Dr. Chigusa Morizane presents Abstract 205 during Oral Abstract Session B.
Chigusa Morizane, MD, PhD, of the National Cancer Center, in Japan, presented the FUGA-BT findings on behalf of the Japanese Clinical Oncology Group, which conducted the study.
Biliary tract cancer is a rare disease that comprises a heterogeneous group of neoplasms, including carcinomas of the intrahepatic bile duct, extrahepatic bile duct, gallbladder, and ampulla of Vater. Most patients have unresectable disease at diagnosis, and those with disease identified earlier who undergo potentially curative surgical resection ultimately develop recurrence.
Gemcitabine plus cisplatin is the standard of care for advanced biliary tract cancer since it provides the best clinical outcomes. Still, patients receiving this regimen typically survive less than 12 months and experience considerable nausea, vomiting, and appetite loss that requires hydration before and after administration, largely because of cisplatin inclusion.
S-1 consists of tegafur (a prodrug of 5-flurouracil) and two biomodulators that maintain high serum 5-flurouracil concentrations while reducing gastrointestinal toxicity. S-1 is widely used to treat various solid tumors in East Asia, especially gastric cancer. The FUGA-BT trial was designed to determine whether replacing cisplatin with S-1, when used in combination with gemcitabine, might yield similar efficacy and better safety compared with conventional therapy.
Toward this end, 354 patients with recurrent or unresectable biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function were randomly assigned to receive gemcitabine/S-1 or gemcitabine/cisplatin from May 2013 through March 2016. Patients were excluded if they previously received chemotherapy or radiotherapy for other malignancies; however, they could have undergone surgery or biliary drainage for biliary tract cancer. The primary objective was to demonstrate the noninferiority of gemcitabine/S-1 versus gemcitabine/cisplatin for the primary endpoint of overall survival (OS).
The study met the primary endpoint. Median OS reached 15.1 months with gemcitabine/S-1 treatment versus 13.4 months with gemcitabine/cisplatin treatment. “These results in both arms were better than expected,” Dr. Morizane said. The hazard ratio (HR) of 0.945 (90% CI [0.777, 1.149]; p = 0.0459) fell within the prespecified threshold for noninferiority of 1.155. Subgroup analysis confirmed the noninferiority of gemcitabine/S-1 versus gemcitabine/cisplatin across relevant patient populations.
Other key efficacy outcomes were also similar for gemcitabine/S-1 as compared with gemcitabine/cisplatin. Median progression-free survival was 6.8 months with gemcitabine/S-1 versus 5.8 months with gemcitabine/cisplatin (HR 0.864, 95% CI [0.697, 1.070]). Likewise, the overall response rates among patients were 29.8% with gemcitabine/S-1 and 32.4% with gemcitabine/cisplatin (p = 0.70).
Overall, the gemcitabine/S-1 regimen demonstrated favorable tolerability when compared with gemcitabine/cisplatin. The incidence of grade 3/4 leukocytopenia (24.9% vs. 31.6%), anemia (6.2% vs. 24.0%), and thrombocytopenia were all reduced, although the incidence of grade 3/4 maculopapular rash (6.2% vs. 0%) was slightly increased. Moreover, no treatment-related deaths occurred with gemcitabine/S-1, whereas three treatment-related deaths occurred with gemcitabine/cisplatin.
A key secondary endpoint of the study was to compare the incidence of clinically relevant adverse events, which included grade 2 or higher fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea. These events occurred in 29.9% of patients who received gemcitabine/S-1 as compared with 35.1% of patients who received gemcitabine/cisplatin.
Dr. Morizane stressed that the gemcitabine/S-1 regimen also had the added convenience of not requiring pre- or post-infusion hydration.
Slightly more than 80% of patients in each arm went on to receive second-line chemotherapy. Of note, 56% of patients originally treated with gemcitabine/S-1 went on to receive gemcitabine/cisplatin, and 55% originally treated with gemcitabine/cisplatin went on to receive S-1 with or without gemcitabine.
Discussant Brian M. Wolpin, MD, of the Dana-Farber Cancer Institute, noted that the FUGA-BT trial addresses several important issues in biliary tract cancer. “These diseases have high morbidity and mortality, we don’t have a lot of treatment options. There are few randomized trials to help us decide what therapy is appropriate, and, as was discussed, there is some moderate inconvenience to receiving IV fluids around the cisplatin when gemcitabine and cisplatin is delivered.”
Dr. Wolpin acknowledged that the FUGA-BT findings support use of gemcitabine/S-1 in Japanese individuals with biliary tract cancer when the mutational profile is unknown. Moving forward, however, he believes that it may be more effective to split the spectrum of biliary tract cancers into their distinct subtypes, as emerging research indicates that the different subtypes feature distinct mutational profiles that may be more amenable to one type of therapy versus another.
– Kara Nyberg, PhD