Gemcitabine Plus S-1 Is Option for Biliary Tract Cancer in Japan

Roxanne Nelson, RN, BSN

January 29, 2018

SAN FRANCISCO — Gemcitabine plus S-1 (Taiho Pharmaceutical) could be a new standard of care for Japanese patients with advanced biliary tract cancer, according to the findings of the phase 3 FUGA-BT trial.

These findings are anticipated to offer clinicians a new option in Japan, commented lead author, Chigusa Morizane, MD, PhD, from the National Cancer Center in Tokyo, Japan, who presented the results here at the Gastrointestinal Cancers Symposium (GICS) 2018.

"Gemcitabine and S-1 demonstrated noninferiority to gemcitabine and cisplatin in overall survival and met its primary endpoint," said Dr Morizane. "It had good tolerability and can be considered a new convenient option of standard of care without the need for hydration."

In biliary tract cancer, curative surgical resection currently offers the only chance for cure, but most patients are initially diagnosed with unresectable disease, explained Dr Morizane. "And even after curative surgery, many patients subsequently develop recurrence."

Because many patients are diagnosed with unresectable disease, more effective and tolerable chemotherapy is needed to improve their prognosis and quality of life, he said.

Gemcitabine has been considered the de facto standard chemotherapy since it received approval in 2006, for the treatment of biliary tract cancer in Japan. S-1 was also approved for biliary tract cancer in 2007, and it is primarily used as a second-line therapy.

The standard of care in Japan for advanced biliary tract cancer is gemcitabine plus cisplatin. However, patients receiving this regimen typically survive less than 12 months, may experience considerable toxicity, and may require hydration before and after administration, primarily because of the cisplatin.

But another expert did not make a big deal out of the hydration issue. Acting as a meeting discussant, Brian M. Wolpin, MD, from the Dana-Farber Cancer Institute, Boston, Massachusetts, said, "There is some moderate inconvenience to receiving IV [intravenous] fluids around the cisplatin when gemcitabine and cisplatin is delivered."

S-1 is composed of tegafur (a pro-drug of 5-fluoroucil), gimeracil, and oteracil potassium. Its use has been investigated in other gastrointestinal cancers in Japanese populations, including pancreatic cancer, for which it significantly increased overall survival in as compared with gemcitabine. It has also been studied as adjuvant therapy in patients with curative resected gastric cancer.

Noninferior But Not Superior

Dr Morizane explained that their study built on promising phase 2 data from a randomized selection design study that compared gemcitabine plus S-1 with S-1 alone. The 1-year survival was better with combination therapy than with S-1 alone, with acceptable toxicity, suggesting this was a promising regimen. (Jpn J Clin Oncol. 2010;40:1189-1191).

"This phase 3 study aimed to confirm the noninferiority of gemcitabine and S-1 to gemcitabine plus cisplatin in terms of overall survival," he said. "If noninferiority was confirmed, we planned to evaluate the superiority of gemcitabine and S-1 to gemcitabine plus cisplatin."

The cohort consisted of 354 patients with recurrent or unresectable biliary tract cancer, who were randomly assigned to receive gemcitabine/S-1 (1 g/m2 of gemcitabine was infused on days 1 and 8, and S-1 at 60, 80, or 100 mg/day according to body surface area was administered from days 1 to 14 of a 21-day cycle) or gemcitabine/cisplatin (1 g/m2 of gemcitabine and 25 mg/m2 of cisplatin was infused on days 1 and 8 of a 21-day cycle).

The study met the primary endpoint of noninferiority.

The median overall survival was 15.1 months with gemcitabine/S-1 treatment vs 13.4 months with gemcitabine/cisplatin (hazard ratio [HR], 0.95; 90% confidence interval [CI], 0.78 - 1.15; P = .046 for noninferiority).

Overall survival was 59.2% in the gemcitabine/S-1 group  vs 58.3% in the gemcitabine/cisplatin group at 1 year.

Median progression-free survival was also superior in the gemcitabine/S-1 group (6.8 months vs 5.8 months: HR, 0.86; 95% CI, 0.70 - 1.07).

However, the response rate was better in patients who received gemcitabine/cisplatin: 32.4% vs 29.8%.

"The P value was significant for noninferiority," said Dr Morizane, "but superiority of gemcitabine/S-1 over gemcitabine/cisplatin was not shown."

Subgroup analysis confirmed the noninferiority of gemcitabine/S-1 vs gemcitabine/cisplatin across patient subgroups.

"These results in both arms were better than expected," Dr Morizane said.

Both treatments were generally well tolerated, although clinically relevant adverse events were higher in the group that received cisplatin (34.7% vs 31.2 %).

Split Them Rather Than Lump Them

In discussing the study, Dr Wolpin noted that the FUGA-BT trial addressed several important questions in biliary tract cancer.

He noted the relatively few randomized trials conducted in this setting that would help in the selection of appropriate therapy.

Dr. Wolpin added that these are relatively uncommon cancers, so conducting larger trials is more difficult. "They are heterogeneous, and until recently, we have had a limited biological understanding of these diseases."

While these results support the use of gemcitabine/S-1 in Japanese patients with a full spectrum of biliary tract cancers, with unreported germline and somatic genetics, he believes that in the future it may be more effective to split them up into their distinct subtypes.

"Rather than lumping than together as one disease, the future is in understanding the drivers in these tumors and using those to make treatment decisions," Dr Wolpin concluded.

The study was conducted by the Japanese Clinical Oncology Group. Dr Morizane has made the following disclosures: honoraria: Fujifilm, Lilly, Nobelpharma, Novartis, Pfizer, Yakult Honsha; consulting or advisory role:  AstraZeneca, Novartis, Taiho Pharmaceutical, Yakult Honsha; research funding (all institutional): Eisai, GlaxoSmithKline, Nobelpharma, ONO Pharmaceutical, Pfizer, Taiho Pharmaceutical, Yakult Honsha. Dr Wolpin has disclosed a consulting/advisory role with Genentech.

Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 205. Presented January 19, 2018.

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