This year, capmatinib, an orally bioavailable, potent and highly selective small-molecule MET inhibitor, was the first targeted therapy approved for METex14-positive metastatic NSCLC.^3,4Vansteenkiste JF et al. Expert Rev Anticancer Ther. 2019;19(8):659-671.
FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. Food and Drug Administration. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-capmatinib-metastatic-non-small-cell-lung-cancer (Accessed 8 October 2020). Results of the phase 2 GEOMETRY mono-1 study showed durable responses and the study results were recently published in the New England Journal of Medicine.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957.

GEOMETRY mono-1 was a prospective, international, open-label, multiple-cohort, phase 2 study evaluating the efficacy and safety of capmatinib in patients with advanced NSCLC with METex14 mutation or MET amplification.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Eligible patients were aged ≥18 with stage IIIB or IV NSCLC without an activating EGFR mutation or ALK fusion, and with at least one measurable lesion.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. MET status was determined by a central laboratory.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Patients were assigned to cohorts based on their MET gene copy number (GCN) status and previous lines of therapy, with five cohorts in total to assess efficacy, although two expansion cohorts were later added for supportive clinical evidence.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. The primary endpoint was overall response, as assessed by blinded independent review committee according to RECIST.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Key secondary endpoints included duration of response, investigator-assessed response and duration of response, disease control, progression-free survival (PFS), and the safety profile.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957.

A total of 364 advanced NSCLC patients were enrolled in this study, of which 97 having METex14 mutation, and 210 with MET amplification.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Patients in Cohorts 1 to 4 had been previously treated and received one or two lines of therapy, while patients in Cohorts in 5A and 5B were treatment-naïve.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. In patients with a METex14 mutation, the overall response rates measured 41% and 68% in previously treated and treatment-naïve patients, with a median duration of response of 9.7 months and 12.6 months, both respectively.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Response to capmatinib was rapid, with majority of patients having a tumour response at first tumour evaluation after treatment initiation.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. The median PFS was 5.4 months in previously treated patients and 12.4 months in treatment-naïve patients.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957.

Among patients with MET amplification, overall response was observed in 12% of patients with a GCN of 6-9, 9% of patients with a GCN 4/5, and 7% in those with GCN <4.[mfn referencenumber=5]Wolf J et al. N Engl J Med. 2020;383(10):944-957.[/mfn] These cohorts were closed for futility at the interim analysis.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. The median PFS was 2.7 months, 2.7 months, and 3.6 months in patients with GCN 6-9, GCN 4/5, and GCN <4, respectively.[mfn referencenumber=5]Wolf J et al. N Engl J Med. 2020;383(10):944-957.[/mfn] Median duration of response was 8.3 months in previously-treated patients and 7.5 months in treatment-naïve patients.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957.

The most reported adverse events (AEs) were peripheral oedema, nausea, and vomiting.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Grade ≥3 AEs were reported in 67% of patients.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Treatment-related serious AEs occurred in 13% of patients, with incidence being lower in cohorts with shorter exposure to capmatinib.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Discontinuation due to treatment-related AEs occurred in 11% of patients.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Death from causes other than advanced NSCLC occurred in 4% of patients, with causes including atrial fibrillation, hepatitis, pneumonia, respiratory distress, sepsis, sudden death, and cardiac arrest.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957. Only one death from pneumonitis was suspected to be related to capmatinib after investigator review.⁵Wolf J et al. N Engl J Med. 2020;383(10):944-957.