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Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer
Jürgen Wolf1, Takashi Seto1, Ji-Youn Han1
1From the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne and University of Cologne, Cologne (J.W.), Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.), the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (T.R.O.), and Hämato-Onkologie Hamburg, Hamburg (E.L.) - all in Germany; the National Hospital Organization Kyushu Cancer Center, Fukuoka (T.S.), Aichi Cancer Center, Nagoya (T.H.), the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.), the Department of Respiratory Medicine, Okayama University Hospital, Okayama (K.O.), and the National Kyushu Cancer Center, Fukuoka (R.T.) - all in Japan; the National Cancer Center, Gyeonggi-do (J.-Y.H.), and the Department of Internal Medicine, Seoul National University Hospital, Seoul (T.-M.K.) - both in South Korea; the Hospital Clinic of Barcelona (N.R.), Translational Genomic and Targeted Therapeutics in Solid Tumors (IDIBAPS) (N.R.), and Vall d'Hebron University Hospital-Vall d'Hebron Institute of Oncology (E.F.), Barcelona; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); the University of Groningen and University Medical Center Groningen, Groningen (H.J.M.G.), Erasmus MC Cancer Institute, Rotterdam (M.J.), and the Netherlands Cancer Institute, Amsterdam (E.F.S.) - all in the Netherlands; the National Cancer Centre Singapore, Singapore (D.S.W.T.); St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (S.V.O.); University Hospital of Lyon-Sud, Lyon (P.-J.S.), and Novartis Pharma, Rueil-Malmaison (S.L.M.) - both in France; the Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium (J.V.); the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); Novartis Pharmaceuticals, East Hanover, NJ (A.R., M.G.); Novartis Pharma, Basel, Switzerland (M.W.-L., M.A.); and Novartis Institutes for BioMedical Research, Cambridge (B.S., O.A.B., X.C.), and Massachusetts General Hospital, Boston (R.S.H.) - both in Massachusetts.
Background:
Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.
Methods:
We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.
Results:
A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.
Conclusions:
Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
Insights
Capmatinib demonstrated significant antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations, especially in treatment-naïve individuals. Efficacy in MET-amplified NSCLC varied by gene copy number, with higher responses in those with gene copy number ≥10.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- MET exon 14 skipping mutations and MET amplifications occur in 3-4% and 1-6% of non-small-cell lung cancer (NSCLC) patients, respectively.
- Capmatinib is a selective MET receptor inhibitor with demonstrated activity in preclinical models of MET-activated cancers.
Purpose of the Study:
- To evaluate the efficacy and safety of capmatinib in patients with advanced NSCLC and MET dysregulation (MET exon 14 skipping mutation or MET amplification).
Main Methods:
- A phase 2, multiple-cohort study enrolled 364 patients with advanced NSCLC stratified by prior therapy and MET status.
- Patients received capmatinib 400 mg twice daily, with overall response and response duration assessed by an independent review committee.
Main Results:
- In patients with MET exon 14 skipping mutations, overall response rates were 41% (previously treated) and 68% (treatment-naïve).
- Median response duration was 9.7 months and 12.6 months, respectively.
- For MET-amplified NSCLC, response rates were higher in patients with gene copy number ≥10 (40% treatment-naïve, 29% previously treated) compared to <10 (7-12%).
- Peripheral edema (51%) and nausea (45%) were the most common adverse events, mostly grade 1 or 2.
Conclusions:
- Capmatinib exhibits substantial antitumor activity in advanced NSCLC with MET exon 14 skipping mutations, particularly in treatment-naïve patients.
- Efficacy in MET-amplified NSCLC is associated with higher gene copy numbers.
- Capmatinib is generally well-tolerated, with peripheral edema and nausea as primary toxicities.
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