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Immune mediated adverse events in the randomized phase 3 TOPAZ 1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer
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Daily Literature Update
Immune mediated adverse events in the randomized phase 3 TOPAZ 1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer
Antonuzzo L, Takahashi H, Park JO, et al. Oncologist. 2025 Jul;30(7):oyaf148. PMID:40622010.
Durvalumab plus gemcitabine and cisplatin improves survival in advanced biliary tract cancer with manageable immune-mediated adverse events, highlighting the importance of monitoring during treatment.
Study Type: Phase 3 randomized, placebo-controlled trial
Population: 680 advanced biliary tract cancer patients
Intervention: Durvalumab (1500 mg) plus gemcitabine and cisplatin vs placebo plus same chemotherapy
Outcomes: Incidence and timing of immune-mediated adverse events (imAEs), overall survival (OS)
Key Findings
- 13.9% imAE incidence with durvalumab vs 4.7% with placebo
- Median time to imAE onset: 127 days (durvalumab) vs 86.5 days (placebo)
- Most imAEs were low grade and manageable, primarily hypothyroidism and skin events
- Durvalumab improved overall survival regardless of imAE occurrence; OS HR with imAEs 0.59 vs 0.83 without
Context & Related Research
- Antonuzzo et al., 2025: TOPAZ-1 primary report, demonstrating OS benefit and manageable imAEs (PMID:40622010), core trial evidence
- Oh et al., 2025: 3-year follow-up confirming long-term survival benefit and safety (PMID:40381735), consolidating durable outcomes
- Reimann et al. & Li et al., 2025: Systematic reviews/meta-analyses supporting chemo-immunotherapy efficacy and tolerability (PMID:40700609, 39980751)
- Gerhardt et al. & Inokawa et al., 2025: Real-world data validating trial results in clinical practice (PMID:40533571, 40765809)
- Lo Prinzi et al., 2025: Impact of corticosteroids negatively influencing outcomes (PMID:40641448), critical for patient management
- Vitiello et al., 2025: Antibiotic use effects on immunotherapy efficacy (PMID:40815107), highlighting confounding factors
- Rimini et al., 2025: Baseline molecular biomarkers influencing prognosis and response (PMID:40608977)
- Vrana et al., 2025: Microbiome research as a future step in understanding immunotherapy toxicity (PMID:40728861)
Clinical Implications
- Durvalumab plus GemCis offers a survival benefit with generally manageable immune side effects.
- Low-grade hypothyroidism and skin reactions are common imAEs and should be monitored and treated accordingly.
- Careful patient management, including consideration of concomitant corticosteroids or antibiotics, can optimize outcomes.
Strengths & Limitations
| Strengths | Limitations |
|---|---|
| Large randomized global phase 3 trial with robust OS and safety data | Exploratory post-hoc design with limited power for imAE subgroup stat. significance |
| Comprehensive assessment of immune-mediated adverse events using landmark analysis | Low number of imAE events limits precision; generalizability limited by eligibility criteria |
Future Directions
Further research is needed for predictive biomarkers of severe imAEs, better understanding of microbiome effects on immunotherapy, and standardized management protocols tailored to chemo-immunotherapy for advanced biliary tract cancer.
Conclusion
Durvalumab plus gemcitabine and cisplatin improves overall survival in advanced biliary tract cancer patients with manageable immune-mediated adverse events, supporting its use regardless of imAE occurrence.
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