Tepotinib further solidifies its place in the treatment of patients with advanced MET exon 14 skipping NSCLC

The phase II VISION trial is the largest clinical trial of a MET inhibitor in METex14 skipping non-small cell lung cancer (NSCLC). In this trial, the primary analysis of Cohort C provided independent confirmation for robust and durable efficacy of tepotinib, with comparable or improved outcomes across endpoints compared to Cohort A. Efficacy was particularly durable in treatment-naïve patients enrolled by tissue biopsy and a promising intracranial activity was observed.

Tepotinib is an oral, once daily, highly selective, potent MET inhibitor approved for MET exon 14 (METex14) skipping NSCLC based mainly on Cohort A of the multi-cohort Phase II VISION study. At IASLC WCLC 2022, results from the primary analysis (with more than nine months of follow-up) of the independent confirmatory Cohort C were presented.

Study design

Patients with advanced METex14 skipping NSCLC, by liquid and/or tissue biopsy (TBx), enrolled in Cohort A (primary analyses) and C (confirmatory analyses), received tepotinib 500 mg (450 mg active moiety) once daily. Primary endpoint was objective response (ORR) by independent review committee (IRC, RECIST v1.1). Pre-planned exploratory analysis of brain lesions was conducted by IRC using RANO-BM criteria.

Results

Patients in the confirmatory Cohort C had a median age of 71 years, 46.6% were male, 43.5% had smoking history, and most had adenocarcinoma histology (75.2%). The primary analysis of Cohort C provided independent confirmation for robust and durable efficacy of tepotinib. The ORR was 54.7%, disease control rate (DCR) was 80.1%, median duration of response (mDOR) 20.8 months, median progression-free survival (mPFS) 13.8 months and median overall survival (mOS) 18.8 months. Efficacy was robust and durable across therapy lines but was particularly meaningful in treatment-naïve patients.

 In Cohort C, METex14 skipping was detected by TBx in 74.5% of patients (T+ patients). In first-line T+ patients (N= 69), ORR was 62.3% with mDOR not estimable and mPFS of 15.9 months. Previously treated T+ patients (N= 51) had an ORR of 51.0% with mDOR of 12.6 months and mPFS of 13.8 months. Across Cohorts A+C, 43 patients with brain metastases were evaluable by RANO-BM (first-line, N= 23; second-line or beyond, N= 20). Of them, 30 (69.8%) received prior brain radiotherapy or surgery. Intracranial (i) disease control rate was 88.4% with imPFS of 20.9 months. In patients with target lesions only (N= 15), iORR was 66.7% with imDOR not estimable.

In Cohorts A+C, treatment-related adverse events (TRAEs) occurred in 91.7% of patients (Grade ≥3 in 34.2%), including peripheral oedema (any grade/Grade ≥3: 66.5%/10.9%), nausea (23.3%/0.6%), hypoalbuminemia (23.0%/3.2%), diarrhoea (22.4%/0.3%), and increased blood creatinine (21.7%/0.6%). Permanent discontinuation due to TRAEs occurred in 14.7% of patients. Patients who required treatment interruptions or dose reductions were able to remain on treatment and continue benefiting from treatment with tepotinib. The median duration of tepotinib treatment across all patients in Cohorts A+C was 7.5 months while the median duration of tepotinib treatment in patients across those cohorts with dose reductions and/or interruptions was 10.5 months.

Conclusion

In VISION, the Cohort C primary analysis provided independent confirmation for robust and durable efficacy of tepotinib, with comparable or improved outcomes across endpoints compared to Cohort A. Efficacy outcomes in Cohort C were particularly durable in treatment-naïve patients identified by tissue biopsy. In an exploratory RANO-BM analysis, promising intracranial activity was observed, indicating that patients with METex14 skipping NSCLC with brain metastases benefit from tepotinib treatment. Safety data confirmed previous observations that tepotinib was generally well tolerated, with mostly mild–moderate AEs, and few discontinuations. Patients who required treatment interruptions or dose reductions were able to remain on treatment and continue benefiting from treatment with tepotinib.

Reference

Thomas M, Garassino M, Felip E, et al. Tepotinib in patients with MET exon 14 skipping NSCLC: Primary analysis of the confirmatory VISION Cohort C. Presented at IASLC WCLC 2022; Abstract OA03.05.