Antibody–drug conjugate combined with chemoimmunotherapy: Redefining the neoadjuvant strategy for human epidermal growth factor receptor 2-overexpressing locally advanced gastric cancer

Abstract

Gastric cancer is one of the malignancies that pose a serious threat to human health worldwide. According to the 2022 global cancer statistics, approximately 968 000 new cases and 660 000 deaths from gastric cancer were reported, ranking fifth in both incidence and mortality among all malignancies.¹ China bears an especially heavy burden of gastric cancer, with 359 000 newly diagnosed cases and 260 000 deaths in 2022, accounting for 37% and 39% of the global totals, respectively.² Because early-stage disease is often clinically silent, most patients are diagnosed at a locally advanced or metastatic stage, resulting in an extremely poor prognosis. Although conventional cytotoxic chemotherapy can delay disease progression to some extent, its limited efficacy has accelerated the development of precision treatment strategies based on molecular classification in gastric cancer. Human epidermal growth factor receptor 2 (HER2) is one of the most clinically relevant and therapeutically actionable biomarkers in gastric cancer, with HER2 positivity detected in approximately 15% of gastric cancer.³ HER2-positive gastric cancer is typically associated with increased tumour aggressiveness and inferior clinical outcomes.⁴ Although trastuzumab plus chemotherapy has become the standard first-line regimen for advanced HER2-positive gastric cancer, the optimal perioperative and neoadjuvant treatment strategy for this subgroup remains undefined. Moreover, pathological response rates in previous exploratory studies have remained unsatisfactory; notably, the NEOHX trial reported a pathological complete response (pCR) rate of only 9.6% with perioperative trastuzumab combined with XELOX,⁵ whereas neoadjuvant trastuzumab deruxtecan monotherapy in the EPOC2003 study achieved a pCR rate of merely 3.7% and a major pathological response (MPR) rate of 14.8%.⁶ Accordingly, the development of more effective perioperative and neoadjuvant regimens aimed at improving R0 resection rates, reducing recurrence risk and enhancing long-term survival remains a major unmet clinical need.

Against this background, the study by Wang et al.⁷ provides encouraging preliminary evidence for addressing these therapeutic challenges. The authors reported a novel triplet regimen consisting of the HER2-targeted antibody–drug conjugate (ADC) disitamab vedotin (DV, RC48), the programmed death-1 (PD-1) inhibitor camrelizumab and the oral fluoropyrimidine S-1 as neoadjuvant therapy for HER2-overexpressing locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Among the 24 patients who subsequently underwent D2 gastrectomy, the pCR rate reached 25.0%, the MPR rate was 45.8%, and the R0 resection rate was 100%; in the full analysis set, the objective response rate (ORR) reached 80.0%. Compared with previously reported historical data,^{5, 6} these outcomes are particularly striking, suggesting that the integration of ADCs with immunotherapy and chemotherapy may represent an important advance in the neoadjuvant management of HER2-overexpressing G/GEJ cancer. In addition, although limited by the small sample size, the exploratory circulating tumour DNA (ctDNA) methylation analysis showed a dynamic decline in tumour fraction during treatment and demonstrated concordance between plasma ERBB2 copy number gain and tissue HER2 status, thereby supporting the potential utility of liquid biopsy for molecular response monitoring in this setting (Figure 1).

The biological rationale for combining an HER2-targeted ADC, a PD-1 inhibitor, and chemotherapy in the perioperative and neoadjuvant treatment of HER2-overexpressing G/GEJ cancer is compelling. RC48 delivers the microtubule-disrupting payload monomethyl auristatin E (MMAE) specifically to HER2-expressing tumour cells. Previous Phase II studies have shown that this agent has promising antitumour activity and a manageable safety profile in patients with HER2-overexpressing locally advanced or metastatic G/GEJ cancer.⁸ Accumulating evidence further suggests that MMAE release may induce immunogenic cell death, promote dendritic cell maturation and enhance cross-presentation of tumour antigens, thereby reshaping the tumour immune microenvironment into a more immunologically favourable state.^{9, 10} This mechanistic synergy may partly explain the favourable pathological response rates observed in the present study, particularly the comparable efficacy between HER2 immunohistochemistry (IHC) 2+ and IHC 3+ tumours, as well as the higher ORR among patients with PD-ligand-1 (PD-L1) combined positive score ≥1.⁷ These findings align with the growing recognition that ADCs may exert not only direct cytotoxic effects but also immunomodulatory activity, potentially converting immunologically ‘cold’ tumours into ‘hot’ tumours and thereby enhancing the efficacy of immune checkpoint blockade.^{9, 10} A Phase I trial evaluating RC48 in combination with PD-1 blockade in HER2-expressing advanced solid tumours has also provided preliminary evidence supporting the safety and antitumour activity of this combinational approach.¹¹

