Robust Efficacy Achieved With Tepotinib in METex14-Altered NSCLC

Tepotinib achieved robust efficacy in patients with non–small cell lung cancer harboring MET exon 14 skipping alterations, according to a primary analysis of cohort C of the phase 2 VISION trial.

Tepotinib (Tepmetko) acieved robust efficacy in patients with non–small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations, according to independently confirmed in data from the primary analysis of cohort C of the phase 2 VISION trial (NCT02864992), with particularly durable activity noted in those who were treatment naïve.1

The findings, which were presented during 2022 World Conference on Lung Cancer, showed that with longer than 9 months of follow-up, tepotinib (n = 161) elicited an objective response rate (ORR) of 54.7% (95% CI, 46.6%-62.5%) per independent review committee (IRC) assessment and by RECIST v1.1 criteria.

Among treatment-naïve patients who were enrolled by tissue biopsy (n = 69), the ORR achieved with tepotinib was even higher, at 62.3% (95% CI, 49.8%-73.7%). In previously treated patients (n = 51), tepotinib induced an ORR of 51.0% (95% CI, 36.6%-65.2%).

“In VISION—the largest clinical trial of a MET TKI in METex14-skipping NSCLC—the cohort C primary analysis provided independent confirmation for robust and durable efficacy of tepotinib, with comparable or improved outcomes across end points compared with cohort A,” Michael Thomas, MD, of the University of Heidelberg, Translational Lung Research Center Heidelberg, and The German Center for Lung Research, in Heidelberg, Germany, said in a presentation of the data. “Safety data confirmed previous observations that tepotinib was generally well tolerated, with mostly mild to moderate adverse effects [AEs] and few discontinuations.”

In February 2021, the FDA granted an accelerated approval to tepotinib for the treatment of adult patients with METex14-altered NSCLC based mainly on findings from cohort A of the multicohort VISION trial.2 At that time point, tepotinib had induced an ORR of 43% (95% CI, 32%-56%) per IRC assessment and RECIST v1.1 criteria among 69 treatment-naïve patients.3

VISION enrolled patients with advanced NSCLC with central confirmation of a MET exon 14 skipping mutation per liquid and/or tissue biopsy. Participants could not have received more than 2 prior lines of therapy, and those with asymptomatic brain metastases were permitted.

Study participants received tepotinib at a once-daily dose of 500 mg. The primary end point of the trial was ORR by IRC and RECIST v1.1 criteria. Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Investigators also conducted an exploratory Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) analysis, in which they evaluated best overall response (BOR) per RANO-BM in patients with at least 1 evaluable post-baseline tumor assessment. Here, disease control was defined as complete response (CR)/partial response (PR)/stable disease (SD) or non-CR/non–progressive disease (PD).

The data cutoff date for cohort C, the confirmatory cohort of the trial, was February 20, 2022. Among the 161 patients in this cohort, the median age was 71.0 years (range, 42-91), and 46.6% were male. Moreover, 54.0% of patients were White, and 42.2% of patients were Asian. Most patients had an ECOG performance status of 1 (74.5%), and the remaining patients had a status of 0 (24.8%). Just under half of patients (43.5%) had a smoking history.

Additionally, 75.2% had adenocarcinoma, 21.1% had brain metastases at baseline, 59.0% were treatment naïve, and 41.0% were previously treated. MET exon 14 skipping mutations were detected in tissue biopsy for 74.5% of patients and in liquid biopsy in 49.1% of patients.

Additional findings from cohort C showed that the median DOR with tepotinib was 20.8 months (95% CI, 12.6–not evaluable [NE]). The DCR with the agent was 80.1% (95% CI, 73.1%-86.0%). The median PFS with tepotinib was 13.8 months (95% CI, 10.4-NE), and the median OS was 18.8 months (95% CI, 14.4-25.5).

In the treatment-naïve cohort, the BOR achieved with the MET TKI was a PR in 62.3% of patients and SD in 24.6% of patients. Moreover, 10.1% of patients experienced PD, and 2.9% were NE. In this cohort, the median DOR was not yet evaluable (95% CI, 10.4-NE); the DCR was 87.0% (95% CI, 76.7%-93.9%). The median PFS was 15.9 months (95% CI, 10.8-NE), and the median OS was 22.7 months (95% CI, 12.7-NE).

