In a long-term follow-up analysis of the randomised phase III PRODIGY study, adding neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 to standard D2 surgery plus adjuvant S-1 chemotherapy significantly prolonged overall survival (OS) compared with surgery followed by adjuvant S-1 in Asian patients with resectable locally advanced gastric cancer. Benefit in progression-free survival (PFS) with neoadjuvant chemotherapy previously reported in the primary efficacy analysis was maintained after a long-term follow-up, confirming the robustness of the PFS benefit which was the primary endpoint of this study.

This is the first demonstration of a long-term OS benefit of neoadjuvant chemotherapy as part of perioperative chemotherapy in an Asian population according to Dr. Yoon-Koo Kang of the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine in Seoul, Republic of Korea and colleagues, who published the findings on 12 July 2024 in the JCO.

The authors wrote in the background that standard adjuvant treatments for locally advanced gastric cancer are different according to geographic region. In Western countries, perioperative chemotherapy is the standard treatment, while in Asia, D2 gastrectomy followed by adjuvant chemotherapy is the standard in this setting.

Recently, two phase III studies have shown the clinical benefit of neoadjuvant chemotherapy in Asian populations. Previously reported findings from the PRODIGY study showed that adding neoadjuvant docetaxel, oxaliplatin, and S-1 to surgery followed by adjuvant S-1 improved PFS compared with upfront surgery followed by adjuvant S-1 in patients with with clinical T2-3/N1 or T4/Nany disease, meeting the study primary endpoint. Furthermore, the RESOLVE study showed that perioperative S-1 plus oxaliplatin improved disease-free survival (DFS) compared with upfront surgery followed by adjuvant capecitabine plus oxaliplatin.

In the PRODIGY study, the OS results were immature at the time of the planned analysis for the primary endpoint of PFS. In the latest article, published in the JCO, the study team reports the long-term survival outcomes from the PRODIGY study at 5 years since the enrolment of the last patient. A total of 238 and 246 patients were randomly assigned to the study arms,  and were treated comprising a full analysis set. As of the data cut-off in September 2022, the median follow-up duration of the surviving patients was 99.5 months.

Compared with surgery plus adjuvant S-1 chemotherapy, neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 added to standard D2 surgery plus adjuvant S-1 chemotherapy significantly increased the OS (adjusted hazard ratio [HR] 0.72; stratified log-rank p = 0.027) with an 8-year OS rate of 63.0% and 55.1% favouring the neoadjuvant arm. Neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 added to standard D2 surgery plus adjuvant S-1 chemotherapy also significantly improved the PFS (HR 0.70; stratified log-rank p = 0.016).

The authors commented that given the recent advances in systemic treatments, along with the introduction of novel immunotherapeutic and targeted agents for patients with gastric cancer, assessing long-term OS outcomes has become more challenging. Therefore, the OS benefit seen in this study would arguably be clinically meaningful, although this study was not designed or powered to compare OS differences.

In line with the Western studies in which a PFS/DFS benefit of perioperative chemotherapy was translated into an OS benefit, long-term results of PRODIGY study support the use of PFS as a valid surrogate endpoint for predicting OS. In this analysis, the difference in the OS rate at 8 years (5 years since the enrolment of the last patient) was more pronounced than that at 5 years: 9.2% at 8 years versus 3.8% at 5 years. Therefore, the results suggest that a follow-up duration longer than 5 years may be required for an appropriate assessment of OS benefit.

In this updated analysis, although the benefit of the neoadjuvant arm was seen across most of the subgroups for OS, patients with cT4 tumours had a more pronounced OS benefit from the addition of neoadjuvant chemotherapy. Therefore, neoadjuvant chemotherapy may be preferentially considered for patients with cT4 disease in Asian populations. This is in contrast to the Western circumstances, where perioperative chemotherapy is recommended for ≥cT2 or cN1 tumours.

These findings highlight that the Western criteria for perioperative chemotherapy cannot be applied to Asian populations, where the inadvertent inclusion of early-stage disease and overtreatment can be potentially problematic. The authors stated that specific therapeutic approaches cannot be directly applied to another setting, although their general concepts could be shared.

The study was previously presented in part at the ASCO 2023 Annual Meeting (2-6 June 2023; Chicago, IL, US).

The study was sponsored by Sanofi.

Reference

Kang Y-K, Kim H-D, Hwan Yook J, et al. Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY. JCO; Published online 12 July 2024. DOI: https://doi.org/10.1200/JCO.23.02167

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