Phase I study of AMG 757, a delta-like ligand 3 (DLL3) targeting, half-life extended bispecific T-cell engager immuno-oncology therapy, in small cell lung cancer (SCLC)

Abstract

Background: AMG 757 simultaneously binds DLL3 on SCLC cells and CD3 on T cells leading to T cell- mediated tumor lysis. Data from an ongoing phase I study of AMG 757 in SCLC are reported. Methods: Safety and efficacy were evaluated in a phase I trial of AMG 757 for patients (pts) with relapsed/refractory SCLC after >= 1 platinum-based regimen (NCT03319940). AMG 757 was administered intravenously (9 dose levels (DLs); dose range: 0.003−30 mg q2w, ± step dosing). Results: As of 03 Nov 2020, 52 pts (median age, 64 [32−80] y; median prior lines of therapy, 2 [1−6]) were enrolled. 79% (41/52) of pts reported treatment (tx)-related adverse events (TRAEs) (Grade [Gr] >= 2, 29/52 [56%], Gr >= 3, 12/52 [23%], Gr >= 4, 4/52 [8%]). TRAEs accounted for 1 tx discontinuation and 1 death (Gr 5 pneumonitis, DL, 0.3 mg). Cytokine release syndrome (CRS; 44%; Lee criteria (2014): Gr 2, 5/52 [10%], Gr 3, 1/52 [2%], no Gr >= 4) was the most common TRAE and typically occurred in cycle 1. Median time to onset of CRS was 9 (3−52) h following an AMG 757 dose; median duration was 60 (3−197) h. Fever (31%), tachycardia (19%), and nausea (14%) were the most common CRS-related symptoms. Significant increases in cytokine (IL-8, MCP-1, IFN-g, IL-10, IL-6, MIP-1a, MIP-1b, TNF-a) levels from baseline in the 24 h following the first AMG 757 dose in cycle 1 were observed in pts experiencing CRS vs. pts who did not experience CRS symptoms. CRS did not result in tx discontinuation or deaths and was managed with supportive care, corticosteroids, and/or anti-IL-6R. 14% (7/51) of pts achieved a confirmed partial response (PR) (modified RECIST 1.1) in 4 DLs (0.3 mg [8% of PR], 1 mg [13%], 3 mg [33%], and 10 mg [20%]). Stable disease was seen in 24% (12/51). Median time to response was 1.8 months; the estimated duration of response was > 6 months in 83% (95% CI: 27%, 98%) of pts with a confirmed PR. An unconfirmed PR was noted in an additional pt (30 mg DL). Conclusions: AMG 757 showed an acceptable safety profile and preliminary evidence for efficacy in pts with SCLC. The most common TRAE—CRS—occurred early in the dosing cycle, did not recur, was typically mild in severity, and manageable. The maximum tolerated dose has not been reached. Dose-finding for monotherapy is ongoing.