Durvalumab Alone or Combined With Novel Agents for Unresectable Stage III Non–Small Cell Lung Cancer

Importance: The PACIFIC trial established durvalumab as the standard-of-care therapy for unresectable, stage III non-small cell lung cancer (NSCLC) without progression following concurrent chemoradiotherapy (cCRT). Novel immunotherapy combinations involving the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab have the potential to build on the durvalumab standard of care. Objective: To report updated results from the phase 2 COAST trial of consolidation durvalumab alone or combined with oleclumab or monalizumab in patients with unresectable, stage III NSCLC and no progression following cCRT. Design, Setting, and Participants: COAST was an open-label, phase 2, multidrug platform randomized clinical trial conducted across 73 sites globally. Patients with an Eastern Cooperative Oncology Group Performance Status of 0 or 1 and no progression following definitive platinum-based cCRT were enrolled between January 2019 and July 2020. The data cutoff for this final analysis was July 18, 2023. Data were analyzed from September 2023 to March 2024. Intervention: Patients were randomized 1:1:1, stratified by histologic type within 42 days after cCRT, to durvalumab alone or durvalumab combined with oleclumab or monalizumab for up to 12 months. Main Outcomes and Measures: The primary end point was investigator-assessed confirmed objective response rate (ORR). Key secondary end points included investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Efficacy end points were assessed in the intention-to-treat population. Safety was assessed in the as-treated population. Results: Of 189 randomized patients (median [range] age, 65 [37-87] years; 129 males [68.3%]; 176 [93.1%] current or former smokers), 186 received treatment consisting of durvalumab plus oleclumab (n = 59), durvalumab plus monalizumab (n = 61), or durvalumab alone (n = 66). Of these patients, 1 (0.5%) self-reported as American Indian or Alaska Native, 14 (7.5%) as Asian, 8 (4.3%) as Black or African American, 1 (0.5%) as Native Hawaiian or Other Pacific Islander, 159 (85.5%) as White, and 3 (1.6%) as other race. After a median (range) follow-up in all patients of 30.1 (0.4-48.9) months, confirmed ORR was numerically higher with durvalumab plus oleclumab (35.0%; 95% CI, 23.1%-48.4%) or monalizumab (40.3%; 95% CI, 28.1%-53.6%) than with durvalumab alone (23.9%; 95% CI, 14.3%-35.9%). However, the difference in ORR for durvalumab plus oleclumab (11.1 [-6.4 to 28.1] percentage points) and durvalumab plus monalizumab (16.9 [-0.8 to 33.4] percentage points) was not statistically significant compared with durvalumab alone. Both combinations prolonged PFS vs durvalumab alone (plus oleclumab: hazard ratio [HR], 0.59 [95% CI, 0.37-0.93]; plus monalizumab: HR, 0.63 [95% CI, 0.40-0.99]) but did not demonstrate nominal associations with longer OS (plus oleclumab: HR, 0.69 [95% CI, 0.40-1.20]; plus monalizumab: HR, 0.77 [95% CI, 0.44-1.33]). Safety was comparable across arms, without new or notable safety signals. Conclusions and Relevance: In the COAST trial, combining consolidation durvalumab with oleclumab or monalizumab provided additional clinical benefit over durvalumab alone. This finding supports further investigation of these novel combinations in the phase 3 PACIFIC-9 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03822351.