In previously treated cohort, the BOR experienced with tepotinib was a PR in 51.0% of patients and SD in 31.4% of patients; 7.8% of patients experienced PD and 9.8% were NE. The median DOR with the agent was 12.6 months (95% CI, 4.3-NE), and the DCR was 82.4% (95% CI, 69.1%-91.6%). The median PFS was 13.8 months (95% CI, 6.9-NE), and the median OS was 19.6 months (95% CI, 14.6-NE).

Tepotinib was also found to have encouraging intracranial activity in patients with brain metastases. Investigators noted that the agent crossed the blood-brain barrier to a significant extent, resulting in concentrations of unbound tepotinib in the brain of 25% vs plasma (Kpu,u = 0.25), within a similar range to other central nervous system–penetrant TKIs.

In cohorts A and C, a total of 43 patients with brain metastases were determined to be evaluable by RANO-BM; 23 of these patients were treatment naïve and 20 were pretreated. Notably, more than half, or 69.8% (n = 30), had previously received brain radiotherapy or surgery.

Among those with target or non-target lesions (n = 43), treatment with tepotinib resulted in an intracranial DCR of 88.4% (95% CI, 74.9%-96.1%), with an intracranial median PFS of 20.9 months (95% CI, 5.7-NE). The intracranial ORR was 66.7% (95% CI, 38.4%-88.2%) in those with target lesions (n = 15). In these patients, the intracranial median DOR had not yet been reached (95% CI, 0.9-NE).

Regarding safety, any-grade treatment-related AEs (TRAEs) were experienced by 91.7% of patients; 34.2% of patients experienced effects that were grade 3 or higher in severity.

The TRAEs that occurred in 10% or more of all patients included peripheral edema (any grade, 66.5%; grade ≥3, 10.9%), nausea (any grade, 23.3%; grade ≥3, 0.6%), hypoalbuminemia (any grade, 23.0%; grade ≥3, 3.2%), diarrhea (any grade, 22.4%; grade ≥3, 0.3%), increased blood creatinine (any grade, 21.7%; grade ≥3, 0.6%), increased alanine aminotransferase (any grade, 13.1%; grade ≥3, 2.2%), and decreased appetite (any grade, 11.2%; grade ≥3, 0.3%).

Additionally, 33.5% of patients experienced TRAEs that led to dose reductions, and 42.5% had TRAEs that resulted in treatment interruption. Approximately 15% (14.7%) of patients experienced TRAEs that resulted in permanent discontinuation of tepotinib.

Investigators examined treatment durations in those who required a dose reduction and/or interruption to understand the impact of treatment modifications.

The median duration of treatment in cohorts A plus C (n = 313) was a mean +/- SD of 10.35 months +/- 9.64 months, with a median of 7.5 months (range, 0.03-63.2). At the time of data cutoff, 15.3% (n = 48) of patients were still receiving tepotinib. In those within cohorts A and C who required dose reductions or interruptions (n = 192), the duration of treatment was a mean +/- SD of 12.78 months +/- 10.46 months, with a median of 10.5 months (range, 0.7-63.2). Here, 20.3% (n = 39) of patients were still receiving tepotinib.

“Patients who required treatment interruptions or dose reductions were able to remain on treatment and continue benefiting from treatment with tepotinib,” Thomas concluded.

References
1. Thomas M, Garassino MC, Felip E, et al. Tepotinib in patients with MET exon 14 skipping NSCLC: primary analysis of the confirmatory VISION cohort C. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA03.05.
2. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. News release. FDA. February 3, 2021. Accessed August 7, 2022. http://bit.ly/3az71Cj

3. Le X, Felip E, Veillon R, et al. Primary efficacy and biomarker analyses from the VISON study of tepotinib in patients (pts) with non-small cell lung cancer (NSCLC) with METex14 skipping. J Clin Oncol. 2020;38(suppl 15):9556. doi:10.1200/JCO.2020.38.15_suppl.9556