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 (<i>MET</i><sup>Amp/Ex14∆</sup>).
D. Ross Camidge, Filip Jankú, Alejandro Martínez‐Bueno, Daniel V.T. Catenacci, Jeeyun Lee, Se‐Hoon Lee, Afshin Dowlati, Kristoffer Staal Rohrberg, Alejandro Navarro, Yong Wha Moon, Mark M. Awad, Rebecca S. Heist, Thomas Tuxen Poulsen, Arielle Yablonovitch, Lindsay Fosler, Helle Rudbaek, Frank Nygaard, Debra L. Wood, Rita P. Dalal, Enriqueta Felip
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 MET Amp/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 MET E x14Δ (n = 12) or MET Amp (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 MET Amp+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 MET Amp and 3/12 MET Ex14Δ ); 11 had SD (DCR 80%; 6/8 MET Amp and 5/12 MET Ex14Δ ); 2 had PD (2/12 MET Ex14Δ ); and 2 were not evaluable. 10 NSCLC pts were MET TKI naive (7 MET Amp and 3 MET Ex14Δ ) 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 MET Ex14Δ and 1 MET Amp+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% MET Ex14 ∆ 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 MET Amp/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 .