Apatinib-based neoadjuvant regimens show promise in resectable gastric cancer meta-analysis

Gastric cancer remains one of the world’s most formidable malignancies, ranking as the fourth leading cause of cancer-related death globally. For patients whose tumors are caught early, five-year overall survival can reach 93.6 percent, but once the disease advances, that figure collapses to 17.9 percent. Tumors arising at the gastroesophageal junction, a heterogeneous group classified mainly by the Siewert system, are rising in incidence worldwide and are particularly severe in East Asia. Surgical resection with lymph node dissection remains the only potentially curative treatment, and perioperative chemotherapy, validated in landmark trials such as MAGIC and FNCLCC/FFCD 9703, has become the international standard of care for resectable gastric and gastroesophageal junction adenocarcinoma.

Yet the standard approach has a stubborn ceiling. Pathologic complete response rates with conventional neoadjuvant chemotherapy hover between roughly 6 and 16 percent, and long-term survival for patients with stage IIIA, IIIB, and IIIC disease remains only 30.5, 20.1, and 8.3 percent respectively. This gap has pushed oncologists to explore whether adding other therapeutic modalities before surgery can push more patients toward complete tumor eradication. A new systematic review and single-arm meta-analysis published in Frontiers in Oncology now offers the first quantitative synthesis of one such candidate: apatinib, an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 developed in China, delivered as part of neoadjuvant regimens for resectable gastric and gastroesophageal junction adenocarcinoma.

The rationale for apatinib rests on a hallmark of cancer biology. Angiogenesis, the formation of new blood vessels, drives the growth and metastasis of aggressive tumors, with vascular endothelial growth factor and its receptors serving as key mediators. VEGFR2, one of three members of the VEGFR family, exerts a pivotal effect on VEGF-mediated tumor angiogenesis. Apatinib selectively targets this receptor and has already demonstrated efficacy in advanced disease: a phase III trial showed that apatinib improved progression-free survival from 1.8 to 2.6 months and overall survival from 4.7 to 6.5 months compared with placebo in patients with advanced gastric cancer refractory to two or more chemotherapy regimens. A phase I study also found that apatinib could enhance the efficacy of paclitaxel, oxaliplatin, and 5-FU/leucovorin in advanced gastric cancer, with objective response rates of 90 percent in the high-dose group versus 66.7 percent in the low-dose group.

To consolidate scattered preliminary clinical data, a team led by Kaiyi Xin and Zhilu Chen, with Yinghao Zhao as corresponding author, from Jilin University hospitals in Changchun, China, conducted a systematic search across PubMed, Embase, the Cochrane Library, Web of Science, and major oncology conference proceedings up to January 1, 2026. The review followed the PRISMA statement and was registered with PROSPERO under identifier CRD42023478481. The initial search identified 483 articles, from which 20 studies enrolling 1026 patients met the inclusion criteria. After excluding one potentially overlapping cohort from the same research group to avoid double-counting patients, the primary analysis rested on 19 studies with 975 patients. These comprised 11 single-arm cohort studies, 7 two-arm randomized controlled trials, and 1 three-arm randomized controlled trial, with study arms categorized as neoadjuvant apatinib combined with chemotherapy, apatinib combined with immunotherapy and chemotherapy, or apatinib combined with chemotherapy and radiotherapy. Each patient received at least two courses of neoadjuvant treatment, and most surgical resections were performed three to five weeks after the final preoperative cycle.

Because most included studies were single-arm trials reporting binary outcomes as proportions, the investigators applied a logit transformation to stabilize variance and used inverse-variance weighting to pool event rates with 95 percent confidence intervals, selecting random- or fixed-effects models based on between-study heterogeneity measured by the I-squared statistic. The headline efficacy numbers are striking. The pooled pathologic complete response rate was 21 percent (95 percent CI, 18 to 25 percent) with remarkably low heterogeneity of I-squared 19.4 percent. The pooled major pathologic response rate, a broader measure of deep tumor regression, reached 39 percent (95 percent CI, 34 to 45 percent). Complete resection with negative margins, the R0 resection rate, was achieved in 93 percent of patients (95 percent CI, 90 to 95 percent), while the pooled surgical resection rate was 92 percent. On imaging, the pooled objective response rate was 70 percent (95 percent CI, 66 to 74 percent) and the disease control rate was 95 percent (95 percent CI, 92 to 96 percent) with essentially no heterogeneity.

Safety outcomes were also quantified. The pooled incidence of grade 3 or higher treatment-related adverse events, graded according to NCI-CTCAE version 4.0, was 31 percent (95 percent CI, 21 to 43 percent), with substantial heterogeneity of I-squared 80.1 percent. Critically, no patients died as a result of these severe adverse events, and surgery was delayed in only one patient, for 93 days, because of treatment-associated pneumonia. The pooled postoperative complication rate was 27 percent (95 percent CI, 22 to 32 percent), and no patient died within 30 days of surgery from postoperative complications. Only one patient required a second operation, eventually recovering, due to bleeding from the gastrointestinal anastomosis. The most common complications, including pneumonia, hemorrhage, abdominal infection, anastomotic leakage, and pleural effusion, mostly belonged to Clavien-Dindo class II and did not dramatically affect survival prognosis.

