The oral, highly selective MET inhibitor tepotinib demonstrated durable clinical activity in patients with locally advanced or metastatic non–small cell lung cancer who harbor a MET exon 14 skipping mutation identified through liquid or tissue biopsy.
Xiuning Le, MD, PhD
The oral, highly selective MET inhibitor tepotinib demonstrated durable clinical activity in patients with locally advanced or metastatic non—small cell lung cancer (NSCLC) who harbor a MET exon 14 (METex14) skipping mutation identified through liquid or tissue biopsy, according to findings from the phase 2 VISION trial (NCT02864992) that were simultaneously presented at the 2020 Virtual Scientific Meeting and published in the New England Journal of Medicine.1,2
At a minimum follow-up of 9 months, tepotinib led to an objective response rate (ORR) of 46.5% (95% CI, 36.4%-56.8%), as assessed by an independent review committee (IRC), and a median duration of response (DOR) of 11.1 months [95% CI, 7.2-not estimable (NE)]. The disease control rate (DCR) was 65.7% (95% CI, 55.4%-74.9%).
“The results are massively positive,” lead study author, Xiuning Le, MD, PhD, of The University of Texas MD Anderson Cancer Center, said in an interview with OncLive. “Tepotinib is a promising targeted therapy with durable clinical activity and manageable toxicity in patients with METex14 skipping NSCLC, including patients with brain metastases.”
METex14 skipping mutations occur in 3% to 4% of patients with NSCLC. The mutation generally occurs in older patients and is mutually exclusive with other frequently occurring genomic alterations in lung cancer.
In September 2019, the FDA granted a breakthrough therapy designation to tepotinib for the treatment of patients with metastatic NSCLC whose tumors harbor METex14 alterations and have progressed on prior platinum-based chemotherapy.3
The designation was based on data from the ongoing VISION trial, of which cohort A included patients with METex14 skipping mutations. Cohort B involves patients with MET amplification; cohort C is currently recruiting patients with METex14 skipping mutations for confirmatory analysis of the results in cohort A.2
To be eligible for enrollment in cohort A, patients had to have locally advanced or metastatic NSCLC harboring a METex14 skipping mutation identified through liquid or tissue biopsy and received no more than 2 prior lines of therapy. Patients with brain metastases were allowed to enroll on trial as long as they were asymptomatic.
Patients received 500 mg of oral tepotinib once daily in 21-day cycles until intolerable toxicity or disease progression.
The primary end point of the trial was ORR by IRC and was assessed across 3 cohorts: liquid biopsy— and/or tissue biopsy–assessed tumors (n = 99), liquid biopsy–assessed tumors (n = 66), and tissue biopsy–assessed tumors (n = 60). Key secondary end points included investigator-assessed ORR, DOR, progression-free survival (PFS), and safety.
As of January 2020, 152 patients received tepotinib, 99 of whom were evaluable for efficacy. At data cutoff, 60 patients in the safety population (n = 152) and 22 patients in the efficacy population (n = 99) were still receiving tepotinib.
Baseline characteristics showed that patients had a median age of 74 (range, 41-94), and that the majority were white (75%), male (54%), and had an ECOG performance status of 1 (77%). Approximately half of the population had a smoking history, and 43%, 34%, and 23% of patients had received 0, 1, or at least 2 prior lines of therapy for advanced or metastatic disease, respectively.
Responses were also shown to be comparable in the liquid- and tissue-biopsy cohorts. In the liquid biopsy cohort, the ORR by IRC was 48.5% (95% CI, 36.0%-61.1%) versus 50.0% (95% CI, 36.8%-63.2%) in the tissue-biopsy cohort.
According to investigator assessment in the combined liquid- and tissue- biopsy cohort, the ORR was 55.6% (95% CI, 45.2%-65.5%), and the median DOR was 14.0 months (95% CI, 9.7-18.3). The DCR was 72.7% (95% CI, 62.9%-81.2%).
The investigator-assessed ORR was 56.1% (95% CI, 43.3%-68.3%) in the liquid-biopsy cohort versus 61.7% (95% CI, 48.2-73.9%) in the tissue-biopsy cohort.
The median DOR in the liquid-biopsy cohort was 9.9 months (95% CI, 7.2-NE) and 14.0 months (95% CI, 7.3-NE) by IRC and investigator assessment, respectively. The DCR was 65.2% (95% CI, 52.4%-76.5%) by IRC and 69.7% (95% CI, 57.1%-80.4%) by investigator assessment.
The median DOR in the tissue-biopsy cohort was 15.7 months (95% CI, 9.7-NE) by IRC and 16.4 months (95% CI, 9.7-NE) by investigator assessment. The DCR was 68.3% (95% CI, 55%-79.7%) and 78.3% (95% CI, 65.8%-87.9%) by IRC and investigator assessment, respectively.
Tumor shrinkage was reported in 89% of patients, and similar responses were observed irrespective of the number of prior lines of therapy patients had received, said Le.
In the combined liquid- and tissue-biopsy cohort, the median PFS was 8.5 months (95% CI, 6.7-11.0) by IRC and 8.6 months (95% CI, 6.7-11.2) by investigator assessment. When broken down by testing method, patients who received liquid biopsy experienced a PFS of 8.5 months (95% CI, 5.1-11) versus 11.0 months with tissue biopsy (95% CI, 5.7-17.1).
The median overall survival (OS) in the combined liquid- and tissue-biopsy group was 17.1 months (95% CI, 12.0-26.8). In the liquid biopsy and tissue biopsy groups, the median OS was 15.8 months (95% CI, 9.5-NE) and 22.3 months (95% CI, 15.3-NE), respectively.
The outcomes in all 11 patients with baseline brain metastases were comparable to those of the overall population. The ORR by IRC was 54.5% (95% CI, 23.4%-83.3%), and the median DOR was 9.5 months (95% CI, 6.6-NE). The median PFS was 10.9 months (95% CI, 8.0-NE).
Tepotinib also showed a manageable safety profile consistent with the class effects of MET inhibitors, said Le. The most common treatment-related adverse events (TRAEs) included peripheral edema (all-grade, 63.2%; grade 3, 7.2%), nausea (all-grade, 25.7%; grade 3, 0.7%), diarrhea (all-grade, 21.7%; grade 3, 0.7%), blood creatinine increase (all-grade, 17.8%; grade 3, 0.7%), hypoalbuminemia (all-grade, 15.8%; grade 3, 2.0%), and amylase increase (all-grade, 11.2%; grade 3/4, 2.7%).
Grade 3 or higher TRAEs occurred in 27.6% of patients. TRAEs leading to dose reductions or discontinuations occurred in 32.9% and 11.2% of patients, respectively.
Pretreatment and on-treatment circulating tumor DNA (ctDNA) assessment served as an exploratory end point of the trial. ctDNA samples were analyzed with a 73-gene next-generation sequencing panel, and responses were defined as a deep (>75%) or complete (100%) reduction of METex14 mutant allele frequency in on-treatment assessment.
ctDNA molecular responses showed a high concordance with ORRs measured by RECIST criteria. Within the liquid biopsy cohort, 51 patients underwent pretreatment and on-treatment ctDNA assessment. Thirty-four patients (66.6%) had depletion of METex14 skipping mutations in ctDNA after achieving a complete molecular response to tepotinib.
“For targeted therapy to show this much definitive efficacy, we’re hopeful that we have enough evidence to convince the FDA to allow us to use tepotinib in patients with METex14 skipping mutations in the near future,” concluded Le.