Immune mediated adverse events in the randomized phase 3 TOPAZ 1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer summary

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Britany: Welcome back to PACULit, your daily literature update for clinical pharmacists and physicians. Today, we’re discussing the phase 3 TOPAZ-1 study, which evaluates immune-mediated adverse events, or imAEs, in advanced biliary tract cancer treated with durvalumab plus gemcitabine and cisplatin. Seth, what’s your initial take on the clinical problem and rationale behind this study?

Seth: Advanced biliary tract cancer, or aBTC, is rare and aggressive with poor prognosis. Gemcitabine plus cisplatin (GemCis) has been the standard first-line therapy but with limited survival benefit. Immune checkpoint inhibitors like durvalumab have transformed treatment in other cancers, but their role in aBTC was unclear before TOPAZ-1. This study aimed to assess safety, especially immune-mediated adverse events, when combining durvalumab with GemCis.

Britany: That’s key because aBTC patients often have compromised liver function and comorbidities, complicating immune toxicities. Before TOPAZ-1, phase 3 data on combining ICIs with chemotherapy in this population were limited. Understanding imAE incidence, timing, and management was a major gap.

Seth: Exactly. Early-phase trials showed promising efficacy with durvalumab plus GemCis but lacked robust safety data. Balancing survival benefits against immune toxicities is crucial. The study included unresectable or metastatic biliary tract cancers—both intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer—reflecting a heterogeneous, global patient population.

Britany: Let’s review the study design. TOPAZ-1 was a phase 3, randomized, double-blind, placebo-controlled trial enrolling 680 patients with histologically confirmed advanced biliary tract cancer. Patients had ECOG performance status 0 or 1 and no prior systemic therapy for advanced disease.

Seth: Patients with active autoimmune diseases, prior immunotherapy, or uncontrolled comorbidities were excluded to reduce confounding. The intervention arm received durvalumab 1500 mg IV every three weeks plus gemcitabine and cisplatin. The control arm received placebo plus the same chemotherapy.

Britany: Chemotherapy was given for up to eight cycles; durvalumab or placebo continued as maintenance until progression or unacceptable toxicity. The primary endpoint was overall survival; secondary endpoints included progression-free survival, objective response rate, and safety. They also examined incidence, timing, and management of imAEs.

Seth: The analysis was intention-to-treat. Survival outcomes used hazard ratios with 95% confidence intervals. Adverse events were reported descriptively, comparing incidence between arms. Subgroup analyses assessed outcomes based on imAE occurrence, providing insight into clinical impact.

Britany: Regarding baseline characteristics, median age was about 65, with balanced sex distribution. Most had ECOG 0 or 1, indicating preserved function despite advanced disease.

Seth: Disease types included intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, reflecting real-world heterogeneity. Global enrollment added diversity, enhancing generalizability.

Britany: Key findings showed imAE incidence of 13.9% in the durvalumab arm versus 4.7% with placebo—a notable but still relatively low increase.

Seth: Median time to imAE onset was 127 days with durvalumab versus 86.5 days with placebo. Most imAEs were low grade, mainly hypothyroidism and skin reactions like rash or pruritus, consistent with known PD-L1 inhibitor profiles.

Britany: Importantly, durvalumab improved overall survival regardless of imAE occurrence. The hazard ratio for death was 0.59 in patients with imAEs versus 0.83 without, suggesting immune toxicity might correlate with better efficacy.

Seth: This aligns with other immunotherapy studies where imAEs may indicate immune activation and response. But we must not overlook toxicity management despite potential efficacy signals.

Britany: Right. Most imAEs were manageable with corticosteroids for severe cases and hormone replacement for hypothyroidism. Early recognition and treatment are vital to keep patients on therapy.

Seth: However, real-world data, like Lo Prinzi et al., suggest corticosteroids might negatively impact outcomes in biliary tract cancer patients receiving chemo-immunotherapy, highlighting the need to balance toxicity management with preserving efficacy.

Britany: Minimizing unnecessary corticosteroid use and carefully weighing risks is essential. Also, prior antibiotic use may influence outcomes by altering the gut microbiome, an emerging area in immunotherapy response and toxicity.

Seth: The microbiome’s role is gaining attention. Vrana et al. discussed how gut flora might modulate immune-related adverse events and treatment efficacy, potentially leading to predictive biomarkers or new interventions.

Britany: On biomarkers, Rimini et al. explored molecular alterations in aBTC patients receiving durvalumab plus chemotherapy. Identifying prognostic and predictive markers could help tailor therapy and anticipate adverse events.

Seth: That would be transformative. Currently, robust predictive biomarkers for severe imAEs in this setting are lacking. TOPAZ-1’s exploratory analyses provide a foundation, but more prospective mechanistic studies are needed.

Britany: Real-world evidence from Germany and Japan supports TOPAZ-1’s efficacy and safety findings, validating the regimen’s applicability in clinical practice.

Seth: Indeed, Gerhardt et al. and Inokawa et al. reported similar survival benefits and manageable toxicity, reinforcing durvalumab plus GemCis as a new standard for advanced biliary tract cancer.

Britany: To summarize, TOPAZ-1 shows adding durvalumab to gemcitabine and cisplatin improves overall survival with a manageable increase in immune-mediated adverse events, mostly low grade hypothyroidism and skin reactions, effectively managed with established protocols.

Seth: Survival benefit appears independent of imAE occurrence, though imAEs may correlate with enhanced efficacy. Clinicians should monitor closely for immune toxicity, avoid unnecessary corticosteroids, and consider antibiotics’ impact on the microbiome.

Britany: Future research should focus on predictive biomarkers for severe imAEs, microbiome roles, and standardized management guidelines specific to chemo-immunotherapy in biliary tract cancer.

Seth: This evolving evidence will optimize outcomes by balancing efficacy and safety. TOPAZ-1 and subsequent studies mark significant progress in this challenging disease.

Britany: Thanks for the insightful discussion, Seth. For our listeners, staying current with these developments is crucial. We encourage reviewing the full TOPAZ-1 publication and related literature.

Seth: Absolutely, Britany. It’s exciting to see immunotherapy advancing in biliary tract cancer, and understanding immune-mediated adverse events will be key to maximizing patient benefit.

Britany: That wraps up today’s PACULit update. Stay tuned for more clinical literature insights, and thanks for listening.