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Abstract
Background Although PD-(L)1 inhibitors demonstrated survival benefits vs chemotherapy in PD–(L)1–high NSCLC, <50% of patients will respond to monotherapy. Combined TIGIT/PD-(L)1 blockade prolonged progression-free survival (PFS) in a phase 2 trial for metastatic, PD–(L)1–high NSCLC. ARC-10 (phase 2, randomized, open–label trial [NCT04736173]) evaluated the efficacy and safety of the combination of domvanalimab (D; Fc–silent anti–TIGIT antibody) and zimberelimab (Z; anti–PD-1 antibody) vs Z monotherapy in front-line stage IIIB–IV NSCLC. Platinum–doublet chemotherapy was included as a control arm in countries where anti–PD-(L)1 monotherapy was not yet standard-of-care.
Methods Patients aged ≥18 years with ≥1 measurable tumor lesion per RECIST v1.1, high PD–(L)1 expression (tumor proportion score ≥50% [PharmDx 22C3 assay]), ECOG PS 0/1, and no actionable genomic alterations were randomized (2:2:1) to intravenous D 15 mg/kg with Z 360 mg (DZ), Z 360 mg, or platinum–doublet chemotherapy every 3 weeks. Primary endpoint was PFS. Secondary endpoints included overall survival (OS), confirmed objective response rate (cORR), and safety.
Results Of 98 randomized patients, 95 received treatment (DZ, n=38; Z, n =40; chemotherapy, n=17). As of May 17, 2024, median follow-up was 24.5 months; 22 patients remained on front-line treatment (DZ, n=11; Z, n=10; chemotherapy, n=1). PFS, OS, and cORR were greater with DZ than with Z and chemotherapy (table 1; figures 1–2). Median OS was not reached for DZ. Twelve–month OS rates were 68%, 57%, and 50% for DZ, Z, and chemotherapy, respectively. Treatment-related adverse events (TRAEs) occurred in 81.6%, 57.5%, and 82.4% of patients receiving DZ, Z, or chemotherapy, respectively. TRAEs leading to death were lower for DZ (2.6%; n=1 sudden death) vs Z (10.0%; n=1 each sudden death, acute kidney injury, acute myocardial infarction, intestinal perforation) or chemotherapy (11.8%; n=1 each febrile neutropenia, ischemic stroke). TRAEs leading to treatment discontinuation were higher for chemotherapy (23.5%) than for DZ (10.5%) and Z (7.5%). Grade ≥3 TRAEs were higher for chemotherapy (47.1%) than for DZ (21.1%) or Z (15.0%). Immune–mediated AEs were similar between DZ (23.7%) and Z (20.0%); 1 DZ-treated patient experienced a grade 3 AE. Infusion–related reactions were low (DZ, 7.9%; Z, 2.5%; chemotherapy, 0%).
Conclusions DZ, an Fc-silent anti-TIGIT plus anti–PD-1 combination therapy, was associated with improved PFS and OS compared with Z or chemotherapy in front-line stage IIIB–IV NSCLC. DZ was well tolerated; addition of D to Z did not show new safety concerns. Ongoing phase 3 studies will further evaluate DZ in NSCLC.
Acknowledgements Arcus Biosciences and Gilead Sciences participated in the study design; study research; collection, analysis, and interpretation of data; and writing, reviewing, and approving of this abstract for submission. All authors had access to the data; participated in the development, review, and approval of the abstract; and agreed to submit this abstract to the SITC 2024 Annual Meeting for consideration as an oral presentation. Arcus Biosciences and Gilead Sciences funded the research for this study and provided writing support for this abstract. Medical writing assistance, funded by Arcus Biosciences, was provided by Jay Parekh, PharmD, ISMPP CMPP, of JB Ashtin.
Trial Registration ClinicalTrials.gov NCT04736173.
Ethics Approval At each site, the study was conducted in full accordance with the 21 Code of Federal Regulations, International Council for Harmonisation guidelines, institutional review board and independent ethics committee guidelines, and all other applicable local or regional regulations. All patients provided written informed consent before enrollment.
ARC-10 study efficacy endpoints
Kaplan-Meier estimate of progression-free survival
Kaplan-Meier estimate of overall survival
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