Pancreatic cancer remains challenging to treat, particularly in patients with unresectable or metastatic disease. Although combination chemotherapy regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel have improved clinical outcomes, disease progression remains common, highlighting the need for more effective treatment strategies.
S-1, an oral fluoropyrimidine, has previously demonstrated activity in pancreatic cancer, including non-inferiority to gemcitabine in advanced disease and superior survival compared with gemcitabine in the adjuvant setting. Building on these findings, investigators evaluated whether adding S-1 to gemcitabine plus nab-paclitaxel could improve antitumor activity in patients with advanced pancreatic cancer.
A multicenter phase II study, known as the GeNeS1S trial, investigated the efficacy and safety of this triplet chemotherapy regimen in patients with locally advanced, recurrent, or metastatic pancreatic cancer.
The findings were published on October 16, 2026, in the European Journal of Cancer, under the original title: “Triplet chemotherapy with Gemcitabine, Nab-paclitaxel, and S-1 achieves high response and conversion rates in advanced pancreatic cancer: A multicenter phase II study (GeNeS1S trial).”
The study was authored by Yoshiaki Nagatani, Naoko Chayahara, Hironaga Satake, Hisateru Yasui, Takeshi Sugimoto, Hirochika Toyama, Kazutoshi Tobimatsu, Eriko Ito, Yutaro Usui, Taiji Koyama, Shiro Kimbara, Yoshinori Imamura, Yohei Funakoshi, Masanori Toyoda, Naomi Kiyota, and Hironobu Minami.
Study Design and Patient Population
GeNeS1S was a prospective, open-label, single-arm phase II trial conducted across four institutions in Japan. The study enrolled 30 patients between September 2018 and April 2024. Eligible patients were aged 20 years or older and had histologically or cytologically confirmed pancreatic adenocarcinoma with locally advanced unresectable, recurrent, or metastatic disease. Patients were required to have an ECOG performance status of 0–1, measurable disease according to RECIST 1.1, and no previous systemic treatment for advanced disease.
Of the 30 enrolled patients, 5 (16.7%) had locally advanced disease, 7 (23.3%) had recurrent disease, and 18 (60.0%) had metastatic disease. The median age was 62.5 years, and all patients received at least one dose of study treatment. The GeNeS1S regimen consisted of gemcitabine at 600 mg/m² and nab-paclitaxel at 90 mg/m² administered intravenously on days 1 and 8, combined with oral S-1 on days 1–14 of each 21-day cycle. The daily dose of S-1 ranged from 50 to 80 mg according to body surface area.
The primary endpoint was objective response rate (ORR), assessed according to RECIST 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), primary tumor response, conversion surgery rate, and safety.
Efficacy Outcomes
The study met its prespecified primary endpoint, with an ORR of 63.3% (19/30; 95% CI, 45.5–78.2%) in the intention-to-treat population.
Among the 30 patients, 2 (6.7%) achieved a complete response, 17 (56.7%) had a partial response, and 7 (23.3%) experienced stable disease. Progressive disease was recorded as the best overall response in 2 patients (6.7%), while another 2 patients were not evaluable for response.
The resulting DCR was 86.7% (26/30; 95% CI, 69.7–95.3%). Among the 19 patients with confirmed responses, median DoR was 8.6 months (95% CI, 4.7–12.5). Four patients continued to have an ongoing response at the data cutoff.
At a median follow-up of 12.3 months, survival outcomes in the overall population were:
- Median PFS: 9.0 months (95% CI, 7.5–10.5).
- Median OS: 15.0 months (95% CI, 12.6–17.4).
In a post hoc exploratory analysis restricted to the 25 patients with recurrent or metastatic disease, median PFS was 8.9 months (95% CI, 7.3–10.4), while median OS was 13.4 months (95% CI, 10.6–16.2). These findings describe the activity of the triplet regimen in a relatively small and heterogeneous population. As the study did not include a control arm, the survival outcomes cannot establish an advantage over existing chemotherapy regimens.
