Research Summary:
Durvalumab after concurrent chemoradiotherapy (cCRT) is standard-of-care for patients with unresectable, Stage III non-small cell lung cancer (NSCLC) without progression. The COAST study evaluated whether adding novel immunotherapies targeting cluster of differentiation 73 (CD73; oleclumab) or natural killer Group 2 member A (NKG2A; monalizumab) to consolidation durvalumab could further improve outcomes in this setting. Oleclumab is a human IgG1 monoclonal antibody that inhibits CD73-mediated extracellular adenosine production, and monalizumab is a humanized IgG4 monoclonal antibody that blocks NKG2A–HLA-E interactions to reduce inhibition of natural killer and CD8+ T cells. Earlier Phase I studies of these agents with durvalumab in advanced NSCLC or ovarian cancer suggested manageable safety and antitumor activity. COAST was designed as a global, Phase II, signal-finding randomized clinical trial to compare consolidation durvalumab alone with durvalumab plus oleclumab or durvalumab plus monalizumab in patients with unresectable, Stage III NSCLC with no progression following definitive platinum-based cCRT. Aggarwal et al1 present the final efficacy and safety analyses with longer follow-up of this trial.
Patients received durvalumab monotherapy (control arm) or durvalumab combined with oleclumab or monalizumab for up to 12 months. Disease characteristics were analyzed by squamous versus nonsquamous histologic subgroups to align with current standards. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key secondary endpoints included duration of response, disease control rate (DCR) at 16 weeks, progression-free survival (PFS) by investigator assessment, 12-month PFS rate, overall survival (OS), and safety. Efficacy was analyzed in the intention-to-treat population (all randomized patients), and safety in the as-treated population (patients who received at least one dose).
Of 258 screened patients, 186 received study treatment, with 66 receiving durvalumab alone, 59 receiving durvalumab plus oleclumab, and 61 receiving durvalumab plus monalizumab. Median age was 65 years (range: 37–87 years), 129 patients (68.3%) were male, and 176 (93.1%) were current or former smokers. At the final data cutoff, median follow-up was 30.1 months (range: 0.4–48.9 months), and all patients had completed study treatment and follow-up. Median treatment exposure was 13 cycles in each combination arm and seven cycles in the durvalumab arm.
Investigator-assessed confirmed ORR was 23.9 percent (95% confidence interval [CI]: 14.3–35.9%) with durvalumab alone, 35.0 percent (95% CI: 23.1–48.4%) with durvalumab plus oleclumab, and 40.3 percent (95% CI: 28.1–53.6%) with durvalumab plus monalizumab. The absolute ORR differences versus durvalumab were 11.1 percentage points (95% CI: −6.4 to 28.1) for durvalumab plus oleclumab and 16.9 percentage points (95% CI: −0.8 to 33.4) for durvalumab plus monalizumab, which were not statistically significant. DCR at 16 weeks was higher in the combination arms (80.0%; 95% CI: 67.7–89.2% with oleclumab, and 79.0%; 95% CI: 66.8–88.3% with monalizumab) than with durvalumab alone (58.2%; 95% CI: 45.5–70.2%), with DCR differences of 21.8 percentage points (95% CI: 4.4–38.2) and 22.8 percentage points (95% CI: 5.6–39.4), respectively. Median duration of response was not reached with durvalumab (95% CI: 14.1 months to not estimable), 29.9 months (95% CI: 17.1 months to not estimable) with durvalumab plus oleclumab, and 23.0 months (95% CI: 10.2 months to not estimable) with durvalumab plus monalizumab. PFS data maturity was 60.8 percent (115 events among 189 patients). Median PFS was 7.3 months (95% CI: 4.0–13.8 months) with durvalumab alone, 21.1 months (95% CI: 10.4–30.9 months) with durvalumab plus oleclumab, and 19.8 months (95% CI: 13.6–31.3) with durvalumab plus monalizumab, corresponding to stratified hazard ratios (HRs) versus durvalumab of 0.59 (95% CI: 0.37–0.93) and 0.63 (95% CI: 0.40–0.99), respectively. Twelve-month PFS rates were 37.6 percent (95% CI: 24.7–50.4%) with durvalumab, 63.5 percent with durvalumab plus oleclumab, and 73.2 percent with durvalumab plus monalizumab. OS maturity was 39.7 percent (75 deaths among 189 patients). Median OS was 40.9 months with durvalumab alone and was not reached in either combination arm.
Safety findings remained consistent with the established durvalumab monotherapy profile, as treatment-emergent adverse events of any grade were common across arms, but Grade 3 or greater events occurred in approximately 32.8 to 45.5 percent of patients. Treatment discontinuation due to adverse events was similar across arms (13.6–15.3% for durvalumab, with comparable rates for oleclumab and monalizumab). Immune-mediated adverse events and adverse events of special interest, including pneumonitis, occurred at comparable frequencies across groups.
Overall, adding oleclumab or monalizumab to durvalumab provided additional clinical benefit compared with durvalumab alone for patients with unresectable, Stage III NSCLC who had not progressed after cCRT. Both combinations continued to show numerically higher ORR and longer PFS than durvalumab monotherapy, with HRs for PFS less than 1.00 and prolonged median PFS greater than 19 months.
References
- Aggarwal C, Martinez-Marti A, Majem M, et al. Durvalumab alone or combined with novel agents for unresectable stage III non-small cell lung cancer: update from the COAST randomized clinical trial. JAMA Netw Open. 2025;8(7):e2518440.