Nab-paclitaxel plus S-1 versus oxaliplatin plus S-1 as first-line treatment in advanced gastric cancer: results of a multicenter, randomized, phase III trial (GAPSO study)

Yu-Hong Dai, Xiong-Jie Yu, Hui-Ting Xu, Liang Zhuang, Ming-Sheng Zhang, Yan-Mei Zou, Qiang Fu, Hong Qiu, Xiang-Lin Yuan, Yu-Hong Dai, Xiong-Jie Yu, Hui-Ting Xu, Liang Zhuang, Ming-Sheng Zhang, Yan-Mei Zou, Qiang Fu, Hong Qiu, Xiang-Lin Yuan

Abstract

Background: This study aimed to investigate the superiority of nab-paclitaxel plus S-1 (AS) over oxaliplatin plus S-1 (SOX) in patients with advanced gastric cancer (AGC).

Methods: In this multicenter, randomized, phase III superiority trial, eligible patients with unresectable, locally advanced gastric adenocarcinoma were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 260 mg/m2 on day 1 or 130 mg/m2 on days 1 and 8; oral S-1 40-60 mg twice daily for 14 days) or SOX (130 mg/m2 oxaliplatin on day 1; oral S-1 40-60 mg twice daily for 14 days) every 3 weeks for up to six cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival, objective response rate, and safety.

Results: Owing to slow enrolment, an unplanned interim analysis was performed, resulting in the early termination of the study on 31 December 2021 (data cutoff). Between March 2019 and March 2021, 97 patients (AS, n = 48; SOX, n = 49) were treated and evaluated for efficacy and safety of AS and SOX. As of the data cutoff, the median follow-up was 23.13 months [95% confidence interval (CI), 13.39-32.87]. The median PFS was 9.03 months (95% CI, 6.50-11.56) in the AS group and 5.07 months (95% CI, 4.33-5.81) in the SOX group, demonstrating a better PFS tendency following AS treatment than SOX treatment (hazard ratio = 0.59; 95% CI, 0.37-0.94; p = 0.03). The most common grade 3 or worse adverse events were anemia, neutropenia, and leukopenia in both groups, with a higher incidence of thrombocytopenia in the SOX group.

Conclusion: Although this study was terminated early, the results demonstrated a better PFS tendency in patients with AGC who were treated with AS than in those treated with SOX, with controllable toxicities.

Trial registration: Clinical Trials.gov identifiers: NCT03801668. Registered January 11, 2019.

Keywords: S-1; advanced gastric cancer; clinical trial; nab-paclitaxel; oxaliplatin.

Conflict of interest statement

Competing Interests: The authors declare that there is no conflict of interest.

© The Author(s), 2022.

Figures

Figure 1.
Figure 1.
Trial profile. AS, nab-paclitaxel plus S-1; COVID-19, coronavirus disease 19; ECOG PS, Eastern Cooperative Oncology Group performance status; SOX, oxaliplatin plus S-1.
Figure 2.
Figure 2.
Survival endpoints in the full analysis set population: (a) PFS (primary endpoint) and (b) OS (secondary endpoint). AS, nab-paclitaxel plus S-1; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; SOX, oxaliplatin plus S-1.
Figure 3.
Figure 3.
Subgroup analyses of PFS based on baseline characteristics. AS, nab-paclitaxel plus S-1; CI, confidence interval; HR, hazard ratio; PFA, progression-free survival; SOX, oxaliplatin plus S-1.

