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Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY
Jürgen Wolf1, Maximilian Hochmair2, Ji-Youn Han3
1Department of Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
Background:
Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib.
Methods:
In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed.
Findings:
Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported.
Interpretation:
These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC.
Funding:
Novartis Pharmaceuticals.
Insights
Capmatinib demonstrated significant response rates in patients with non-small-cell lung cancer (NSCLC) harboring a MET exon 14-skipping mutation (METex14). These findings support capmatinib as an effective targeted therapy for both treatment-naive and previously treated NSCLC patients with METex14.
Area of Science:
- Oncology
- Medical Genetics
Background:
- Capmatinib has shown prior activity in non-small-cell lung cancer (NSCLC) with MET exon 14-skipping mutations (METex14).
- The GEOMETRY mono-1 study aimed to provide further evidence for capmatinib's efficacy.
Purpose of the Study:
- To report final outcomes from the phase 2 GEOMETRY mono-1 study of capmatinib in patients with METex14 NSCLC.
- To evaluate the long-term efficacy and safety of capmatinib in advanced NSCLC.
Main Methods:
- A non-randomized, multi-cohort, open-label, phase 2 trial involving patients with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC.
- Patients received capmatinib 400 mg orally twice daily; outcomes were assessed by blinded independent central review.
- Final clinical outcomes from METex14 cohorts and safety from all cohorts were reported.
Main Results:
- Overall response rates were 68% in 60 treatment-naive patients and 44% in 100 previously treated patients with METex14 NSCLC.
- Median follow-up was 46.4 months for treatment-naive and 66.9 months for previously treated patients.
- Most common adverse events included peripheral edema (47%) and nausea (35%); 44% experienced Grade 3-4 serious adverse events.
Conclusions:
- Long-term results confirm METex14 as a targetable oncogenic driver in NSCLC.
- Capmatinib is a viable targeted treatment option for both treatment-naive and previously treated patients with METex14 NSCLC.
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