In search of the best perioperative treatment for gastroesophageal cancer: is there a role for antiangiogenesis?

The more the better? In the perioperative treatment of gastroesophageal cancer, historically, chemotherapy doublets and triplets have been used, with FLOT (5-FU, oxaliplatin, docetaxel) emerging as the preferred regimen, at least in the Western world (1). More recently, the addition of an immune checkpoint inhibitor, durvalumab, to FLOT, has been shown to improve outcomes in endpoints such as pathologic complete response (pCR) and event-free survival (EFS). A pCR rate of 19.2% was reported and can serve as a benchmark for subsequent trials (2).

In the East, SOX (S-1, oxaliplatin) is an established standard regimen, with an efficacy possibly similar to that of FLOT (3,4). Understandably, clinical researchers have also tried to improve its efficacy. In an article published in the Journal of Clinical Oncology (5), Li et al. describe the primary outcome of a randomized trial, the DRAGON IV/CAP 05 trial, where 2 strategies were tested against each other: SOX alone versus SOXRC, that is, SOX plus camrelizumab (an immune checkpoint inhibitor) and low-dose rivoceranib (an oral anti-VEGFR-2 inhibitor). The third strategy, combining SOX with high-dose rivoceranib (SOXR), was abandoned, given concerning safety signals. The hypothesis was that the pCR rate would be improved with SOXRC in comparison with SOX alone. Key secondary endpoints included total pCR rate and major pathologic response (MPR) rate. All those endpoints have been described in the paper.

As should be the case with any quality randomized trial, there was scientific rationale underlying the hypothesis of the investigators. Neoangiogenesis may be associated with immunosuppression leading to the concept that blockade of neoangiogenesis could boost the immune reaction to the presence of tumor cells (6,7). In the clinical setting, there are indeed reports suggestive of synergy between antiangiogenics and immune checkpoint inhibitors in the treatment of several cancers, especially at the metastatic stage (8-10) and there is ongoing investigation in that regard (11). It must be noted, however, that while antiangiogenic therapy is successful in second-line treatment and further for metastatic gastro-esophageal adenocarcinoma (12,13), it has often failed in first line (14,15), highlighting the complex and, possibly, evolving influence of neoangiogenesis in the development of the disease. The DRAGON IV/CAP 05 trial met its primary endpoint, the pCR rate being 18.3% with SOXRC and 5% with SOX, a statistically significant difference. Just as importantly, some surgical outcomes such as R0 resection and duration of hospitalization were similar between the two groups, although the 30-day and 90-day mortality rates were not reported. Not unexpectedly, toxicity was greater with SOXRC, but manageable with dose modifications. No lethal complications were seen with either of the two regimens, reassuringly.

As encouraging as these results are, our enthusiasm is tempered by some limitations of the trial. The interpretation of the primary endpoint is complicated by the authors’ choice to pick a rarely used definition of pCR: rather than ypT0N0, they adopted ypT0, meaning that even patients with positive lymph nodes after neoadjuvant therapy could be counted as complete responders if they had ypT0 status. However, an apparent superiority continues to hold in favor of SOXRC when one looks at the secondary outcomes (total pCR and MPR rates), contributing to the overall impression that SOXRC is superior to SOX. No information about SOXR results is given, whether in terms of efficacy or safety. Consequently, it is not possible to tease out the respective contribution of rivoceranib and camrelizumab to the improvement of the primary endpoint that is reported, especially as a pCR rate of 18.3% (total pCR rate 16.7%) appears comparable to the results of several immunochemotherapy regimens that do not incorporate antiangiogenics (16,17). The lack of survival data also limits the interpretation of the results, given the controversy surrounding the adequacy of pCR as a surrogate for long-term outcomes such as disease-free survival and overall survival (18,19). A final concern in my view is the size of the trial population: 360 patients for what turns out to be a signal-seeking study makes me wonder whether this trial has been overpowered, mobilizing a lot of resources and exposing many patients to an unproven therapy.

Fortunately, the DRAGON IV/CAP 05 trial does signal that SOXRC may be superior to SOX. We will need confirmation of those results with publication of the EFS data, as promised by the authors, before adding that combination to the armamentarium of perioperative regimens in locally advanced gastroesophageal cancers. Trials comparing immunochemotherapy to immunochemotherapy plus an anti-angiogenic therapy would also be welcome in that space. Of note, new bispecific antibodies with dual anti-angiogenic and anti-PD-1/PD-L1 properties are currently under investigation in various tumor types (20).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-779/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-779/coif). The author has no conflicts of interest to declare.

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