Intracranial activity of tepotinib in patients (pts) with MET exon 14 (METex14) skipping NSCLC enrolled in VISION.

9084 Background: Brain metastases (BMs) are reported in 20–40% of pts with METex14 skipping NSCLC and present a high unmet need with poor prognosis. Tepotinib is a highly selective MET inhibitor that has demonstrated intracranial activity in preclinical MET-driven lung cancer orthotopic BM models, and has high binding in brain tissue with 25% of free tepotinib levels in brain, relative to plasma. In VISION Cohort A (N = 152), tepotinib had robust and durable clinical activity in pts with METex14 skipping NSCLC, with an objective response rate (ORR) of 45% and a median duration of response (mDOR) of 11.1 months. Here, we report the intracranial activity of tepotinib. Methods: In the Phase II VISION study, pts with METex14 skipping NSCLC received 500 mg QD (450 mg active moiety) oral tepotinib. Study eligibility allowed for pts with BM (neurologically stable on symptomatic therapy with stable steroids, and pts with asymptomatic BM). Primary endpoint: systemic OR per RECIST v1.1; subgroup analysis in pts with BM (determined by RECIST v1.1) was predefined. An ad hoc retrospective analysis of brain lesions determined by CT/MRI was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, which accounts for pts’ clinical status and steroid use. Responses were determined in pts with ≥1 evaluable post-baseline tumor assessment (due to the retrospective nature and resulting incomplete data, confirmation was not required). For pts with non-measurable lesions per RANO-BM (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020. Results: Based on RECIST v1.1, 23 pts in Cohort A had BM at baseline. Systemic efficacy in pts with BM (ORR 47.8% [95% CI: 26.8, 69.4], mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population. 15 pts were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before tepotinib initiation [range 2.6–44]). Systemic best objective responses (BORs) were partial response (PR, n = 9), stable disease (SD, n = 3), and progressive disease (PD; n = 3). Of 7 pts with measurable CNS disease per RANO-BM (all of whom received prior radiotherapy), intracranial BORs were PR (n = 5; including 3 with complete disappearance of target lesions), SD (n = 1) and PD (n = 1). Of 8 pts with NTL only, 7 achieved intracranial disease control and 1 had PD. Of the 7 pts with disease control, 3 had CR of the enhancing NTL. Conclusions: Tepotinib demonstrated robust systemic activity in pts with METex14 skipping NSCLC with BM; this is complemented by intracranial activity in an ad hoc analysis using RANO-BM. Small pt numbers, a large proportion of pts with prior radiotherapy for BM, and the retrospective nature of analysis should be considered. Prospective evaluation of intracranial activity data from VISION Cohort C is ongoing. Clinical trial information: NCT02864992.