Acasunlimab (DuoBody-PD-L1x4-1BB) alone or in combination with pembrolizumab (pembro) in patients (pts) with previously treated metastatic non-small cell lung cancer (mNSCLC): Initial results of a randomized, open-label, phase 2 trial.
Joachim G.J.V. Aerts, Luis Paz‐Ares, Carole Hélissey, Federico Cappuzzo, Gilles Quéré, Dariusz M. Kowalski, José Carlos Benítez, Florian Guisier, Benjamin Besse, Shirish M. Gadgeel, Thomas Wehler, Ignacio Gil‐Bazo, Michael Chisamore, Cem Z. Görgün, Ilhan Celik, Marie Holst Mørch, Patricia Garrido Castro, Teng Jin Ong, Enriqueta Felip
Abstract
2533 Background: Most pts with mNSCLC without actionable gene alterations have limited options after progression on first-line checkpoint inhibitor (CPI)–containing treatment (tx). Given failures of recent trials in this setting, single-agent chemotherapy remains the main tx option despite limited effectiveness (eg, docetaxel ORR 10–14%) and considerable toxicity. Acasunlimab is a bispecific antibody designed to elicit antitumor immune response via conditional 4-1BB activation strictly dependent on simultaneous PD-L1 binding. Preclinical and PK/PD findings support combining acasunlimab with additional PD-1 blockade to further potentiate anti-tumor activity and potentially extend durability. Initial results from the ongoing randomized, phase 2 trial (NCT05117242) evaluating acasunlimab as monotherapy (mono) and in combination with pembro (combo) in pts with mNSCLC are reported. Methods: Eligible pts had PD-L1+ mNSCLC, with progression after ≥1 prior anti–PD-(L)1 tx. Tumor PD-L1 status was assessed by central testing (TPS≥1%, PD-L1 IHC 22C3 PharmDx); this subset is presented in the efficacy analyses. Following safety run-in, pts were randomized to acasunlimab mono (arm A, 100 mg Q3W x 2 cycles then 500 mg Q6W) or combo (arm B, 100 mg + pembro 200 mg Q3W; arm C, 100 mg + pembro 400 mg Q6W). Primary efficacy endpoint was ORR per RECIST v1.1. Stratification factors were PD-L1 expression and histology. Results: As of Jan 9, 2024, 98 pts (63 with central PD-L1+ status) were enrolled: 23 (16) pts arm A; 39 (22) pts arm B; 36 (25) pts arm C. Among evaluable PD-L1+ pts, 86% received prior pembro tx; 64% had prior concurrent CPI + chemotherapy. Unconfirmed ORR and DCR were 31% and 50% for arm A, 25% and 65% for arm B, and 30% and 75% for arm C, respectively. Confirmed ORRs (and mDoR) were 13% (2 mo), 21% (6 mo), and 22% (NR), with 6-mo PFS rates of 0%, 18%, and 33% for arms A, B, and C, respectively. No responses were observed among centrally confirmed PD-L1-negative pts. The most common TRAEs (all grades; grade ≥3) were asthenia (17.4%; 8.7%), diarrhea (17.4%; 0%), nausea (17.4%, 0%), anemia (13%; 4.3%) and liver-related events (13%; 8.7%) for mono, and liver-related events (18.7%; 13.3%), fatigue (14.7%; 0%), asthenia (13.3%; 0%), and diarrhea (12%; 0%) for combo. Transaminase elevations were generally asymptomatic and manageable with steroids and/or tx delay. Early peripheral pharmacodynamics were consistent with acasunlimab-mediated immune activation in all arms, with a more pronounced increase in CD8 T-cell proliferation with combo. Conclusions: In PD-L1+ pts with mNSCLC following progression on prior CPI tx, acasunlimab + pembro combo showed a manageable safety profile and promising efficacy, with deeper responses and durable disease control in pts treated Q6W. Enrollment is ongoing. Clinical trial information: NCT05117242 .