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Non–small-cell lung cancer with MET exon 14 skipping mutations: efficacy of Tepotinib

A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non–small-cell lung cancer ( NSCLC ).
Researchers have evaluated the efficacy and safety of Tepotinib ( Tepmetko ), a highly selective MET inhibitor, in this patient population.

In this open-label, phase 2 study, Tepotinib was administered ( at a dose of 500 mg ) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation.

The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up.
The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.

As of January 1, 2020, a total of 152 patients had received Tepotinib, and 99 patients had been followed for at least 9 months.

The response rate by independent review was 46% ( 95% confidence interval [ CI ], 36 to 57 ), with a median duration of response of 11.1 months ( 95% CI, 7.2 to could not be estimated ) in the combined-biopsy group.

The response rate was 48% ( 95% CI, 36 to 61 ) among 66 patients in the liquid-biopsy group and 50% ( 95% CI, 37 to 63 ) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods.

The investigator-assessed response rate was 56% ( 95% CI, 45 to 66 ) and was similar regardless of the previous therapy received for advanced or metastatic disease.

Adverse events of grade 3 or higher that were considered by investigators to be related to Tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%.
Adverse events led to permanent discontinuation of Tepotinib in 11% of the patients.

A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.

In conclusion, among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of Tepotinib was associated with a partial response in approximately half the patients.
Peripheral edema was the main toxic effect of grade 3 or higher. ( Xagena )

Paik PK et al, N Engl J Med 2020; 383: 931-943