Durvalumab Alone or Combined With Novel Agents for Unresectable Stage III Non Small Cell Lung Cancer Update From the COAST Randomized Clinical Trial

Aggarwal C, Martinez-Marti A, Majem M, et al. JAMA Netw Open. 2025 Jul 1;8(7):e2518440. doi:10.1001/jamanetworkopen.2025.18440.

Introduction

The COAST trial examines combining durvalumab with oleclumab or monalizumab to improve outcomes in unresectable stage III NSCLC patients after chemoradiotherapy.

Study Overview

Study Type: Open-label phase 2 randomized trial

Population: 189 patients with unresectable stage III NSCLC post cCRT

Intervention: Durvalumab alone vs durvalumab + oleclumab vs durvalumab + monalizumab

Outcomes: Objective response rate, progression-free survival, overall survival, safety

Key Findings

• ORR higher with combinations: 35.0% (oleclumab), 40.3% (monalizumab) vs 23.9% (durvalumab alone); not statistically significant
• Both combos significantly prolonged PFS: HR 0.59 (oleclumab), 0.63 (monalizumab)
• No OS benefit detected yet for combinations
• Safety similar across groups; no new safety signals

Context & Related Research

• Antonia et al., 2017: PACIFIC trial demonstrated durvalumab consolidation improved PFS and OS over placebo in unresectable stage III NSCLC, establishing current standard of care (PMID: 29114832).
• Spigel et al., 2022: Five-year PACIFIC follow-up confirmed durable OS benefits with durvalumab (PMID: 35378484), supporting long-term treatment efficacy.
• Aggarwal et al., 2025: COAST phase 2 showed novel combinations extend PFS with no new safety issues, building on PACIFIC (PMID: 40663352).
• Barlesi et al., 2024: PACIFIC-9 trial (ongoing phase 3) designed to confirm OS benefits of durvalumab + oleclumab or monalizumab vs durvalumab alone (PMID: 36216358).

Clinical Implications

• Novel combinations show PFS benefits and maintain safety in unresectable stage III NSCLC post cCRT.
• OS benefit not yet established; use to be confirmed by phase 3 trials.
• These approaches may represent a promising advance for patients without progression after cCRT.

Strengths & Limitations

Future Directions

Further phase 3 investigation (PACIFIC-9) is essential to validate overall survival benefit and long-term safety of durvalumab combinations with oleclumab or monalizumab. Biomarker-driven studies and combination strategies should also be explored.

Conclusion

Combining consolidation durvalumab with oleclumab or monalizumab shows promise in improving progression-free survival for unresectable stage III NSCLC, supporting further phase 3 investigation to confirm long-term clinical benefit.

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Citations

1. Antonia et al., 2017. New England Journal of Medicine. PMID: 29114832.
2. Spigel et al., 2022. Journal of Thoracic Oncology. PMID: 35378484.
3. Aggarwal et al., 2025. JAMA Network Open. PMID: 40663352.
4. Barlesi et al., 2024. ClinicalTrials.gov. PMID: 36216358.