References

    1. Sung H, Ferlay J, Siegel RL, et al.. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209–249.
    1. Zhu Z, Gong YB, Xu HM. Neoadjuvant therapy strategies for advanced gastric cancer: current innovations and future challenges. Chronic Dis Transl Med 2020; 6: 147–157.
    1. Necula L, Matei L, Dragu D, et al.. Recent advances in gastric cancer early diagnosis. World J Gastroenterol 2019; 25: 2029–2044.
    1. Japanese Gastric Cancer A. Japanese gastric cancer treatment guidelines 2018. 5th ed. Gastric Cancer 2021; 24: 1–21.
    1. Muro K, Van Cutsem E, Narita Y, et al.. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann Oncol 2019; 30: 19–33.
    1. Gao K, Wu J. National trend of gastric cancer mortality in China (2003-2015): a population-based study. Cancer Commun (Lond) 2019; 39: 24.
    1. Marano L, Polom K, Patriti A, et al.. Surgical management of advanced gastric cancer: an evolving issue. Eur J Surg Oncol 2016; 42: 18–27.
    1. Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol 2019; 14: 26–38.
    1. Lee KW, Chung IJ, Ryu MH, et al.. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer 2021; 24: 156–167.
    1. Kang Y-K, Chin K, Chung HC, et al.. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol 2020; 21: 1045–1056.
    1. Ajani JA, D’Amico TA, Almhanna K, et al.. Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016; 14: 1286–1312.
    1. Koizumi W, Narahara H, Hara T, et al.. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008; 9: 215–221.
    1. Song Z, Wu Y, Yang J, et al.. Progress in the treatment of advanced gastric cancer. Tumour Biol 2017; 39: 1010428317714626.
    1. Shirasaka T, Shimamato Y, Ohshimo H, et al.. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996; 7: 548–557.
    1. Tsushima T, Hironaka S, Boku N, et al.. Safety and efficacy of S-1 monotherapy in elderly patients with advanced gastric cancer. Gastric Cancer 2010; 13: 245–250.
    1. Huang D, Ba Y, Xiong J, et al.. A multicentre randomised trial comparing weekly paclitaxel + S-1 with weekly paclitaxel + 5-fluorouracil for patients with advanced gastric cancer. Eur J Cancer 2013; 49: 2995–3002.
    1. Mochiki E, Ogata K, Ohno T, et al.. Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer. Br J Cancer 2012; 107: 31–36.
    1. Sugimoto N, Fujitani K, Imamura H, et al.. Randomized phase II trial of S-1 plus irinotecan versus S-1 plus paclitaxel as first-line treatment for advanced gastric cancer (OGSG0402). Anticancer Res 2014; 34: 851–857.
    1. Bian NN, Wang YH, Min GT. S-1 combined with paclitaxel may benefit advanced gastric cancer: evidence from a systematic review and meta-analysis. Int J Surg 2019; 62: 34–43.
    1. Naganuma M, Tahara K, Hasegawa S, et al.. Adverse event profiles of solvent-based and nanoparticle albumin-bound paclitaxel formulations using the Food and Drug Administration adverse event reporting system. SAGE Open Med 2019; 7: 2050312119836011.
    1. Roy V, LaPlant BR, Gross GG, et al.. Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531). Ann Oncol 2009; 20: 449–453.
    1. Desai N. Nanoparticle Albumin-Bound Paclitaxel (Abraxane®). In: Otagiri M, Chuang VTG. (eds) Albumin in medicine. Singapore: Springer Singapore, 2016, pp.101–119.
    1. Li J-A, Xu X-F, Han X, et al.. Nab-paclitaxel plus s-1 shows increased antitumor activity in patient-derived pancreatic cancer xenograft mouse models. Pancreas 2016; 45: 425–433.
    1. Nakayama N, Ishido K, Chin K, et al.. A phase I study of S-1 in combination with nab-paclitaxel in patients with unresectable or recurrent gastric cancer. Gastric Cancer 2017; 20: 350–357.
    1. He MM, Wang F, Jin Y, et al.. Phase II clinical trial of S-1 plus nanoparticle albumin-bound paclitaxel in untreated patients with metastatic gastric cancer. Cancer Sci 2018; 109: 3575–3582.
    1. Cella D, Peterman A, Hudgens S, et al.. Measuring the side effects of taxane therapy in oncology. Cancer 2003; 98(4): 822–831.
    1. Yamada Y, Higuchi K, Nishikawa K, et al.. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. Ann Oncol 2015; 26: 141–148.
    1. Palumbo R, Sottotetti F, Bernardo A. Targeted chemotherapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in metastatic breast cancer: which benefit for which patients? Ther Adv Med Oncol 2016; 8: 209–229.
    1. Kundranda MN, Niu J. Albumin-bound paclitaxel in solid tumors: clinical development and future directions. Drug Design Dev Ther 2015; 9: 3767–3777.
    1. Wang X, Wang ML, Zhou LY, et al.. Randomized phase II study comparing paclitaxel with S-1 vs. S-1 as first-line treatment in patients with advanced gastric cancer. Clin Transl Oncol 2013; 15: 836–842.
    1. Dai Y, Yu X, Xu H, et al.. A multicenter randomized phase III study of albumin-bound paclitaxel combined with S-1 (AS) versus oxaliplatin combined with S-1 (SOX) for first-line treatment of advanced gastric cancer (GAPSO study). J Clin Oncol 2022; 40(4_Suppl): 282–282.
    1. Overman MJ, Maru DM, Charnsangavej C, et al.. Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury. J Clin Oncol 2010; 28: 2549–2555.
    1. Jardim DL, Rodrigues CA, Novis YAS, et al.. Oxaliplatin-related thrombocytopenia. Ann Oncol 2012; 23: 1937–1942.
    1. da Costa R, Passos GF, Quintao NLM, et al.. Taxane-induced neurotoxicity: Pathophysiology and therapeutic perspectives. Br J Pharmacol 2020; 177: 3127–3146.
    1. Pachman DR, Qin R, Seisler D, et al.. Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505). Support Care Cancer 2016; 24: 5059–5068.
    1. Janjigian YY, Shitara K, Moehler M, et al.. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021; 398: 27–40.
    1. Peng Z, Wei J, Wang F, et al.. Camrelizumab combined with chemotherapy followed by camrelizumab plus apatinib as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma. Clin Cancer Res 2021; 27: 3069–3078.
    1. Boku N, Ryu MH, Kato K, et al.. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol 2019; 30: 250–258.
    1. ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. In International conference on harmonisation E9 Expert Working Group. Stat Med 1999; 18: 1905–1942.
    1. Gupta SK. Intention-to-treat concept: a review. Perspect Clin Res 2011; 2: 109–112.
    1. Abraha I, Cherubini A, Cozzolino F, et al.. Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study. BMJ 2015; 350: h2445.
    1. Panés J, García-Olmo D, Van Assche G, et al.. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 2016; 388: 1281–1290.
    1. Vermeire S, O’Byrne S, Keir M, et al.. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014; 384: 309–318.
    1. Govindan R, Szczesna A, Ahn MJ, et al.. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 2017; 35: 3449–3457.
    1. Kim GM, Jeung H-C, Rha SY, et al.. A randomized phase II trial of S-1-oxaliplatin versus capecitabine–oxaliplatin in advanced gastric cancer. Eur J Cancer 2012; 48: 518–526.
    1. Abraha I, Montedori A. Modified intention to treat reporting in randomised controlled trials: systematic review. BMJ 2010; 340: c2697.

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