Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in Patients With c-Met Protein–Expressing Non–Small-Cell Lung Cancer

Abstract

PURPOSE Overexpression of c-Met protein and epidermal growth factor receptor ( EGFR) mutations can co-occur in non–small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study ( NCT02099058 ) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met–positive (+) NSCLC. PATIENTS AND METHODS This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an EGFR-activating mutation ( EGFR-M +) and progression on a prior EGFR TKI. End points included safety, pharmacokinetics, objective response rate (ORR), and progression-free survival (PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+ patients with H-scores ≥ 225 were classified as c-Met high. RESULTS As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for EGFR-M + patients (n = 28) was 32.1%. Of EGFR-M + patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was 6.8 months for non-T790M+ and for those whose T790M status was unknown, versus 3.7 months for T790M+. CONCLUSION Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.

MET Amplification as a Resistance Driver to TKI Therapies in Lung Cancer: Clinical Challenges and Opportunities

“…Therefore, numerous clinical studies have shown preliminary efficacy using this approach. In patients with EGFR-mutant NSCLC and MET amplification with disease progression on EGFR TKI treatment, subsequent treatment with an MET inhibitor and EGFR-TKI combination rendered clinical benefits in a series of phase I/II studies (Table 1) [71][72][73][94][95][96][97][98][99][100][101]. The TATTON trial [71] demonstrated the clinical benefits of osimertinib plus savolitinib in patients with previously treated EGFR-mutant MET-amplified NSCLC, with an objective response rate (ORR) of 44%.…”

Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies

“…Conversely, ORR was 40% and DCR was 80% in EGFR WT patients (n 5 5). 65 The Luminosity trial was conducted to evaluate c-MET potential predictive biomarkers for Teliso-V treatment. In the nonsquamous EGFR WT subgroup, the ORR was 53.8% in c-MET high and 25% in c-MET intermediate (c-Met overexpression high: ≥50% tumor cells at 31 intensity; intermediate: 25%-49%).…”

“…In a phase Ib study, Teliso-V was evaluated in combination with erlotinib in patients with c-MET-positive NSCLC. 65 In the population of EGFR mutation (del19 or L858R)–positive patients at resistance to EGFR TKI (n = 28), ORR was 32.1% and DCR was 85.7%, with an mPFS of 5.9 months. In those EGFR mutation–positive patients with high c-MET expression (n = 15), ORR was 52.6%.…”

Exploring the Next Frontier in Non–Small-Cell Lung Cancer With High MET and Mutated Epidermal Growth Factor Receptor

“…In the companion to this article, Camidge et al 7 described the safety and preliminary activity of telisotuzumab vedotin (Teliso-V), an antibody-drug conjugate (ADC) targeting MET, in combination with epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib in patients with MET protein-expressing NSCLC. Teliso-V is the first-in-class therapeutic to target MET as a tumor-associated antigen in tumors with high MET expression and delivers monomethyl auristatin E (MMAE) as a cytotoxic payload to the cells (Fig 1).…”

“…Camidge et al 7 explored the safety and efficacy of the combination of Teliso-V and the first-generation EGFR kinase inhibitor erlotinib in patients with high MET expression and oncogenic EGFR in patients with NSCLC after prior progression after EGFR inhibitor treatment. In total, 36 of 42 patients were efficacy evaluable with a median progression-free survival of this group of 5.9 months (95% CI, 2.8 to not reached).…”