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August 17, 2025 2 secs
This episode reviews the COAST trial, which evaluated durvalumab alone or in combination with two novel immunomodulators—oleclumab (anti-CD73) and monalizumab (anti-NKG2A)—as consolidation therapy after platinum-based concurrent chemoradiotherapy in unresectable stage III NSCLC. In this phase 2, open-label, randomized study (n=186), patients with ECOG 0–1 were assigned to durvalumab alone, durvalumab plus oleclumab, or durvalumab plus monalizumab for up to 12 months. The primary endpoint was confirmed objective response rate; secondary endpoints included progression-free survival, overall survival, and safety. Results showed higher objective response rates with the combinations (durvalumab alone 23.9%; with oleclumab 35.0%; with monalizumab 40.3%), and significant improvements in progression-free survival for both combination arms (hazard ratios ~0.59 and ~0.63, respectively) compared with durvalumab alone. No OS improvement was observed yet, consistent with the phase 2 design and limited follow-up. Safety profiles were similar across arms, with immune-related events aligning with known durvalumab toxicities and no major increases in toxicity from adding oleclumab or monalizumab. Mechanistically, oleclumab reduces adenosine-mediated immunosuppression by blocking CD73, while monalizumab relieves NKG2A-mediated inhibition of NK and CD8+ T cells, theoretically enhancing PD-L1 blockade efficacy. Clinicians should note the selective eligibility (post-cCRT, ECOG 0–1) and ongoing need for phase 3 confirmation (PACIFIC-9) to determine OS benefit and potential shifts in standard of care. Practical takeaways include vigilant monitoring for immune-related adverse events, adherence to durvalumab consolidation, and awareness of potential overlapping toxicities. The COAST data are encouraging but require further validation before changing practice.
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