A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1.

Abstract

378 Background: BTC is a rare, heterogenous cancer with poor prognosis. Reports on immunogenic features of BTC suggest checkpoint inhibition may result in antitumor immune responses, and limited clinical activity has been seen with single agents in advanced settings. Durvalumab (PD-L1 inhibitor) + GemCis showed promising antitumor activity in advanced BTC in a phase 2 study. TOPAZ-1 (NCT03875235) is the first global phase 3 study to evaluate first-line immunotherapy + GemCis in advanced BTC. Methods: In this double-blind study, pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized 1:1 to receive durvalumab (1500 mg every 3 weeks [Q3W]) or placebo + GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by durvalumab (1500 mg Q4W) or placebo until disease progression or unacceptable toxicity. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer). The primary objective was to assess overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff for this interim analysis (11 August 2021), 685 pts were randomized to durvalumab + GemCis (n=341) or placebo + GemCis (n=344; Table). The primary objective was met: durvalumab + GemCis significantly improved OS vs placebo + GemCis (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p=0.021). PFS was also significantly improved with durvalumab vs placebo (HR, 0.75; 95% CI, 0.64–0.89; p=0.001). ORR was 26.7% with durvalumab and 18.7% with placebo. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 62.7% of pts receiving durvalumab and 64.9% of pts receiving placebo. TRAEs led to discontinuation of any study medication in 8.9% of pts receiving durvalumab and 11.4% of pts receiving placebo. Conclusions: In pts with advanced BTC, durvalumab + GemCis significantly improved OS and PFS vs placebo + GemCis with manageable safety, indicating durvalumab + GemCis may be a new first-line standard of care regimen. Clinical trial information: NCT03875235. [Table: see text]

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“…ORR was 26.7% with durvalumab and 18.7% with placebo. Grade 3/4 treatment-related adverse events (TRAEs) were comparable between the two arms [ 92 ]. Interestingly, separation of both the PFS and OS curves between the two groups appeared to occur after chemotherapy was completed, raising the question of the benefit of durvalumab when chemotherapy was concurrently administered.…”

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“…It should be noted that preliminary results of the TOPAZ-1 trial evaluating durvalumab in combination with in advanced CCA displayed encouraging results, revealing that the checkpoint inhibitor durvalumab + gemcitabine & cisplatin (GemCis) significantly improved overall (OS) and progression-free survival (PFS) in patients with advanced CCA compared to placebo + GemCis with acceptable safety margins. This implies that durvalumab + GemCis could be a new first-line standard of care regimen in the near future [ 11 ].…”

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“…Median PFS was 12.2 months, and median OS was 19.2 months, which compares favorably to historical controls. Lately, positive results with the addition of durvalumab to chemotherapy was achieved in the TOPAZ-1 trial ( 8 ). In the study, durvalumab combined with cisplatin and gemcitabine conferred a 20% reduction in the risk of death compared with gemcitabine and cisplatin alone, meeting the primary endpoint of the trial, PFS and response rate were also improved with the combination ( 8 ).…”

“…Lately, positive results with the addition of durvalumab to chemotherapy was achieved in the TOPAZ-1 trial ( 8 ). In the study, durvalumab combined with cisplatin and gemcitabine conferred a 20% reduction in the risk of death compared with gemcitabine and cisplatin alone, meeting the primary endpoint of the trial, PFS and response rate were also improved with the combination ( 8 ). Although FOLFIRINOX is an effective regimen in pancreatic cancer, in advanced biliary cancers it was not superior to gemcitabine and cisplatin in the phase II randomized trial PRODIGE 38 AMEBICA ( 9 ).…”