.

Yonemura Masataka

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

rinshoshiken.toroku2@novartis.com

Yonemura Masataka

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

+81-120-003-293

rinshoshiken.toroku2@novartis.com

completed

Jan. 22, 2020

Interventional

randomized, open label, multicenter phase II study

treatment purpose

2

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

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
Other protocol-defined inclusion/exclusion criteria may apply.

Both

Non small cell lung cancer (NSCLC)

investigational material(s)
Generic name etc :
INN of investigational material : Capmatinib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material :

control material(s)
Generic name etc :
INN of investigational material : Pembrolizumab
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material :

Progression-free survival (PFS) based on local investigator assessment as per RECIST 1.1

- Objective response rate (ORR), Disease control rate (DCR), Time-to-response (TTR), Duration of response (DOR) based on local investigator assessment as per RECIST 1.1
- Overall survival (OS)
- Incidence of adverse events is defined as number of participants with adverse events (AEs), serious adverse events (SAEs) and AEs leading to dose interruption, dose reduction and dose discontinuation.
- Pharmacokinetic parameters and concentration
- Antidrug antibodies (ADA)

Dec. 11, 2019