Safety and preliminary clinical activity of the MET antibody mixture, Sym015 in advanced non-small cell lung cancer (NSCLC) patients with MET amplification/exon 14 deletion (METAmp/Ex14∆).

Abstract

9510 Background: Sym015, a mixture of 2 humanized antibodies, triggers MET degradation by a unique mechanism with superior specificity compared to tyrosine kinase inhibitors (TKIs). The Sym015-01 phase (P)1a trial met, the primary objective of identifying the recommended P2 dose (RP2D) as 18 mg/kg on cycle 1 day 1 followed by 12 mg/kg Q2W. The P2a was expanded to enroll METAmp/Ex14∆ NSCLC patients (pts) based on preliminary efficacy findings. Here we present interim safety (n = 45) and efficacy (NSCLC cohort, n = 20) results from P2a. Methods: The expansion NSCLC Cohort enrolled pts with METEx14Δ (n = 12) or METAmp (n = 8 defined as > 5 MET copies by NGS or MET/CEP7 ratio > 2.2 updated to ≥3.0 by in situ hybridization; including 1 with METAmp+Ex14Δ). Tumor MET status was confirmed centrally and longitudinal ctDNA was analyzed by Guardant360. Results: By January 2020, 45 pts (median age 61.7 years) have been treated in P2a. Median duration of exposure (DoE) was 3.8 months (m) (n = 45; range 0.4+ to 22 m). Treatment emergent adverse events occurred in 93%, treatment related AEs (TRAE) in 42.2% and TRAE ≥G3 in 13.3% pts. No pts discontinued or died due to TRAE. The most common TRAE in ≥10% pts were fatigue (13.3%) and peripheral edema (11.1%). Of 20 NSCLC pts, 5 had confirmed PR (ORR 25%; 2/8 METAmp and 3/12 METEx14Δ); 11 had SD (DCR 80%; 6/8 METAmp and 5/12 METEx14Δ); 2 had PD (2/12 METEx14Δ); and 2 were not evaluable. 10 NSCLC pts were MET TKI naive (7 METAmp and 3 METEx14Δ) and had 50% ORR and 100% DCR (5 PR and 5 SD; DoR range 1 to 18.3 m; DoE 1.5 to 22 m); 10 NSCLC pts were prior MET TKI treated (9 METEx14Δ and 1 METAmp+Ex14Δ) with DCR 60%, (6 SD; DoE 0.4-9.6 m). Median PFS was 5.5 m overall (95% CI 3.5-9.7 m). Median PFS for MET TKI naive and MET TKI pre-treated NSCLC pts was 6.5 m (95% CI 3.4-21.9 m) and 5.4 m (95% CI 1.2-9.7 m) respectively. Median OS was not reached for overall or for prior MET TKI subgroups. 89% METEx14∆ tumor tissue to blood concordance (8/9 NSCLC pts) was observed. Conclusions: Sym015 was well-tolerated at the RP2D with a response rate similar to MET TKI in MET-treatment naïve METAmp/Ex14Δ NSCLC and seems to delay disease progression in MET TKI pretreated NSCLC pts. Combination with MET TKI to delay or prevent resistance should be further explored. Clinical trial information: NCT02648724 .