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About half of patients with advanced non-small cell lung cancer (NSCLC) associated with a type of MET anomaly achieved durable responses with the MET inhibitor tepotinib, a multicenter open-label trial showed.

By independent review, the targeted therapy led to an overall response rate (ORR) of 46% in 99 evaluable patients, increasing to 56% when treating physicians assessed response. The responses had a median duration of 11 months. The response rate was consistent whether MET exon 14 skipping mutations were detected by liquid or tissue biopsy.

Grade ≥3 adverse events occurred in 28% of patients, and 11% of patients discontinued treatment because of adverse events, Paul Paik, MD, of Memorial Sloan Kettering Cancer Center in New York City, and coauthors reported in the (NEJM).

"Outcomes with currently available therapies are typically poor in patients with NSCLC with MET mutations associated with exon 14 skipping, who are generally older (median age 74 years) than patients who have more common and treatable molecular alterations," the authors noted. "In our trial, the patients' quality of life was maintained during receipt of tepotinib. Symptoms of dyspnea were stable, whereas cough symptoms were reduced."

"Results from this study have led to regulatory approval of tepotinib and its companion diagnostic assay for detection of MET alterations ... in March 2020 in Japan," they added. "These findings validate MET exon 14 skipping mutations as bona fide therapeutic targets and underscore the importance of routine testing for these MET alterations by means of liquid or tissue biopsy."

A showed response rates of 7% to 68% with the MET inhibitor capmatinib (Tabrecta) in a heterogeneous population of patients with NSCLC and MET exon 14 skipping or MET amplification, including previously treated and untreated patients.

Poor-Prognosis Disease

MET alterations, including exon 14 skipping, are primary oncogenic drivers in 3% to 4% of NSCLC, Paik and coauthors noted in their introduction. Several adenosine triphosphate (ATP)-competitive small-molecule inhibitors that target MET are being evaluated for NSCLC with MET exon 14 skipping. The drugs include nonselective type 1a inhibitors, such as crizotinib (Xalkori), and selective type 1b inhibitors, such as tepotinib, savolitinib, and capmatinib.

Paik and colleagues reported findings from a phase II trial of tepotinib in advanced/metastatic NSCLC and a confirmed MET exon 14 skipping mutation. The primary endpoint was ORR by independent review in patients followed for at least 9 months.

At data cutoff, investigators had treated 152 patients, 99 of whom had been followed for 9 months or more. The 99 patients had a median age of 74. About 45% had previously untreated disease, a third had received one prior regimen, and about a fourth had received two or more prior regimens.

MET exon 14 skipping was detected by liquid biopsy in 66 patients and by tissue biopsy in 60 patients (27 patients with positive results by both types of biopsy). The 46% ORR by independent review included patients who had either or both types of biopsy, although ORR did not differ by type of biopsy. The 56% ORR by investigator assessment did not differ by patients' treatment history. All but 11 of the 99 patients had some degree of tumor shrinkage.

In a subgroup of 51 patients with baseline and on-treatment liquid biopsies, 34 (67%) had molecular responses. The authors reported that 24 of the 34 (71%) had radiographic responses by independent review.

Capmatinib Results

As previously reported, the FDA granted accelerated approval to capmatinib for metastatic NSCLC associated with MET exon 14 skipping. The conditional approval was based on outcomes in 97 patients with MET exon skipping (69 previously treated). Juergen Wolf, MD, of University Hospital Cologne in Germany, and coauthors reported findings for 364 patients, which included the 97 in data submitted to the FDA.

In the 97 patients, capmatinib led to an ORR of 68% in the untreated subgroup and 41% in the patients who received one or two prior lines of therapy. Median duration of response was 9.7 months.

The MET inhibitor's activity in 210 patients with MET amplification varied by gene copy number. The ORR ranged between 7% and 12% among 101 patients with gene copy number less than 10. In the patients with gene copy number ≥10, capmatinib led to an ORR of 29% in 41 previously treated patients, increasing to 40% in 68 patients who had received no prior therapy for advanced/metastatic NSCLC.

The median duration of exposure to capmatinib ranged from 6.6 to 48.2 weeks across various subgroups. Across all 364 patients, the most common adverse events, irrespective of cause, were peripheral edema, nausea, and vomiting. Grade ≥3 adverse events, also irrespective of causality, occurred in 67% of the patients.

The most common treatment-related adverse events (≥10% of patients) were peripheral edema, nausea, vomiting, and increased blood creatinine level. Treatment-related serious adverse events occurred in 13% of patients, and 11% of patients discontinued treatment as a result of treatment-related events.

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