First Treatment Specific to MET Mutations in Lung Cancer Receives FDA Approval: Capmatinib

On 6 May 2020, the US Food and Drug Administration (FDA) granted accelerated approval, in cases of stage 4 (spread to other parts of the body) non-small cell lung cancer (NSCLC) in adults, to the drug capmatinib (Tabrecta). Capmatinib is used in patients with MET (mesenchymal-epithelial transition) exon 14 skipping caused by genetic alterations in lung cancer, and is the first FDA-approved treatment for this group.

At the same time, the FDA approved the FoundationOne CDx test to determine eligibility for capmatinib by detecting the MET exon 14 skipping mutation. The test is called FoundationOne CDx (F1CDx).

Lung cancers are divided into 2 main groups: small cell and non-small cell. As shown below, non-small cell lung cancers are further divided into numerous subgroups with different genetic and biological characteristics. New targeted drugs are developed each year to target the genetic alterations that define these subgroups. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers.

Lung cancer is often diagnosed at an advanced stage, when the cancer has metastasized to other organs. Cancer metastasis develops through a series of successive genetic alterations, and MET exon 14 skipping is considered a critical event in cancer metastasis. MET exon 14 skipping is caused by mutations found in 3-4% of patients with lung cancer.

Tabrecta is a small-molecule drug in the "kinase inhibitor" class, taken orally as a pill. It works by blocking a key enzyme that helps stop tumor cell growth (see types of cancer drugs).

GEOMETRY mono-1: The Study That Led to FDA Approval of Capmatinib (Tabrecta)

• The efficacy of capmatinib in patients with metastatic NSCLC with a MET exon 14 skipping mutation was demonstrated in a multicenter, non-randomized, open-label study enrolling 97 patients. This clinical trial was called GEOMETRY mono-1.
• Patients received 400 mg of capmatinib twice daily until disease progression or unacceptable side effects.
• The main efficacy outcome measured in the study, as determined by a blinded independent review committee, was the overall response rate.
• Among 28 patients who had not received any previous treatment, the overall response rate was 68% (95% CI: 48, 84), and the duration of response was 12.6 months (95% CI: 5.5, 25.3).
• Among 69 previously treated patients, the overall response rate was 41% (95% CI: 29, 53), and the duration of response was 9.7 months (95% CI: 5.5, 13.0).

• The most common (affecting at least 20% of patients) side effects are peripheral edema, nausea, fatigue, vomiting, shortness of breath, and decreased appetite. Capmatinib may also cause interstitial lung disease, hepatotoxicity, photosensitivity, and embryo-fetal toxicity. Based on a clear positive signal for phototoxicity in early laboratory studies in cells, patients may be more sensitive to sunlight and are advised to take precautions to cover their skin, use sunscreen, and avoid tanning while taking capmatinib.
• The recommended capmatinib dose is 400 mg twice daily, with or without food.