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%

Background
Non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer
diagnoses. About 30% of subjects have surgically resectable disease at
diagnosis. However 70% of NSCLC patients present with advanced disease. For
patients with locally advanced NSCLC, concurrent chemoradiation is the
recommended treatment. Patients with advanced/metastatic NSCLC without
targetable oncogenic drivers are usually treated with chemotherapy and
immunotherapy. Patients with targetable alterations are treated with targeted
treatments. The median overall survival of metastatic NSCLC patients treated
with platinum*based doublet chemotherapy as first-line chemotherapy is 11-14
months. Given the current limited survival of patients with NSCLC, even in
early stages of disease, new treatments options are needed.
Immunotherapy has shaped the treatment landscape of advanced NSCLC patients.
Monoclonal antibodies that block the interactions between PD-1 and immune
suppressing ligands, PD-L1 and PD-L2 (nivolumab, durvalumab, pembrolizumab, and
atezolizumab) have demonstrated significant activity as monotherapy and
superiority over single agent chemotherapy in pretreated NSCLC.
Pembrolizumab is approved as monotherapy for the first-line treatment of
locally advanced and metastatic NSCLC patients whose tumors have a PD-L1
expression * 50%.
Capmatinib is an orally active inhibitor of the MET receptor tyrosine kinase.
Capmatinib exhibits immunomodulatory activity 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 compared to the treatment of single agent
checkpoint inhibitor. This study will evaluate the efficacy and safety of
capmatinib combined with pembrolizumab in comparison to pembrolizumab 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.
In the current study we will test the effects of the combination of capmatinib
and pembrolizumab in comparison with pembrolizumab alone in patients with
locally advanced or metastatic NSCLC with a PD-L1 expression * 50%.

Primary:
To evaluate the efficacy of capmatinib plus pembrolizumab in comparison to
pembrolizumab alone. Secondary:
* To evaluate the anti-tumor activity of capmatinib plus pembrolizumab in
comparison to pembrolizumab alone.
* To characterize the safety profile of capmatinib plus pembrolizumab and
pembrolizumab alone.
* To characterize the pharmacokinetics of capmatinib and pembrolizumab.
* To evaluate the prevalence and incidence of immunogenicity of pembrolizumab.

Phase II, randomized, open-label study evaluating efficacy and safety of
pembrolizumab monotherapy or the combination of pembrolizumab and capmatinib.
Approximately 96 subjects will be randomized in a 2: 1 ratio to one of the
treatment arms (pembrolizumab alone or capmatinib in combination with
pembrolizumab).
Subjects will receive a maximum of 35 courses of 3 weeks duration. Early
treatment discontinuation in case of intolerable side effects or disease
progression.

Treatment with pembrolizumab alone or the combination of pembrolizumab and
capmatinib.

Risk: Adverse effects of study treatment.
Burden:
Max 37 visits until the end of treatment. Follow-up until progression every 12
weeks (if applicable). Follow-up for survival every 12 weeks.
Screening 4 weeks.
Treatment:
Capmatinib: tablets twice daily.
Pembrolizumab: I.V. infusion 500 mL every 3 weeks (max. 35 cycles)
Study procedures:
Physical examination: max. 37 times.
Blood tests: max. 37 times, approx. 5-40 mL per occasion.
Tumor biopsy: 0-1 at screening.
Pregnancy test (if relevant): max. 37 times.
ECG: once.
CT/MRI scan: at screening and every 9 weeks until week 45; every 12 weeks
thereafter.
Optional: tumor biopsy at the end of treatment; use of personal data and
biological samples.