Phase III RCT: Adding Nab-Paclitaxel to Gemcitabine-Cisplatin Fails to Improve Survival in Advanced Biliary Tract Cancers

Background: Biliary tract cancers (BTCs)—including intrahepatic and extrahepatic cholangiocarcinomas and gallbladder carcinoma—are often diagnosed at advanced stages, leaving few curative options. Gemcitabine-cisplatin (GC) has been the longstanding frontline therapy, yielding modest survival benefits. Preclinical research suggested that nab-paclitaxel might enhance drug delivery to desmoplastic tumors, and an encouraging phase II trial (GAP: gemcitabine, nab-paclitaxel, and cisplatin) spurred further investigation.

Objective: SWOG S1815 was designed to determine whether adding nab-paclitaxel (GAP regimen) to standard GC therapy would improve overall survival (OS) for patients newly diagnosed with locally advanced or metastatic BTCs.

Methods: This phase III, randomized, open-label trial enrolled patients with histologically or cytologically confirmed advanced BTC, excluding those with ampullary cancer (no prior systemic therapy for advanced disease). Participants were randomized 2:1 to receive either GAP (gemcitabine 800 mg/m^2, cisplatin 25 mg/m^2, nab-paclitaxel 100 mg/m^2 on days 1 and 8 of a 21-day cycle) or standard GC (gemcitabine 1,000 mg/m^2 plus cisplatin 25 mg/m^2 on days 1 and 8). The primary outcome was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and toxicity. Disease site (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma) and stage (locally advanced or metastatic) were key stratification factors.

Results: Among 441 eligible patients, 67% had intrahepatic cholangiocarcinoma, 16% had gallbladder carcinoma, and 17% had extrahepatic cholangiocarcinoma, with 73% presenting metastatic disease. Median OS was 14.0 months (95% confidence interval [CI], 12.4-16.1) in the GAP arm versus 13.6 months (95% CI, 9.7-16.6) in the GC arm (hazard ratio [HR], 0.91; P = .41). Similarly, median PFS did not significantly differ (7.5 months v 6.3 months; HR, 0.89; P = .32). Subset analyses hinted that patients with gallbladder carcinoma and those with locally advanced disease might benefit more from the GAP triplet, but these findings were not statistically conclusive. Although ORR was higher with GAP (31% v 21%; P = .03), this did not translate into improved OS. Treatment-related toxicities were more frequent with the triplet regimen. Grade 3 or higher hematologic adverse events occurred in 60% of GAP patients versus 45% of those on GC (P = .003). Additionally, several grade 3-4 nonhematologic toxicities (such as ALT increase, anorexia, constipation, diarrhea, edema, fatigue, hypomagnesemia, nausea, sepsis, sensory peripheral neuropathy, and vomiting) were significantly more common with GAP. Seven treatment-related deaths occurred in the GAP arm, versus one in the GC arm, underscoring the regimen’s higher toxicity burden.

Conclusions: In this unselected BTC population, adding nab-paclitaxel to standard gemcitabine-cisplatin did not confer an OS advantage. Although higher ORR was observed, the toxicity profile was notably increased. Based on these findings, adding nab-paclitaxel to GC does not improve OS and is associated with increased toxicity. Therefore, GC remains the standard first-line treatment for advanced BTC. However, similar to what was observed in the PRODIGE 38 AMEBICA trial, which compared mFOLFIRINOX to GC, there was no survival advantage with the triplet regimen.

Implications for Practice: From a real-world perspective, the triplet regimen elevates both toxicity and likely treatment costs, without demonstrable survival benefit for the broader BTC population. Clinicians may consider GAP in highly selected subsets (for instance, localized unresectable gallbladder disease) or in research settings. Until further evidence clarifies which patients might benefit, GC remains the standard first-line treatment for advanced BTC.

Study Strengths and Limitations: Strengths include the large, multi-institutional, US-based randomized design and robust accrual (enrollment of a sufficient number of participants).* Limitations involve the heterogeneous nature (diversity) of BTCs and the absence of centralized radiologic review (a process where imaging studies are reviewed by a central group of experts rather than solely by local investigators). Furthermore, the trial did not incorporate cost-effectiveness analyses or routine genomic stratification *(classifying patients based on the genetic characteristics of their tumors), which could have refined patient selection.

Future Research: Ongoing investigations seek to integrate precision oncology—encompassing genetic profiling and circulating tumor DNA—to identify subgroups that may benefit from targeted or intensified cytotoxic strategies. Perioperative or adjuvant approaches with GAP or similar triplets might prove more effective in earlier-stage disease. Studies combining novel immunotherapies or targeted agents with chemotherapy could address the evolving BTC landscape.

Reference: Shroff RT, King G, Colby S, et al. SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers. Journal of Clinical Oncology.
DOI: https://doi.org/10.1200/JCO-24-01383