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A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor
Ibiayi Dagogo-Jack1, Philicia Moonsamy2, Justin F Gainor1
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Introduction:
Capmatinib is approved for MET exon 14-altered NSCLC on the basis of activity in targeted therapy-naive patients. We conducted a phase 2 study to assess the efficacy of capmatinib in patients previously treated with a MET inhibitor.
Methods:
Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping alterations received capmatinib 400 mg twice daily. The primary end point was the objective response rate. Secondary end points included progression-free survival, disease control rate (DCR), intracranial response rate, and overall survival. Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms.
Results:
A total of 20 patients were enrolled between May 2016 and November 2019, including 15 patients with MET skipping alterations and five patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range: 4-374). Two patients (10%) achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among five patients who discontinued crizotinib for intolerance, the DCR was 83%, including two patients with the best tumor shrinkage of -25% and -28%. Intracranial DCR among four patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median progression-free survival and overall survival were 5.5 (95% confidence interval: 1.3-11.0) and 11.3 (95% confidence interval: 5.5-not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in postcrizotinib, precapmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib.
Conclusions:
Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially owing to overlapping resistance mechanisms.
Insights
Capmatinib showed modest efficacy in patients with MET-altered non-small cell lung cancer (NSCLC) previously treated with MET inhibitors like crizotinib. Resistance mechanisms may overlap, limiting further benefit in this pretreated population.
Area of Science:
- Oncology
- Medical Science
- Pharmacology
Background:
- Capmatinib is approved for MET exon 14-altered non-small cell lung cancer (NSCLC) in treatment-naive patients.
- Efficacy of capmatinib in patients previously treated with MET inhibitors is not well-established.
Purpose of the Study:
- To assess the efficacy of capmatinib in advanced NSCLC patients previously treated with a MET inhibitor.
- To identify potential resistance mechanisms to capmatinib after prior MET-directed therapy.
Main Methods:
- A phase 2 study enrolled 20 patients with MET-altered NSCLC previously treated with crizotinib.
- Patients received capmatinib 400 mg twice daily; primary endpoint was objective response rate (ORR).
- Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and overall survival (OS); circulating tumor DNA (ctDNA) was analyzed.
Main Results:
- The objective response rate (ORR) was 10% (2/20), with a disease control rate (DCR) of 80%.
- Median progression-free survival (PFS) was 5.5 months and median overall survival (OS) was 11.3 months.
- MET mutations and MAPK pathway alterations were detected in ctDNA, potentially indicating resistance mechanisms.
Conclusions:
- Capmatinib demonstrates modest activity in crizotinib-pretreated MET-altered NSCLC.
- Overlapping resistance mechanisms may contribute to the limited efficacy in this pretreated population.
