FDA Grants Priority Review to Capmatinib in METex14+ NSCLC

The FDA has granted a priority review designation to a new drug application (NDA) for capmatinib (INC280) for use as treatment for newly diagnosed and previously treated patients with locally advanced or metastatic MET exon14 skipping (METex14)—mutated non—small cell lung cancer (NSCLC).¹

The priority designation, which will expedite the review and development of capmatinib in this setting, 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.

Capmatinib is a highly potent and selective MET inhibitor. Currently, no targeted therapies are approved to treat patients with METex14-mutated NSCLC. The mutations are identified in approximately 3% to 4% of all patients with NSCLC, and these patients typically have a poor prognosis.

“We are extremely encouraged by the FDA’s Priority Review designation for capmatinib, a MET inhibitor that may be a major treatment advance for patients with this particularly aggressive form of lung cancer,” John Tsai, MD, head of Global Drug Development and Chief Medical Officer, Novartis, the developer of capmatinib, said in a statement.

“Results of the GEOMETRY mono-1 trial clearly identify METex14 as an oncogenic driver and we are inspired to bring capmatinib, potentially the first METex14 targeted therapy, to patients and to reimagine medicine and outcomes for people with lung cancer.”

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 non—small cell lung cancer.

References

1. Novartis announces MET inhibitor capmatinib (INC280), the first potential treatment for METex14 mutated advanced non-small cell lung cancer, granted priority FDA review. Published February 11, 2020. https://bit.ly/31L00cF. Accessed February 11, 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.