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

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 METpositive 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, C trough >EC 90 (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. | 537 BANG et Al. K E Y W O R D Scapmatinib, MET amplification, MET dysregulation, phase 1, solid tumors

Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

“…Interestingly, very-high MET mRNA expression closely correlated with MET gene amplification by NGS or FISH and was mutually exclusive with METΔex14. Therefore, it is not surprising that the phenotype of the patients with very-high MET mRNA agrees with the characteristics previously reported in patients with high MET amplification (defined as FISH gene copy number, GCN≥6 or ≥10) [16,17,39,40].…”

Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer

“…23 Tivantinib has been previously studied in NSCLC patients, and was discontinued due to futility in an interim analysis; 24 , n = 38) demonstrated clinical safety and determined the dose to be safe was 400 mg b.i.d. 31,32 Preliminary anti-tumor efficacy was reported in NCT01324479 and NCT02276027 in MET altered tumors. 33,34 Capmatinib efficacy in METex14 NSCLC was established in the GEOMETRY mono-1 trial (NCT02414139), a multicenter, non-randomized, open-label, multicohort, and phase II study enrolling 97 metastatic METex14 NSCLC patients.…”

Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a 2‐drug cocktail in patients with MET‐dysregulated advanced solid tumours: A phase I, multicentre, open‐label, single‐sequence drug–drug interaction study

“…11,12 Phase I and Phase II studies have shown a manageable safety and robust efficacy profile of capmatinib, both as monotherapy and in combination with other anticancer therapies, in patients with solid tumours. [13][14][15][16][17][18][19][20] The therapeutic dose of capmatinib is 400 mg twice daily. In clinical trials, patient populations are selected with limited or no comorbidities and concurrent medications are not permitted, follow-up period is much narrower, and the toxicities are detected earlier, so patient populations enrolled may not accurately represent the general oncology population.…”