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The FDA has granted a priority review designation to new drug application for tepotinib as a treatment for patient with metastatic non–small cell lung cancer whose tumors harbor a MET exon 14 skipping mutation identified via an FDA-approved test.
The FDA has granted a priority review designation to new drug application (NDA) for tepotinib as a treatment for patient with metastatic non–small cell lung cancer (NSCLC) whose tumors harbor a MET exon 14 (METex14) skipping mutation identified via an FDA-approved test.1
The NDA is based on data from the phase 2 VISION study (NCT02864992), which showed that the oral, highly selective MET inhibitor elicited an objective response rate (ORR) of 46.5% per independent review committee (IRC) assessment (95% CI, 36.4%-56.8%), a median duration of response (DOR) of 11.1 months (95% CI, 7.2–not estimable [NE]) and a disease control rate (DCR) of 65.7% (95% CI, 55.4%-74.9%).2
“METex14 skipping alterations drive a particularly aggressive form of NSCLC in a patient population that is generally elderly, facing poor clinical prognosis and in urgent need of new therapeutic options,” Luciano Rossetti, Global Head of Research & Development for the Biopharma business of Merck KGaA, stated in a press release. “With this acceptance and review under the Real-Time Oncology Review program, we look forward to working with the FDA and to making this precision medicine available to patients in the United States as soon as possible.”
The priority review designation follows a September 2019 decision by the FDA to grant tepotinib a breakthrough therapy designation for the treatment of patients with metastatic NSCLC harboring METex14 skipping alterations who progressed on platinum-based chemotherapy.
In the ongoing, single-arm, phase 2 study, patients with METex14 skipping mutations were enrolled to cohort A, those with MET amplification were enrolled to cohort B, and those with METex14 skipping mutations are currently being recruited to cohort C for a confirmatory analysis of the findings from cohort A.3
Patients were eligible for inclusion on cohort A if they had locally advanced or metastatic disease harboring a METex14 skipping mutation identified with a liquid or tissue biopsy and did not receive more than 2 previous lines of treatment. Notably, patients with brain metastases were permitted to enroll as long as they were not symptomatic.
In the trial, patients were given oral tepotinib at a once-daily dose of 500 mg given in 21-day treatment cycles until unacceptable toxicity or progressive disease.
The primary end point of the trial was ORR per IRC, and this was evaluated across 3 patient cohorts: liquid biopsy– and/or tissue biopsy–assessed tumors (n = 33), liquid biopsy–assessed tumors (n = 66), and tissue biopsy–assessed tumors (n = 60). Secondary end points of the trial were investigator-assessed ORR, DOR, progression-free survival (PFS), and safety.
A total of 152 patients received tepotinib as of January 2020 and 99 of these patients were determined to be efficacy evaluable. At the data cutoff, 60 of 152 patients in the safety population and 22 of the 99 in the efficacy population were still on study treatment.
Participants had a median age of 74 years, 75% were white, and 54% were male; the majority of patients, or 77%, had an ECOG performance status of 1. Additionally, half of the patients had a smoking history, and 43%, 34%, and 23% of patients received 0, 1, or at least 2 previous lines of treatment, respectively, for advanced or metastatic disease.
Data presented during the 2020 ASCO Virtual Scientific Meeting showed that responses to tepotinib were similar between the liquid- and tissue-biopsy cohorts. Specifically, the ORR per IRC was 48.5% in the liquid-biopsy cohort (95% CI, 36.0%-61.1%) versus 50.0% in the tissue-biopsy cohort (95% CI, 36.8%-63.2%). In the combined biopsy cohort, the ORR was highest, at 55.6% (95% CI, 45.2%-65.5%). The median DOR was 14.0 months (95% CI, 9.7-18.3), while the DCR was 72.7% (95% CI, 62.9%-81.2%).
Additionally, the ORRs per investigator assessment in the liquid-biopsy and the tissue-biopsy cohorts were 56.1% (95% CI, 43.3%-68.3%) and 61.7% (95% CI, 48.2%-73.9%), respectively.
In the liquid-biopsy cohort, the median DOR by IRC and investigator assessment was 9.9 months (95% CI, 7.2-NE) and 14.0 months (95% CI, 7.3-NE), respectively; the DCRs were 65.2% (95% CI, 52.4%-76.5%) and 69.7% (95% CI, 57.1%-80.4%), respectively.
In the tissue-biopsy cohort, the median DOR by IRC and investigator assessment was 15.7 months (95% CI, 9.7-NE) and 16.4 months (95% CI, 9.7-NE), respectively, and the DCRs were 68.3% (95% CI, 55.0%-79.7%) and 78.3% (95% CI, 65.8%-87.9%), respectively.
Notably, the majority of participants, or 89%, experienced tumor shrinkage following treatment with tepotinib. Moreover, similar responses were reported, regardless of the number of previous lines of treatment.
In the combined biopsy cohort, the median PFS with tepotinib was 8.5 months (95% CI, 6.7-11.0) per IRC and 8.6 months (95% CI, 6.7-11.2) per investigator assessment. The median PFS in those who just received liquid biopsy was 8.5 months (95% CI, 5.1-11.0) versus 11.0 months in those who just received tissue biopsy (95% CI, 5.7-17.1).
The median OS in the combined biopsy cohort was 17.1 months (95% CI, 12.0-26.8), while it was 15.8 months in the liquid-biopsy cohort (95% CI, 9.5-NE) and 22.3 months in the tissue-biopsy cohort (95% CI, 15.3-NE).
The outcomes of patients with brain metastases at baseline (n = 11) proved to be similar to that of the overall patient population. In this subgroup, the ORR per IRC was 54.5% (95% CI, 23.4%-83.3%), the median DOR was 9.5 months (95% CI, 6.6-NE), and the median PFS was 10.9 months (95% CI, 8.0-NE).
With regard to safety, tepotinib showed a profile that proved to be consistent with what is typically seen with MET inhibitors. The most commonly reported treatment-emergent toxicities included peripheral edema (all-grade, 63.2%; grade 3, 7.2%), nausea (25.7%; 0.7%), diarrhea (21.7%; 0.7%), increased blood creatinine (17.8%; 0.7%), hypoalbuminemia (15.8%; 2.0%), and increased amylase (11.2%; 2.7%).
Grade 3 or higher adverse effects were reported in 27.6% of patients; these AEs resulted in dose reductions in 32.9% of patients and discontinuation in 11.2% of patients.
In March 2020, tepotinib became the first MET inhibitor to receive regulatory approval by the Japanese Ministry of Health, Labour, and Welfare for use in patients with unresectable, advanced, or recurrent NSCLC harboring METex14 skipping alterations.