SUMMARY: The FDA on August 10, 2022, granted regular approval to TABRECTA® (Capmatinib), for adult patients with metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have a mutation leading to Mesenchymal-Epithelial Transition (MET) exon 14 skipping, as detected by an FDA-approved test. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
MET is a widely expressed Receptor Tyrosine Kinase and plays a pivotal role in cell growth, proliferation, and survival. The MET gene encodes for a protein known as the Hepatocyte Growth Factor (HGF) Receptor. Upon binding by Hepatocyte Growth Factor (HGF), the HGF Receptor is activated, with resulting activation of the downstream RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby serving different important biological functions. Alterations in the MET gene leading to abnormal MET signaling, has been identified in different types of cancers including thyroid, lung, breast, liver, colon, kidney, ovary, and gastric carcinoma.
Two key MET alterations include MET exon 14 skipping mutations and MET amplification. MET exon 14 skipping mutations occur in approximately 5% of NSCLC patients with enrichment in sarcomatoid lung cancers (22%). MET exon 14 skipping mutation is a recognized oncogenic driver and is a molecular genetic abnormality indicating the presence of a splice site mutation that results in a loss of transcription of exon 14 of the MET gene. Most exon 14 mutations occur in never-smokers and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping generally have very high response rates to MET inhibitors and molecular testing for MET exon 14 skipping should therefore be performed on all lung cancers, because this is a targetable alteration. MET amplification has been more commonly seen in smokers, and responses in patients with MET-amplified tumors might be more variable and dependent on level of amplification, with higher responses noted in tumors with more than 5-6- fold amplification. Tumors with MET exon 14 skipping mutations usually do not harbor activating mutations in EGFR, KRAS, or BRAF or concurrent ALK, ROS1 or RET translocations. However, it appears that cMET exon 14 skipping is not mutually exclusive with cMET amplification.
TABRECTA® is a highly potent and selective, reversible inhibitor of MET tyrosine kinase. The FDA in May 2020 granted accelerated approval for the same indication based on the primary findings from the GEOMETRY mono-1 trial, which is a non-randomized, open-label, multi-cohort, Phase II study, conducted to evaluate the efficacy and safety of single-agent TABRECTA® in adult patients with EGFR wild-type, ALK-negative, metastatic NSCLC, whose tumors have a mutation that leads to MET exon 14 skipping (METex14), as detected by an RNA-based RT-PCR. The conversion to regular approval was based on data from an additional 63 patients (Total N=160), as well as an additional 22 months of follow- up time, to assess durability of response and verify clinical benefit.
In this updated analysis, a total of 160 patients (N=160) with metastatic NSCLC and confirmed MET exon 14 skipping mutations were included, of whom 60 patients were treatment naïve and 100 patients were previously treated. The patients received TABRECTA® at 400 mg orally twice daily until disease progression or unacceptable toxicity. The median patient age was 71 years and all NSCLC histologies including sarcomatoid/carcinosarcoma were included. Majority of the patients (77%) were white and 23% were Asian, 61% never smoked, 83% had adenocarcinoma, and 16% had CNS metastases. Among previously treated patients, 81% received one, 16% received two, and 3% received three prior lines of systemic therapy. Amongst previously treated patients, 86% received prior platinum-based chemotherapy. The Primary efficacy outcome was Overall Response Rate (ORR), and additional efficacy outcomes included Duration of Response, Time to Response, Disease Control Rate, Progression Free Survival (PFS) and Safety, as determined by a Blinded Independent Review Committee (BIRC).
Among the treatment-naïve patients (N=60), the ORR was 68% with a median Duration of Response of 12.6 months. Among the previously treated patients (N=100), the ORR was 44%, with a median Duration of Response of 9.7 months. The most common adverse events (occurring in at least 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. TABRECTA® can also cause Interstitial Lung Disease, hepatotoxicity and photosensitivity.
It was concluded that TABRECTA® is a new treatment option for patients with MET exon 14 skipping- mutated advanced NSCLC, regardless of the line of therapy, with deep and durable responses, and with manageable toxicity profile.
Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study. Wolf J, Garon EB, Groen HJM, et al. DOI: 10.1200/JCO.2021.39.15_suppl.9020 Journal of Clinical Oncology – published online before print May 28, 2021.
