From the Journals

First drug for MET+ NSCLC shows high response rates


The first targeted therapy for patients with advanced non–small cell lung cancer (NSCLC) harboring MET mutations, capmatinib (Tabrecta), has shown deep and durable responses, conclude investigators of the pivotal trial that led to the drug’s approval.

Responses were seen in all patients regardless of how many previous drugs they had been treated with, although responses were particularly pronounced among patients who were treatment naive.

Capmatinib and a companion assay received FDA approval in May 2020 for the treatment of adults with metastatic NSCLC harboring MET exon 14–skipping mutations.

These MET mutations occur in 3%-4% of NSCLC patients. MET amplifications occur in 1%-6% of NSCLC patients. They have been associated with poor response to chemotherapy and immunotherapy.

“Prior to this approval, there weren’t any approved therapies for this group of patients,” noted Edward Garon, MD, associate professor of hematology and oncology at the University of California, Los Angeles, who led the pivotal trial.

“There are several drugs that have been used off label for MET exon 14 skipping mutations, but none with an indication for it,” he said in an interview.

Garon emphasized that capmatinib was particularly robust for patients who had not received prior therapy, although he added that it was also very effective for those who had been previously treated.

“The drug has been approved and it is available, and we have already written prescriptions for it at our clinic,” said Dr. Garon, “although, at our clinic, the majority of patients using it were part of the [pivotal] clinical trial.”

That trial is the phase 2 GEOMETRY mono-1 study. Results from the study were presented at a meeting earlier this year and have now been published in the New England Journal of Medicine.

It was conducted in a cohort of 364 patients with advanced NSCLC. Patients were stratified into five cohorts and two expansion cohorts, which were assigned according to MET status and previous lines of therapy. Across cohorts 1 through 5, a total of 97 patients had a MET exon 14–skipping mutation, and 210 had MET amplification. All patients were treated with capmatinib 400 mg twice daily.

Among patients with a MET exon 14 skipping mutation, an overall response was observed in 41% of previously treated patients and in 68% of those who had not previously been treated.

“That is a very high response rate, and clearly this drug is targeting this mutation,” said Fred Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, Mount Sinai Health System, New York, who was approached for comment. “It’s very active, and you don’t get those responses with chemotherapy.”

The median duration of response was 9.7 months among previously treated patients and 12.6 months among those who were treatment naive. Median progression-free survival (PFS) was 5.4 months and 12.4 months, respectively.

In the cohort of patients with MET amplification, the overall response was 12% among those whose tumor tissue had a gene copy number of 6-9. The overall response rate was 9% among those with a gene copy number of 4 or 5, and it was 7% among those with a gene copy number of less than 4.

Median PFS was 2.7 months for patients whose tumor tissue had a gene copy number of 6-9 and in those with a gene copy number of 4 or 5. PFS rose to 3.6 months for patients with a gene copy number of less than 4.

The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%). These events were mostly of grade 1 or 2. Treatment-related serious adverse events occurred in 13% of patients. The incidence was lower in the groups with shorter duration of exposure. Treatment was discontinued in 11% of patients (consistent across cohorts) because of adverse events.

Dr. Hirsch commented that the results for patients with NSCLC and brain metastases were particularly noteworthy. “Brain metastases are, unfortunately, a common problem in patients with lung cancer,” he said. “Now, we have a drug that is effective for MET mutation and CNS involvement and can penetrate the blood-brain barrier, and this is a very encouraging situation.”

He pointed out that 7 of 13 patients with brain metastases responded to treatment with capmatinib. “Four patients have a complete response, and that is very encouraging,” said Dr. Hirsch. “This is clearly a deal-breaker in my opinion.”


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