The robust efficacy achieved with tepotinib in patients with non-small cell lung cancer harboring MET exon 14 skipping alterations was independently confirmed in data from the primary analysis of the cohort C of the phase 2 VISION trial.

The robust efficacy achieved with tepotinib (Tepmetko) in patients with non-small cell lung cancer (NSCLC) harboring MEET Exon 14 skipping alterations were independently confirmed in data from the primary analysis of Cohort C of the Phase 2 VISION trial (NCT02864992), with particularly long-lasting activity noted in treatment-naïve individuals. treatment.1

The results, which were presented at the 2022 World Conference on Lung Cancer, showed that over 9 months of follow-up, tepotinib (n=161) elicited an objective response rate (ORR) of 54.7% (95% CI, 46.6%-62.5%) based on Independent Review Committee (IRC) assessment and RECIST v1.1 criteria.

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

“In VISION, the largest clinical trial of a MET TKI in MEETex14-jump NSCLC – primary analysis of Cohort C provided independent confirmation of robust and durable efficacy of tepotinib, with comparable or improved results across all endpoints compared to 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 during a presentation of the data. “The safety data confirmed previous observations that tepotinib was generally well tolerated, with predominantly mild to moderate adverse reactions. [AEs] and few dropouts.

In February 2021, the FDA granted accelerated approval for tepotinib for the treatment of adult patients with MEETex14-impaired NSCLC based primarily on results from Cohort A of the multicohort VISION trial.2 At that time, tepotinib induced an ORR of 43% (95% CI, 32% to 56%) according to IRC assessment and RECIST v1.1 criteria in 69 treatment-naïve patients.3

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

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

The investigators also conducted an exploratory analysis of Response Assessment in Brain Metastases in Neuro-Oncology (RANO-BM), in which they assessed best overall response (BOR) by RANO-BM in patients with at least least 1 evaluable tumor assessment after baseline. Here, disease control was defined as complete response (CR)/partial response (PR)/stable disease (SD) or no CR/non-progressive disease (PD).

The data cut-off date for Cohort C, the trial confirmation cohort, 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 men. In addition, 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%). Slightly less than half of the patients (43.5%) had a history of smoking.

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

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

In the treatment naïve cohort, the BOR obtained with the MET TKI was PR in 62.3% of patients and SD in 24.6% of patients. In addition, 10.1% of patients presented with PD and 2.9% with 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% to 93.9%). Median PFS was 15.9 months (95% CI, 10.8-NE) and median OS was 22.7 months (95% CI, 12.7-NE).

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

Tepotinib has also been shown 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 brain unbound tepotinib concentrations of 25% of plasma (Kpu, u=0.25), in a similar range to that of other TKIs entering the central nervous system. .

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. In particular, more than half, or 69.8% (n = 30), had already received radiotherapy or brain surgery.

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

Regarding safety, treatment-related AEs (TRAE) of any grade were experienced by 91.7% of patients; 34.2% of patients presented effects of severity of grade 3 or more.

AETRs occurring 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%).

In addition, 33.5% of patients experienced RTAEs that led to dose reductions and 42.5% had RTUEs that led to treatment discontinuation. Approximately 15% (14.7%) of patients experienced TEARs leading to permanent discontinuation of tepotinib.

Investigators looked at treatment durations in those who needed dose reduction and/or interruption to understand the impact of treatment changes.

The median duration of treatment in the A plus C cohorts (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 closure, 15.3% (n=48) of patients were still receiving tepotinib. Among those in Cohorts A and C who required dose reductions or interruptions (n=192), treatment duration 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 therapy and continue to benefit from tepotinib therapy,” Thomas concluded.

References

  1. Thomas M, Garassino MC, Felip E, et al. Tepotinib in patients with MEET exon 14 skipping NSCLC: primary analysis of the VISION C confirmatory cohort. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abbreviated OA03.05.
  2. FDA grants accelerated approval for tepotinib for metastatic non-small cell lung cancer. Press 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 analyzes from the VISON study of tepotinib in patients (pts) with METex14 skipping non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(supplement 15):9556. doi:10.1200/JCO.2020.38.15_suppl.9556