Among patients with newly diagnosed advanced biliary tract cancers (BTCs), the addition of taxane with the gemcitabine, nab-paclitaxel and cisplatin regimen, also known as GAP, did not improve overall survival (OS), and more toxicity was encountered with GAP compared with gemcitabine and cisplatin (GC), according to study findings published in Journal of Clinical Oncology.
“To our knowledge, SWOG S1815 was the first randomized, phase 3 trial conducted entirely in the United States for newly diagnosed advanced BTCs,” study authors wrote, “The study accrued over 450 patients in just over two years, demonstrating the large unmet need for novel therapies for this patient population.”
The median OS was 14 months and 13.6 months for the GAP and GC groups, respectively. The median progession-free survival was 7.5 months and 6.3 months, respectively. According to the study, these data do not represent a significant difference in OS between the two treatment groups.
An exploratory subset analyses showed greater OS and progression-free survival (PFS) benefits with GAP treatment compared to GC in locally advanced disease versus metastatic disease, though not statistically significant. GAP also showed greater PFS improvement in gallbladder cancer patients compared to those with intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma, but not OS.
“These [exploratory subset analysis] results suggest tumor heterogeneity and differences in therapeutic susceptibility among BTCs, as these effects were not observed in TOPAZ-1 with GC plus durvalumab,” study authors wrote.
Regarding safety, a total of 421 participants (95%) were evaluable for side effects. Grade 3 (severe) to 4 (life-threatening) treatment-related side effects seen in at least 10% of participants included anemia, neutropenia and thrombocytopenia. Significantly more participants in the GAP group had grade 3 or worse hematologic side effects compared to the GC group (60% versus 45%).
Nonhematologic side effects were more frequent in the GAP group, including ALT increase, anorexia, constipation, diarrhea, edema, fatigue, hypomagnesemia, nausea, sepsis, sensory peripheral neuropathy and vomiting. Seven deaths occurred in the GAP group, with one in the GC group. The GAP group had significantly higher rates of dose modifications (88% versus 78%), while rates of treatment discontinuation due to toxicity were similar across groups.
“Not surprisingly, grades 3 and 4 hematologic [side effects] and grade 3 peripheral sensory neuropathy were higher with GAP treatment versus GC alone,” study authors wrote. “Therefore, despite the promising efficacy signal in the phase 2 study of GAP, this phase 3 study did not confirm the benefit of triplet cytotoxic therapy in an unselected BTC population.”
A total of 441 patients were eligible and analyzable, of which, 67% had intrahepatic cholangiocarcinoma, 16% had gallbladder carcinoma and 17% had extrahepatic cholangiocarcinoma. A total of 73% of patients had metastatic disease.
Patients were randomly assigned to receive either GAP, which included gemcitabine 800 milligrams per square meter (mg/m2), cisplatin 25 mg/m2 and nab-paclitaxel 100 mg/m2 intravenously (through the vein) once daily on days one and eight of a 21-day cycle, or GC, which included gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 intravenously once daily on days one and eight of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity and followed up to three years after random assignment or death.
The primary end goal of the study was OS, defined as time from random assignment to death due to any cause, with censoring at the time of last contact.
“Acknowledging the heterogeneous biology of biliary malignancies, there is a need for rational genomic, transcriptomic and artificial intelligence tools to not only select patients for targeted molecular and immune therapies, but also to guide targeted cytotoxic chemotherapies in future clinical trials,” study authors concluded.
Reference:
“SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers,” By Dr. Rachna T. Shroff, et al. Journal of Clinical Oncology.
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