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Longer survival and delayed disease progression when adding S-1 to gemcitabine-cisplatin in newly diagnosed patients with advanced biliary tract cancer

The combination of gemcitabine and cisplatin (GC) is currently the established palliative chemotherapy for patients with advance biliary tract cancer (BTC). Data from a phase III trial presented at ESMO 2018 challenge this standard by showing that the addition of S-1 to this chemotherapy doublet leads to a statistically significant prolongation in the overall (OS) and progression-free survival (PFS). Adding S-1 to GC also almost tripled to response rate from 15% with GC alone to 41% with the triple combination.

Results of a previously reported phase I/II study (KHBO1002) suggested promising clinical efficacy of the GC plus S-1 (GCS) combination in patients with advanced BTC. In this trial, the median OS with GCS was 16.2 months. These data formed the basis for the KHBO1401-MITSUBA trial in which 246 newly diagnosed patients with advanced BTC were randomized between GC and GC plus S-1. OS was the primary endpoint of the trial, while PFS, overall response rate (ORR) and safety were the key secondary objectives. In order to be eligible for the trial patients had to be chemotherapy-naïve, had to have an ECOG performance status of 0–2 and were required to have an adequate organ function. In the GCS arm, gemcitabine and cisplatin were administered intravenously at doses of 1000 and 25 mg/m2, respectively, on day 1, and oral S-1 was administered daily at a dose of 80 mg/m2 on days 1-7 every 2 weeks. In the GC arm, 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin were infused on days 1 and 8 and repeated every 3 weeks.

The median age of the 246 patients enrolled in the study was 68 years. The median OS with the GCS combination was 13.5 months as compared to 12.6 months seen with GC alone. This difference proved to be borderline significant at a hazard ratio of 0.791 (95%CI: 0.628-0.996; one-sided p= 0.046). At two years, this OS difference translated into a 6.5% absolute difference in survival rate in favour of the GCS combination (28.5% vs. 22.0%). Also with respect to PFS, adding S-1 to GC led to a significant improvement. With GC alone, the median PFS was 5.5 months, while this was two months longer with GCS (HR[95%CI]: 0.748[0.577-0.970]; one-sided p= 0.015). At one year, 16.3% of patients treated with GC were free of progression, while this increased to 25.2% when S-1 was added. Almost three times as much patients treated with GCS experienced a tumour response compared to GC alone, with ORRs of 41.5% and 15.0%, respectively (p< 0.001). The disease control rate (DCR) with GCS was 79.8% vs. 62.0% with GC alone.

Compared to GC treated patients, patients in GCS arm experienced more diarrhoea (24% vs. 14%), stomatitis (28% vs. 13%) and rash (23% vs. 7%). However, these adverse events were almost exclusively low grade (grade 1/2). Surprisingly, sensory neuropathy was more common in GC treated patients than in the GCS cohort (11% vs. 3%).

In summary, this phase III study demonstrates a significant OS and PFS benefit of GCS over GC as first-line treatment for advanced BTC. Also the response rate was significantly higher with GCS than with GC and this did not come at the cost of unacceptable toxicity. As such, the investigators concluded that GCS could represent a new standard treatment for patients with advanced BTC.


Sakai D, Kanai M, Kobayashi S, et al. Randomized phase III study of Gemcitabine, Cisplatin plus S-1 (GCS) versus Gemcitabine, Cisplatin (GC) for Advanced Biliary Tract Cancer (KHBO1401-MITSUBA). Presented at ESMO 2018; Abstract 615O.

Speaker Takehiko Sakai


Takehiko Sakai, MD, PhD, Osaka University graduate school of medicine


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