Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

Abstract

Background: 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). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.

Methods: In this open-label, phase 2 study, we administered tepotinib (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.

Results: 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.

Conclusions: 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. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Figure 1.

Response Rate and Change from Baseline in Tumor Burden. At the top of the graph, the objective response rate among the 99 patients in the efficacy population (combined-biopsy group) is shown, according to whether the MET exon 14 skipping mutation was detected by liquid biopsy or tissue biopsy; 27 patients had positive results according to both methods. The waterfall plot shows the change in the sum of the longest diameters of lesions from baseline to the best post-baseline assessment by independent reviewers. Data for 2 patients are not shown, since baseline or on-treatment measurements were not available. Four patients who had a decrease of more than 30% in the sum of target lesions on independent review were classified as having progressive disease as the best response because of the growth of new lesions. These 4 patients all had a partial response to therapy, according to investigator assessment. At the time of data cutoff, treatment was ongoing in 2 of the 4 patients (17.3 months and 11.8 months); another patient discontinued treatment after 16.2 months because of an adverse event, and 1 patient discontinued treatment for other reasons after 5.4 months and no additional imaging was performed. The gold and purple boxes show whether the MET exon 14 skipping mutation was detected by tissue biopsy or liquid biopsy, and the boxes below show the number of previous lines of therapy that each patient received. The best overall response as assessed by investigators is shown at the bottom of the figure.

Figure 2.

Progression-free Survival, According to Biopsy Group. Shown are Kaplan-Meier estimates of progression-free survival among patients who underwent liquid biopsy or tissue biopsy; 27 patients underwent both biopsy methods. The duration of progression-free survival was defined as the time from the first administration of tepotinib to the date of the first documentation of progressive disease or death from any cause within 84 days after the last tumor assessment, whichever occurred first. Of the 60 events in the combined group, 36 events were progressive disease and 24 events were death.

Figure 3.

Baseline Molecular Profiles and Response to Treatment in Patients with Biomarker Profiles Assessed in Liquid-Biopsy Samples. Shown are the results of molecular profiling of circulating free DNA (cfDNA) in liquid-biopsy samples obtained from 62 patients at baseline. Sequence variants and copy-number variations were assessed with the use of the Guardant360 assay, version 2.10. In ad hoc exploratory analysis, the objective response rate by independent review was 47% in patients with either wild-type or mutated TP53. There was a trend toward better progression-free survival in patients with wild-type TP53. SNV denotes single-nucleotide variant.

Figure 4.

Best Response to Treatment and Molecular Response in Patients with Matched Baseline and On-Treatment Liquid-Biopsy Samples. Matched baseline and on-treatment biomarker profiles from liquid-biopsy samples were available for 51 patients. Of these patients, 17 had a best molecular clearance of less than 75% of cfDNA. The clinical response as determined by independent review was a partial response in 2 patients, stable disease in 4 patients, and progressive disease in 6 patients; 5 patients could not be evaluated. Four patients had a molecular cfDNA response but were classified as having progressive disease by independent review. Of these patients, 2 had growth in new lesions: 1 had no other baseline alterations, and the other had a co-occurring NF1 mutation. The other 2 patients had new lesions at progression: 1 had co-occurring amplifications in EGFR and a GNAS mutation, and the other had a TP53 mutation. Shown at the bottom of the figure are the detected MET alterations at baseline and during treatment and the type of alteration that led to the MET exon 14 skipping. Numbers for MET exon 14 skipping represent the mutant allele frequencies, and numbers for MET amplification indicate plasma copy numbers. At the time of data cutoff, biomarker analyses from samples obtained at the time of disease progression were immature, with data available for only a few patients; however, one patient had a MET Y1230H mutation detected at the time of progress.