The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for capmatinib (Tabrecta) as a single agent in adult patients with advanced non-small cell lung cancer (NSCLC) who had a METex14 skipping mutation and required systemic therapy after prior immunotherapy or platinum-based chemotherapy.

Based on results from the phase 2 GEOMETRY mono-1 trial (NCT02414139), in which capmatinib had an overall response rate (ORR) of 51.6% (95% CI, 33.1%-69.8%)in a cohort of patients receiving second-line therapy (n=31); this included a partial response rate (PR) of 51.6% and a stable disease rate of 35.5%. 2 The median duration of response (DOR) was 8.4 months (95% CI, 4.2 – not evaluable), and the disease control rate (DCR) for this subset was 90.3% (95% CI, 74.2%-98.0%). Median progression-free survival (PFS) was 6.9 months (95% CI, 4.2-13.3).

Among all previously treated patients (n=100), capmatinib produced an ORR of 44.0% (95% CI, 34.1%-54.3%), with a PR rate of 44.0% and stable disease of 36.0% . The median DOR for capmatinib use in this population was 9.7 months (95% CI, 5.6-13.0), and the DCR was 82.0% (95% CI, 73.1%-89.0%). The median PFS in these patients was 5.5 months (95% CI, 4.2-8.1).

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The positive CHMP of capmatinib provides patients with a treatment option targeting their tumors," said Juergen Wolf, MD, of the Center for Integrative Oncology at the University Hospital Cologne, principal investigator of the GEOMETRY mono-1 trial, in a press release. "If approved by the European Commission, new targeted therapies such as capmatinib - supported by early and extensive molecular testing of patients' tumors, could better guide treatment decisions and ensure patients receive appropriate cancer care. "

Patients with stage IIIB/IV non-small cell lung cancer who were at least 18 years of age with METex14 were included in the study. Patients must have an ECOG performance status of 0 or 1 with at least 1 measurable lesion per RECIST V1.1. EGFR wild-type disease and ALK rearrangement criteria need to be negative. Of note, those patients with neurologically stable or asymptomatic brain metastases were allowed.

Study participants received twice-daily doses of capmatinib 400 mg and were divided into cohorts based on prior treatment route and MET status.

Cohort 4 included patients who had been preconditioned and received second- or third-line therapy (n=69); cohort 5b included untreated patients receiving capmatinib in the first-line (n=28); Patients who were pretreated with the drug in second-line therapy (n=31), and group 7 included patients who were not treated in first-line therapy (n=32).

The primary endpoint of the trial was ORR per blinded independent review committee (BIRC), the secondary endpoint was DOR per BIRC. Other secondary endpoints included DCR as assessed by BIRC and investigator, DOR and ORR as assessed by investigator, duration of response and PFS as assessed by BICR and investigator, overall survival, safety and pharmacokinetics.

At the data cutoff date of September 18, 2020, a total of 160 patients were included in the 4 cohorts; 60 patients received no treatment and 100 patients received preconditioning. In addition, 31.7% of untreated patients and 14.0% of pretreated patients remained on capmatinib. The most common reason for discontinuation was disease progression.

The median age of the 160 patients was 71 years (48-90 years). The majority of patients were female (60.6%), Caucasian (76.9%), with ECOG presentation ≥1 (75.0%), never smoker (60.6%), and adenocarcinoma (82.5%). In addition, 16.3% of patients had brain metastases.

Regarding safety, capmatinib has been found to have an acceptable toxicity profile and no new signals have been reported. Of the 373 patients included in all cohorts, 98.4% experienced any grade of toxicity.

Regardless of causality, the most common adverse reactions (AEs) included peripheral edema (54.2%), nausea (45.0%), vomiting (28.2%), increased serum creatinine (26.5%), dyspnea (23.3%), fatigue (22.3%) and decreased appetite (21.2%).

In addition, 86.9% of patients experienced treatment-related adverse events, the most common of which were peripheral edema (46.1%) and nausea (34.3%). Serious adverse events (SAEs) of any grade occurred in 50.9% of patients, of which 13.1% were expected to be related to capmatinib.

Adverse events leading to treatment discontinuation occurred in approximately 16% (16.1%) of patients. Four patients had fatal serious adverse events, including cardiac arrest (0.3%), hepatitis (0.3%), organizing pneumonitis (0.3%), and pneumonitis (0.3%).

Marie France Tschudin said: "Every 30 seconds someone dies from lung cancer. The need for more treatment options is critical. Through research and targeted therapies such as capmatinib, we are working to change this statistic and make a difference to the world. Making positive impact on the lives of cancer patients," added the president of Innovative Medicines International and chief commercial officer of Novartis in a press release. "Today's announcement represents an important step forward for people in EU countries whose previously treated advanced non-small cell lung cancer has resulted in a METex14 skipping mutation."

Reference

[1]https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.9020

[2]Wolf J, Garon EB, Groen HJ, et al. Capmatinib in MET exon 14-mutated, advanced NSCLC: updated results from the GEOMETRY mon-1 study. J Clin Oncol. 2021;39(suppl 15):9020. doi:10.1200/JCO.2021.39.15_suppl.9020