Novartis Announces Pivotal GEOMETRY mono-1 Study Results of Tabrecta (Capmatinib) in METex14-Mutated Metastatic Non-Small Cell Lung Cancer Published in The New England Journal of Medicine

Compiled by Keke

On September 2, The New England Journal of Medicine (NEJM) published the positive results from GEOMETRY mono-1, a pivotal Phase 2 clinical study of Novartis’ Tabrecta (capmatinib, formerly known as INC280). The data demonstrated favorable overall response rate (ORR) and duration of response (DOR) for Tabrecta in adult patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping (METex14) mutations.

This is a multi-cohort Phase 2 clinical study evaluating the efficacy of capmatinib in patients with advanced non-small cell lung cancer (NSCLC) characterized by MET dysregulation, with a total enrollment of 364 patients. Patients were stratified based on prior lines of therapy and MET status (MET exon 14 skipping mutations or MET amplification determined by gene copy number in tumor tissue). Patients received capmatinib (400 mg tablets) twice daily. The primary endpoint was overall response (OR, including complete or partial response); the key secondary endpoint was duration of response (DOR).

The latest data released from these studies include efficacy confirmed by the Blinded Independent Radiology Committee (BIRC) in patients with METex14-mutated NSCLC (n=97) receiving capmatinib treatment:

• In patients who had not previously received treatment (n=28), the ORR was 68% (95% CI, 48-84);
• In patients who had previously received first- or second-line therapy (n=69), the ORR was 41% (95% CI, 29-53);
• In patients who had not previously received treatment (with 19 responders), the median DOR was 12.6 months (95% CI, 5.6–not estimable);
• In previously treated patients (28 responders), the median DOR was 9.7 months (95% CI, 5.6–13.0).

For patients who have previously received treatment and have MET amplification with a gene copy number of less than 10, the efficacy of capmatinib is limited, with an objective response rate (ORR) of 7%-12%.

For patients with MET amplification and a gene copy number of 10 or higher:

• In patients who had previously received treatment, the OR was 29% (95% CI, 19–41);
• In patients who had not previously received treatment, the OR was 40% (95% CI, 16–68).

Among the 14 patients with MET exon 14 skipping mutations enrolled in the trial, 13 had brain metastases at baseline (3 treatment-naïve and 10 previously treated). In a post hoc analysis, intracranial responses were observed in 7 patients, including 4 complete responses.

Furthermore, the most common treatment-related adverse events (incidence ≥20%) associated with capmatinib were peripheral edema (43%), nausea (34%), increased blood creatinine (18%), and vomiting (19%). Most adverse events were Grade 1 or Grade 2.

The results demonstrated that capmatinib exhibited significant antitumor activity in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations, particularly in treatment-naïve patients.In patients with advanced NSCLC and MET amplification, capmatinib demonstrates greater efficacy in tumors with high gene copy numbers than in those with low gene copy numbers.

Novartis believes that this study adds to the scientific consensus that METex14 is an oncogenic driver. Identifying the presence of METex14 is a viable strategic option for patients with metastatic lung cancer, and therefore, the study also underscores the importance of broad molecular testing in patients with NSCLC.

Among the 2 million newly diagnosed lung cancer patients worldwide each year, non-small cell lung cancer (NSCLC) accounts for approximately 85%. Nearly 70% of NSCLC patients harbor genomic mutations. MET is a receptor tyrosine kinase encoded by the MET gene and typically plays an important role in cell signaling, proliferation, and survival. Many cancers are associated with aberrant signaling in the MET receptor pathway, which can be caused by various mechanisms, including point mutations and insertions/deletions leading to exon 14 skipping. Until recently, effective targeting of MET faced certain obstacles, one of which was the identification of an optimal biomarker. MET exon 14 skipping (METex14) is a recognized oncogenic driver, found in approximately 3%–4% of patients with newly diagnosed advanced NSCLC. The emergence of drugs such as Tabrecta has established METex14 as a predictive biomarker for MET-targeted therapy.

Chemical Structural Formula of Capmatinib

The active pharmaceutical ingredient of Tabrecta is capmatinib, an oral, potent, and selective MET inhibitor that Novartis licensed from Incyte in 2009. In May this year, the drug was approved by the U.S. FDA as the first therapy for adult patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations.

Reference Sources:

1.Novartis announces NEJM publication of pivotal study of Tabrecta in patients with METex14 metastatic non-small cell lung cancer

2.Capmatinib in MET Exon 14–Mutated or MET-Amplified Non–Small-Cell Lung Cancer