On May 6, 2020, the oral mesenchymal-epithelial transition (MET) kinase inhibitor capmatinib was granted accelerated approval for the treatment of adult patients who have metastatic non–small cell lung cancer (NSCLC) with tumors that have a mutation that leads to MET exon 14 skipping, as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2 The FDA simultaneously approved the FoundationOne CDx assay as a companion diagnostic for capmatinib.

Supporting Efficacy Data

Approval was supported by findings in the phase II multicenter multicohort GEOMETRY mono-1 trial (ClinicalTrials.gov identifier NCT02414139).^2,3 In the trial, a cohort of 97 patients with metastatic NSCLC with confirmed MET exon 14 skipping received oral capmatinib at 400 mg twice daily until disease progression or unacceptable toxicity. Patients had to have EGFR wild-type and ALK-negative status. Those with symptomatic central nervous system (CNS) metastases, clinically significant uncontrolled cardiac disease, or prior treatment with any MET or hepatocyte growth factor inhibitor were not eligible for the study. The primary efficacy outcome measure was overall response rate on blinded independent review committee assessment, using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Among the 97 patients, 28 were treatment-naive, and 69 had received prior therapy (platinum-based chemotherapy in 88%). Median age was 71 years (range = 49–90 years). Overall, 60% were female, 75% were white, and Eastern Cooperative Oncology Group performance status was 0 in 24% and 1 in 75%. Further, 60% were never smokers, 80% had adenocarcinoma, and 12% had CNS metastases.

Among the 28 treatment-naive patients, the overall response rate was 68% (95% confidence interval [CI] = 48%-–84%), with a complete response in 4%, and the median response duration was 12.6 months (95% CI = 5.5–25.3 months). Among the 69 previously treated patients, the overall response rate (all partial responses) was 41% (95% CI = 29%–53%), and the median response duration was 9.7 months (95% CI = 5.5–13.0 months).

How It Works

Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation, leading to increased downstream MET signaling.

Capmatinib inhibited cancer cell growth driven by a mutant MET variant lacking exon 14 at clinically achievable concentrations. The agent also demonstrated antitumor activity in murine tumor xenograft models derived from human lung tumors with either a mutation leading to MET exon 14 skipping or MET amplification. Capmatinib blocked the phosphorylation of MET induced by binding of hepatocyte growth factor or by MET amplification. It further inhibited MET-mediated phosphorylation of downstream signaling proteins and proliferation and survival of MET-dependent cancer cells.

How It Is Used

Patients must be selected for treatment with capmatinib based on the presence of a mutation that leads to MET exon 14 skipping in tumor specimens, as detected by an FDA-approved test.

The recommended dosage of capmatinib is 400 mg orally twice daily. Recommended dose reductions for adverse reactions are sequentially to 300 mg twice daily and to 200 mg twice daily. Treatment should be permanently discontinued in patients who cannot tolerate 200 mg twice daily.

Prescribing information provides instructions on dosage modification for interstitial lung disease/pneumonitis; increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) without increased total bilirubin; increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis; increased total bilirubin without concurrent increased ALT and/or AST; and other grade 2, 3, and 4 adverse reactions. Treatment should be permanently discontinued for interstitial lung disease/pneumonitis of any grade.

Concomitant use of capmatinib with strong or moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided. These agents reduce exposure to capmatinib, which may reduce antitumor activity.

Safety Profile

Safety data for capmatinib are derived from 334 patients in cohorts in the GEOMETRY mono-1 trial, who received 400 mg twice daily until disease progression or unacceptable toxicity. Among these patients, 31% received treatment for at least 6 months and 16% for at least 12 months.

The most common adverse events of any grade (≥ 20% of patients) were peripheral edema (52%), nausea (44%), fatigue (32%), vomiting (28%), dyspnea (24%), and decreased appetite (21%). The most common grade 3 or 4 adverse events included peripheral edema (9%), fatigue (8%), dyspnea (7%), and nausea (3%). The most common grade 3 or 4 laboratory abnormalities were increased AST (5%), decreased phosphate levels (5%), and increased amylase (4%).

Serious adverse events occurred in 51% of patients, with those occurring in at least 2% of patients including dyspnea (7%), pneumonia (5%), pleural effusion (4%), general physical health deterioration (3%), vomiting (2%), and nausea (2%). Adverse events led to dose interruptions in 54% of patients (due to peripheral edema, increased blood creatinine, nausea, vomiting, increased lipase, increased ALT, dyspnea, increased amylase, increased AST, increased blood bilirubin, fatigue, and pneumonia in > 2% each) and to dose reductions in 23% (attributable to peripheral edema, increased ALT, increased blood creatinine, and nausea in > 2% each). Adverse events led to treatment discontinuation in 16% of patients, with the most frequent causes being peripheral edema (1.8%), pneumonitis (1.8%), and fatigue (1.5%). One patient died of an adverse event (pneumonitis).

Capmatinib has warnings/precautions for interstitial lung disease/pneumonitis, hepatotoxicity, risk of photosensitivity, and embryofetal toxicity. Patients should be monitored for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis. Treatment should be permanently discontinued in patients with interstitial lung disease/pneumonitis. Liver function tests should be monitored. Patients should be advised to limit direct ultraviolet exposure. Patients should be advised not to breastfeed while taking capmatinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-capmatinib-metastatic-non-small-cell-lung-cancer. Accessed May 11, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Tabrecta (capmatinib) tablets. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213591s000lbl.pdf. Accessed May 11, 2020.

3. Wolf J, Seto T, Han JY, et al: Capmatinib (INC280) in MET ex14-mutated advanced non-small cell lung cancer: Efficacy data from the phase II GEOMETRY mono-1 study. 2019 ASCO Annual Meeting. Abstract 9004. Presented June 3, 2019.