Primary Tumor Response and Conversion Surgery
The investigators also evaluated changes in the primary pancreatic lesion and the possibility of subsequent surgical resection in patients with locally advanced disease. Among 23 patients with measurable primary pancreatic tumors, the ORR was 65.2% (15/23), while the DCR reached 95.7% (22/23). No primary tumor progression was observed among evaluable patients.
In the subgroup with locally advanced pancreatic cancer, all 5 patients achieved a partial response, corresponding to an ORR of 100%. Following systemic treatment, 3 of these 5 patients (60.0%) underwent conversion surgery, achieving either R0 or R1 resection.
However, all three patients subsequently developed recurrent disease. Disease-free survival after surgery was 4.3, 6.5, and 7.3 months, respectively. Two patients experienced distant metastatic recurrence, while one developed local recurrence.
All three patients remained alive at the November 30, 2024, data cutoff, with a median postoperative follow-up of 16.5 months. Although conversion surgery was feasible in three patients, the small subgroup and subsequent recurrences limit conclusions regarding long-term clinical benefit. Decisions about surgical eligibility were made through multidisciplinary assessment, without uniform protocol-defined conversion criteria.
Safety and Treatment Tolerability
Hematologic adverse events were relatively frequent during treatment with GeNeS1S. Grade 3 or higher hematologic toxicities occurred in 50.0% of patients, with neutropenia being the most common, reported in 43.3%. Grade 3 or higher anemia and thrombocytopenia each occurred in 3.3% of patients.
Among non-hematologic adverse events, grade 3 or higher anorexia and biliary tract infection were each reported in 6.7% of patients. Grade 3 or higher diarrhea occurred in 3.3%. Dose reductions were required in 12 of 30 patients (40.0%), primarily because of neutropenia. No cases of febrile neutropenia or treatment-related deaths were reported.
The investigators reported that adverse events were managed with dose modifications and supportive care. Nevertheless, the frequency of hematologic toxicity remains relevant when considering further investigation of this three-drug combination.
Clinical Implications and Future Directions
The GeNeS1S trial provides preliminary evidence of antitumor activity with gemcitabine, nab-paclitaxel, and S-1 in patients with advanced pancreatic cancer. The ORR of 63.3% met the study’s prespecified efficacy endpoint, while disease control and primary tumor responses were also observed. The conversion to surgery in three patients with locally advanced disease suggests that the regimen warrants further investigation in settings where tumor shrinkage may influence resectability.
However, several limitations must be considered. The trial included only 30 patients and had no randomized comparator. It also enrolled patients with locally advanced, recurrent, and metastatic disease, making the overall survival estimates difficult to interpret across different clinical settings.
Importantly, the study was not designed to determine whether adding S-1 improves survival compared with gemcitabine plus nab-paclitaxel alone or with other established combination regimens. The authors proposed further investigation of GeNeS1S, particularly in borderline resectable or locally advanced pancreatic cancer, where response to preoperative treatment may influence subsequent surgical management.
Conclusion
The multicenter phase II GeNeS1S trial met its primary endpoint, reporting a 63.3% objective response rate with gemcitabine, nab-paclitaxel, and S-1 in patients with locally advanced, recurrent, or metastatic pancreatic cancer.
The regimen demonstrated antitumor activity, including primary tumor responses and conversion to surgery in a small subgroup of patients with locally advanced disease. However, all three patients who underwent conversion surgery subsequently experienced recurrence, and grade 3 or higher hematologic adverse events were frequent.
These findings support further evaluation of the GeNeS1S regimen but do not establish superiority over current treatment options. Larger randomized studies are needed to determine whether the observed response rates translate into improved survival and whether this approach has a role in the management of locally advanced or borderline resectable pancreatic cancer.
The full article is available in European Journal of Cancer.
