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

Document Type

Conference Proceeding

Publication Date

5-29-2024

Publication Title

J Clin Oncol

Keywords

acasunlimab, bispecific antibody, docetaxel, pembrolizumab, programmed death 1 ligand 1, adult, aged, anemia, antineoplastic activity, asthenia, cancer inhibition, CD8+ T lymphocyte, cell proliferation, conference abstract, controlled study, diarrhea, drug combination, drug therapy, fatigue, human, hypertransaminasemia, immune response, intravenous drug administration, major clinical study, metastasis, monotherapy, nausea, non small cell lung cancer, PD-L1 test kit, pharmacodynamics, phase 2 clinical trial, randomized controlled trial, response evaluation criteria in solid tumors, side effect, special situation for pharmacovigilance

Abstract

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 mgQ3W x 2 cycles then 500mg Q6W) or combo (arm B, 100mg + pembro 200mg 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%and65%for arm B, and30%and75%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.

PubMed ID

Not assigned.

Volume

42

Issue

16

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