Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

Abstract

Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations. See related commentary by Rosner and Spira, p. 1055

Brain penetration and efficacy of tepotinib in orthotopic patient-derived xenograft models of MET-driven non-small cell lung cancer brain metastases

“…In the orthotopic experiments, tepotinib induced pronounced tumor regression, including complete or nearcomplete regressions, in both models tested. Together with clinical evidence of systemic and intracranial responses to tepotinib in patients with METex14 skipping NSCLC and brain metastases [9,10,[25][26][27][28], these data support the further prospective evaluation of the intracranial efficacy of tepotinib in patients with NSCLC with MET alterations.…”

“…The preclinical activity of tepotinib in PDXs from NSCLC brain metastases with MET amplification adds to the body of data demonstrating tumor growth inhibition and regression with tepotinib in subcutaneous xenograft models of MET-driven NSCLC, hepatocellular carcinoma and gastric cancer, as well as glioblastoma [39][40][41]. In line with preclinical data, there is mounting evidence for the clinical activity of tepotinib in METex14 skipping NSCLC brain metastases [9,10,[25][26][27][28]. For example, in VISION Cohort A, the efficacy of tepotinib in patients with asymptomatic and/or neurologically stable brain metastases at baseline was comparable to that in the overall METex14 skipping population [9,10].…”

“…In the clinical setting, brain permeability of tepotinib can be inferred from intracranial responses observed in patients with METex14 skipping NSCLC both in VISION [10,25] and case reports from clinical practice [26][27][28] (discussed further below). Direct evidence of CNS penetration was provided in two of these cases, which documented cerebrospinal fluid concentrations of tepotinib of 62 nM and 49.7-59.3 nM [27,28], which exceed the half-maximal inhibitory concentration of tepotinib for MET (1.7 nM) [7].…”

“…The potent and highly selective MET inhibitor tepotinib has recently been approved for treatment of metastatic METex14 skipping NSCLC [7,8]. In the phase 2 VISION trial, once daily oral tepotinib 500 mg (450 mg active moiety) provided durable clinical responses in patients with advanced NSCLC harboring METex14 skipping alterations [9,10]. The study additionally showed antitumor activity of tepotinib in a separate cohort of patients with NSCLC with MET amplification as a primary driver [11].…”

“…Clinical evidence supporting the intracranial activity of tepotinib in patients with METex14 skipping NSCLC has recently been provided by several case reports [25][26][27][28], and an ad hoc analysis of intracranial responses in VISION patients who had brain metastases at baseline [10]. To complement such clinical data, preclinical experiments can provide important information regarding the potential for activity against brain lesions [24].…”