Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts

Yung-Jue Bang, Wu-Chou Su, Martin Schuler, Do-Hyun Nam, Wan Teck Lim, Todd M Bauer, Analia Azaro, Ronnie Tung Ping Poon, David Hong, Chia-Chi Lin, Mikhail Akimov, Samson Ghebremariam, Sylvia Zhao, Monica Giovannini, Brigette Ma, Yung-Jue Bang, Wu-Chou Su, Martin Schuler, Do-Hyun Nam, Wan Teck Lim, Todd M Bauer, Analia Azaro, Ronnie Tung Ping Poon, David Hong, Chia-Chi Lin, Mikhail Akimov, Samson Ghebremariam, Sylvia Zhao, Monica Giovannini, Brigette Ma

Abstract

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).

Keywords: MET amplification; MET dysregulation; capmatinib; phase 1; solid tumors.

Conflict of interest statement

Annual value of remuneration received:

  1. Mikhail Akimov from Novartis (employment).

  2. Samson Ghebremariam from Novartis (employment).

  3. Monica Giovannini (self) from Novartis (employment).

  4. Monica Giovannini (family member) from Bluebirdbio (employment).

Annual profit from shares received:

  1. Mikhail Akimov has Novartis Stock.

  2. Samson Ghebremariam has Novartis Stock.

  3. Monica Giovannini (self) has Novartis Stock.

  4. Monica Giovannini (family member) has Bluebirdbio Stock.

Total annual value of daily allowances/honoraria received:

  1. David Hong from AbbVie (research grants), Adaptimmune (research grants, and consulting or advisory role), Amgen (research grants), AstraZeneca (research grants), Bayer (research grants, and consulting or advisory role), BMS (research grants), Daiichi Sankyo (research grants), Eisai (research grants), Fate Therapeutics (research grants), Genentech (research grants, consulting or advisory role), Genmab (research grants), Ignyta (research grants), Infinity (research grants), Kite (research grants), Kyowa (research grants), Lilly (research grants), LOXO (research grants), Merck (research grants), MedImmune (research grants), Mirati (research grants), MiRNA (research grants), Molecular Templates (research grants), Mologen (research grants), NCI‐CTEP (research grants), Novartis (research grants), Pfizer (research grants, and consulting or advisory role), Seattle Genetics (research grants, and consulting or advisory role), Takeda (research grants, and consulting or advisory role), Alpha Insights (consulting or advisory role), Axiom (consulting or advisory role), Baxter (consulting or advisory role), GLG (consulting or advisory role), Group H (consulting or advisory role), Guidepoint Global (consulting or advisory role), Infinity (consulting or advisory role), Janssen (consulting or advisory role), Merrimack (consulting or advisory role), Medscape (consulting or advisory role), Numab (consulting or advisory role), and Trieza Therapeutics (consulting or advisory role).

Total annual value of manuscript fees received:

  1. Todd M. Bauer from Pfizer (paid to third part vendor for medical writing/editorial support).

Total annual value of research funds, endowments, endowed chairs, and researcher‐employment costs received:

  1. Yung‐Jue Bang (for clinical trials to the institution) from AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, BMS, GSK, Pfizer, Eli Lilly, Boehringer‐Ingelheim, MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, Daiichi Sankyo, Astellas, BeiGene, Green Cross, CKD Pharma, Genexine. Martin Schuler (research grants provided to academic institution from AstraZeneca, Bristol‐Myers Squibb, Novartis. Wan Teck Lim from Novartis (personal fees). Todd M. Bauer (to the institution) from Daiichi Sankyo, Medpacto (grants), Incyte (grants), Mirati Therapeutics (grants), MedImmune (grants), Abbvie (grants), AstraZeneca (grants), MabVax (grants), Stemline Therapeutics (grants), Merck (grants), Lilly (grants), GlaxoSmithKline (grants), Novartis (grants), Genentech (grants), Deciphera (grants), Merrimack (grants), Immunogen (grants), Millennium (grants), Phosplatin Therapeutics (grants), Calithera Biosciences (grants), Kolltan Pharmaceuticals (grants), Principia Biopharma (grants), Peloton (grants), Immunocore (grants), Roche (grants), Aileron Therapeutics (grants), Bristol‐Myers Squibb (grants), Amgen (grants), Onyx (grants), Sanofi (grants), Boehringer‐Ingelheim (grants), Astellas Pharma (grants), Five Prime Therapeutics (grants), Jacobio (grants), Top Alliance BioScience (grants), Janssen (grants), Clovis Oncology (grants), Takeda (grants), Karyopharm Therapeutics (grants), Foundation Medicine (grants), ARMO Biosciences (grants), Leap Therapeutics (grants and other), Ignyta (grants, non‐financial support and other), Moderna Therapeutics (grants, non‐financial support and other), Pfizer (grants, personal fees and other), Loxo (grants, personal fees and non‐financial support), Bayer (grants, personal fees and non‐financial support), Guardant Health (personal fees and non‐financial support from) outside the submitted work. David Hong from Molecular Match (Advisor), OncoResponse (founder), and Presagia Inc. (Advisor). Brigette Ma from Novartis (personal fees [advisory role] and research grant), BI (personal fees [advisory role]), BMS (personal fees [advisory role]), and MSD (personal fees [advisory role]), and Roche (personal fees [speaker]).

Other annual remuneration received:

  1. David Hong from LOXO, MiRNA, ASCO, AACR, SITC, and Genmab.

  2. Mikhail Akimov from Novartis.

  3. Samson Ghebremariam from Novartis.

  4. Monica Giovannini (self) from Novartis (employment).

  5. Monica Giovannini (family member) from Bluebirdbio (employment).

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1
Figure 1
Best percentage change from baseline in sum of tumor diameters according to investigator assessment in dose‐expansion cohorts (N = 18)*. *Patients with measurable baseline disease and at least one valid postbaseline (BIRC) assessment (best percentage change from baseline 0 [n = 11]). BIRC, blinded independent review committee; GCN, gene copy number; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; unk, unknown.

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