FDA Approves Capmatinib for METex14+ NSCLC

The FDA has granted an accelerated approval to capmatinib (Tabrecta) for patients with metastatic MET exon14 skipping (METex14)—mutated non—small cell lung cancer (NSCLC).¹

The approval is based on primary findings from the phase II GEOMETRY mono-1 study (NCT02414139), in which capmatinib showed a 67.9% objective response rate (ORR; 95% CI, 47.6%-84.1%) by independent review (IR) in treatment-naive patients with METex14-altered NSCLC.²

The FDA simultaneously approved the FoundationOne CDx assay (F1CDx) for use as a companion diagnostic for capmatinib to detect tumor mutations that lead to MET exon 14 skipping.

“Non—small cell lung cancer is a complex disease, with many different possible mutations that may encourage the cancer’s growth,” lead GEOMETRY investigator Juergen Wolf, MD, Center for Integrated Oncology, University Hospital Cologne, stated in a press release. “MET exon 14 skipping is a known oncogenic driver. With today’s decision by the FDA, we can now test for and treat this challenging form of lung cancer with a targeted therapy, offering new hope for patients with NSCLC harboring this type of mutation.

Capmatinib is a highly potent and selective MET inhibitor. The mutations are identified in approximately 3% to 4% of all patients with NSCLC, and these patients typically have a poor prognosis.

Capmatinib is being examined across several cohorts of the GEOMETRY trial; cohorts 4 and 5b were presented at the 2019 ASCO Annual Meeting. Cohort 4 comprised pretreated patients with METex14 alterations in the second- or third-line setting (n = 69), while cohort 5b included treatment-naive patients (n = 28).

The median age across both cohorts was 71 years, and approximately 75% of patients had an ECOG performance status of 1. In cohort 4, 15.9% of patients had brain metastases versus 10.7% in cohort 5b. The most common prior therapy used was platinum-based chemotherapy (88.4%).

In pretreated patients, the ORR by IR with capmatinib was 40.6% (95% CI, 28.9%-53.1%). Moreover, the disease control rate (DCR) was 78.3% (95% CI, 66.7%-87.3%). The ORR by IR was 67.9% (95% CI, 47.6%-84.1%) for treatment-naïve patients, and the DCR was 96.4% (95% CI, 81.7%-99.9%).

Results also showed that the median duration of response by IR was 9.72 months in pretreated patients and 11.14 months in those who received the agent upfront. The median progression-free survival was 5.42 months in the pretreated group and 9.69 months for those treated in the frontline setting.

Approximately half of the patients with brain metastases at baseline experienced an intracranial response with capmatinib (7 of 13; 54%). Of these patients, 4 had a complete resolution of brain lesions (31%), and the intracranial DCR was 92.3% (12 of 13).

Patients who had prior therapy with crizotinib (Xalkori) or any other cMET or HGF inhibitor, have EGFR or ALK abnormalities, clinically significant or uncontrolled heart disease, had prior therapy with agents that cannot be discontinued ≥1 week prior to the first capmatinib treatment and for the duration of the study, impairment of gastrointestinal function or gastrointestinal disease, may receive treatment with any enzyme-inducing anticonvulsant, and a presence or history of interstitial lung disease or interstitial pneumonitis were excluded from enrollment on the trial.

Safety, which was assessed across all cohorts examined in the study, also included patients with MET dysregulated NSCLC (N = 334). Grade 3 treatment-related adverse events (TRAEs) occurred in 31.1% of patients and a grade 4 adverse event (AE) was seen in 4.5% of patients. The most common grade 3/4 AEs were peripheral edema (7.5%) and fatigue (3.0%). The most common all-grade treatment-related AEs were peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%).

The FDA previously granted capmatinib a breakthrough therapy designation for use as a first-line treatment for patients with METex14—mutated NSCLC. The accelerated approval of capmatinib in this setting is contingent on the results of a confirmatory trial.

“Lung cancer is increasingly being divided into multiple subsets of molecularly defined populations with drugs being developed to target these specific groups,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “Tabrecta is the first approval specifically for the treatment of patients with non—small cell lung cancer whose tumors have mutations that lead to MET exon 14 skipping. This patient population now has an option for a targeted therapy, which they didn’t have prior to today.”

References

1. Novartis announces FDA approval of MET inhibitor Tabrecta™ for metastatic non-small cell lung cancer with METex14. Published May 6, 2020. https://bit.ly/2SIEmTc. Accessed May 6, 2020.
2. Wolf J, Setons T, Han J-Y, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019;37(suppl; abstr 9004). doi: 10.1200/JCO.2019.37.15_suppl.9004.