In exploratory subgroup analyses, the pooled pathologic complete response rate was 12 percent in the apatinib plus chemotherapy group and 22 percent in the apatinib plus immunotherapy and chemotherapy group, with a descriptive estimate of 33 percent in the single apatinib plus chemoradiotherapy study. Similar directional differences appeared in major pathologic response, objective response, and R0 resection rates, which were 93.5 percent in the chemotherapy subgroup and 96.7 percent in the immunotherapy subgroup. The incidence of severe treatment-related adverse events was 23 percent in the immunotherapy subgroup versus 39 percent in the chemotherapy subgroup. The authors emphasize, however, that these are indirect, non-randomized comparisons derived from independent single-arm cohorts and are presented descriptively as hypothesis-generating, not as evidence of comparative efficacy.

The biological plausibility of combining apatinib with immune checkpoint inhibitors adds technical depth to these findings. Beyond directly suppressing tumor angiogenesis, apatinib targets components of the tumor microenvironment outside tumor cells and promotes the infiltration and activation of CD8-positive T lymphocytes. Immune checkpoint inhibitors targeting PD-1 have demonstrated antitumor activity in gastric and gastroesophageal junction adenocarcinoma, and apatinib-based regimens combined with PD-1 inhibition have shown activity in advanced disease and other solid tumors. In a three-arm randomized controlled study by Xiong and Li, the apatinib plus immunotherapy and chemotherapy group showed improved one-, two-, and three-year disease-free survival and overall survival compared with the other groups, though it caused a higher incidence of peripheral neuropathy, while the apatinib plus chemotherapy group increased the incidence of hypertension. Possible explanations include PD-1 inhibitor-induced autoreactive antibodies, cytotoxic T cells, and inflammatory cytokines affecting neural integrity, as well as apatinib-induced endothelin-1 activation and oxidative stress.

The authors also confront important limitations. The evidence base is predominantly non-comparative and heterogeneous, drawn mostly from single-arm phase II trials and retrospective cohort studies, some of which are conference abstracts without full-text peer review. Most trials have not yet reached predefined long-term endpoints, so the impact on overall and disease-free survival remains unconfirmed. Substantial clinical heterogeneity existed across studies in apatinib dose, combination regimens, number of neoadjuvant cycles, tumor stage, histology, and patient selection. Notably, the included studies generally did not stratify outcomes by histologic type or differentiation grade, and whether apatinib can overcome the relative resistance of poorly differentiated diffuse-type tumors to conventional neoadjuvant chemotherapy remains unclear. Age-related tolerability also warrants attention: a phase II study in elderly patients reported high incidences of fatigue and hypertension, and the NMPA-approved drug label in China advises caution in patients over 70 years, with individualized management including regular blood-pressure monitoring, routine urinalysis for proteinuria, and possible dose reduction to 250 mg/day for patients with poor tolerability.

Sensitivity analyses, including leave-one-out calculations and re-inclusion of the excluded overlapping cohort, confirmed that the pooled estimates remained essentially unchanged, and Egger’s regression test revealed no statistically significant publication bias for any outcome. The overall picture is one of feasibility rather than proof: apatinib-containing neoadjuvant therapy appears deliverable with an acceptable safety profile in selected patients, achieving pathologic response rates that may inform future hypothesis-driven research. The authors conclude that these descriptive estimates provide a basis for the design of future large multicenter randomized controlled trials to validate the role of apatinib in the neoadjuvant setting, while cautioning that no conclusion regarding comparative efficacy or safety superiority over conventional therapy can yet be drawn. For a cancer whose standard of care has plateaued, that call for rigorous randomized evidence may prove the most consequential finding of all.

Subject of Research: Apatinib-containing neoadjuvant therapy for resectable gastric and gastroesophageal junction adenocarcinoma

Article Title: Efficacy and safety of apatinib-containing neoadjuvant regimens for resectable gastric and gastroesophageal junction adenocarcinoma: a systematic review and single-arm meta-analysis

Article References: Xin, K., Chen, Z., Yang, L., Qin, L., Chen, S., Xiao, T., & Zhao, Y. (2026). Efficacy and safety of apatinib-containing neoadjuvant regimens for resectable gastric and gastroesophageal junction adenocarcinoma: a systematic review and single-arm meta-analysis. Frontiers in Oncology, 16, Article 1910490. https://doi.org/10.3389/fonc.2026.1910490

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1910490

Keywords: apatinib, gastric cancer, gastroesophageal junction adenocarcinoma, neoadjuvant therapy, pathologic complete response, meta-analysis, VEGFR2 inhibitor, immunotherapy, R0 resection, surgical oncology, Frontiers in Oncology, Efficacy