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.
Authors: Aerts Joachim , Paz-Ares Luis G. , Helissey Carole , Cappuzzo Federico , Quere Gilles , Kowalski Dariusz , Benitez Jose Carlos , Guisier Florian , Besse Benjamin , Gadgeel Shirish M. , Wehler Thomas , Gil-Bazo Ignacio , Chisamore Michael Jon , Gorgun Cem , Celik Ilhan , Holst Mørch Marie , Garrido Castro Patricia , Ong Teng Jin , Felip Enriqueta 
Published: June 2024

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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 .