Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC).
Authors: Owonikoko Taofeek K. , Champiat Stéphane , Johnson Melissa Lynne , Govindan Ramaswamy , Izumi Hiroki , Lai W. Victoria Victoria , Borghaei Hossein , Boyer Michael J. , Boosman Rene J. , Hummel Horst-Dieter , Blackhall Fiona Helen , Reguart Noemi , Dowlati Afshin , Zhang Yiran , Mukherjee Sujoy , Minocha Mukul , Zhou Yanchen , Shetty Aditya , Hashemi Sadraei Nooshin , Paz-Ares Luis G. 
Published: June 2021

8510 Background: DLL3, an inhibitory Notch ligand, is a promising target as it is highly expressed in SCLC compared to normal tissue. AMG 757, a half-life extended BiTE immuno-oncology therapy, binds DLL3 on tumor cells and CD3 on T cells, leading to T cell-dependent killing of tumors. Results from the first nine dosing cohorts showing preliminary efficacy of AMG 757 (confirmed partial response [PR], 14% of pts) were previously presented. Here, updated safety, efficacy, and pharmacokinetic data from 10 cohorts from the ongoing phase 1 study of AMG 757 in SCLC are reported (NCT03319940). Methods: AMG 757 (0.003100 mg) was administered IV every 2 weeks ± step dosing. Eligible patients (pts) had SCLC that progressed after ≥1 platinum-based regimen. Antitumor activity was assessed by modified RECIST 1.1. Results: As of 11 Jan 2021, 64 pts enrolled at 10 dose levels (DLs; 0.003100 mg) had received ≥1 AMG 757 dose and were available for analyses. Median age was 64 (range, 3280) y; 63 pts (98%) had ECOG PS 01 and median number of prior lines of therapy was 2 (range, 16), with 28 pts (44%) receiving prior PD-1/PD-L1 therapy. Median treatment duration was 6 (range, 0.171) wk. Treatment-related AEs occurred in 53 pts (83%): 16 (25%) ≥ grade (G) 3, 4 (6%) ≥G4, 1 (2%) G5 (pneumonitis; DL5 [0.3 mg]). AEs led to discontinuation in 1 pt (G3 encephalopathy, DL10 [100 mg]). Cytokine release syndrome (CRS; graded per Lee 2014 criteria) was reported in 27 pts (42%): G2 in 7 (11%), ≥G3 in 1 (2%). CRS presented mainly as fever (31%), tachycardia (17%), nausea (13%), fatigue (9%), and hypotension (9%). CRS was usually reversible and was managed with supportive care, corticosteroids, and/or anti-IL-6R. CRS did not lead to any treatment discontinuations. Sixty pts treated across 10 DLs, with a median follow-up of 4.2 (range, 0.218.6) mo, were evaluated for efficacy. Confirmed PR across all DLs was reported in 8/60 pts (13%), with 5/8 pts (63%) pts achieving unconfirmed PR at 100 mg (DL10). The median time to response was 1.7 (range, 1.23.7) mo. The estimated duration of response was >6 months in 71% pts (95% CI: 26, 92) with any PR. Disease control rate was 43%, with any tumor shrinkage in 23/60 pts (38%). AMG 757 serum exposures increased approximately dose proportionally within the evaluated dose range. Conclusions: AMG 757 has an acceptable safety profile at doses up to 100 mg. Responses were rapid and durable. Encouraging anti-tumor activity was seen across dose ranges, with ongoing unconfirmed PR in 5/8 pts (63%) at the highest DL. The study is ongoing; updated data, including response rates and duration of response, will be presented. Clinical trial information: NCT03319940.