Nevertheless, the authors appropriately acknowledged several important limitations, including the single-arm design, limited sample size and relatively short follow-up, all of which indicate that the current findings should still be regarded as preliminary. Notably, univariate logistic regression failed to identify significant predictors of pCR or MPR, underscoring the need for larger biomarker-stratified studies to improve patient selection and response prediction. Even so, this work remains conceptually important because it demonstrates the feasibility and potential therapeutic value of ADCs-based chemoimmunotherapy in the neoadjuvant setting for HER2-overexpressing G/GEJ cancer, while also extending treatment concepts established in advanced disease, including those from the KEYNOTE-811 trial,¹² into the perioperative and neoadjuvant treatment setting.

Beyond its direct efficacy findings, this study also prompts broader reconsideration of how perioperative and neoadjuvant HER2-driven G/GEJ cancer should be classified and managed. Historically, HER2-targeted therapy in gastric cancer has largely been restricted to advanced or metastatic disease, in part because early adjuvant studies yielded disappointing results. For example, subgroup analyses of the ToGA trial did not demonstrate a definitive survival benefit from trastuzumab in patients with HER2-positive locally advanced gastric cancer.¹³ However, the treatment landscape is now evolving rapidly. The recent MATTERHORN trial showed that perioperative durvalumab combined with the 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) regimen improved event-free survival in patients with resectable G/GEJ cancer and increased the pCR rate from 7.2% to 19.2%.¹⁴ In parallel, the INNOVATION trial is evaluating perioperative trastuzumab with or without pertuzumab in this setting.¹⁵ Collectively, these studies suggest that multimodal strategies integrating targeted therapy and immunotherapy are emerging as a major direction in the management of resectable G/GEJ cancer. The incorporation of an ADC into the neoadjuvant setting in the present study further strengthens this evolving therapeutic paradigm.⁷ The favourable pCR and MPR rates, together with the 100% R0 resection rate and 66.7% nodal downstaging rate, indicate that the combination of RC48, camrelizumab and S-1 may achieve an effective control of both the primary tumour and regional nodal disease, thereby potentially lowering the risks of local recurrence and distant dissemination (Figure 1).

Importantly, the regimen exhibited an overall manageable safety profile, with grade ≥3 treatment-related adverse events reported in 31.3% of patients, predominantly haematologic toxicities, and no perioperative surgical complications observed.⁷ Although these findings require validation in larger cohorts, they nonetheless support the feasibility of applying this triplet strategy without delaying definitive surgery. In addition, although exploratory in nature, the ctDNA methylation analysis suggests that non-invasive molecular monitoring may dynamically reflect treatment-related reductions in tumour burden, offering a potential tool for early response assessment and minimal residual disease detection.¹⁶ However, these observations should be interpreted with caution, as the limited sample size, single-centre design and lack of a control group in the ctDNA analysis restrict the generalizability of the findings. Future studies should therefore prioritize large-scale, multicentre, randomized controlled trial designs with extended survival follow-up and integrated biomarker programmes to prospectively validate predictive and pharmacodynamic markers, including ctDNA dynamics, tumour immune microenvironment features and HER2 heterogeneity.

Finally, this study highlights several important translational and clinical research directions worthy of further investigation. First, the responses observed in patients with HER2 IHC 2+ tumours, who are traditionally considered less suitable for standard anti-HER2 therapy, suggest that ADCs-based approaches may broaden the therapeutic scope beyond the conventional HER2-amplified population.¹¹ Second, incorporating ctDNA methylation analysis into perioperative and neoadjuvant trials may facilitate adaptive treatment strategies based on molecular response, allowing real-time intensification or de-intensification according to residual disease status.¹⁶ Furthermore, the combination of ADCs and PD-1 inhibitors raises an important hypothesis for future study: The immunomodulatory properties of ADCs may enhance immunotherapy efficacy even in PD-L1-low or microsatellite stable/mismatch repair proficient tumours.¹⁷ As perioperative and neoadjuvant treatment strategies for G/GEJ cancer continue to evolve toward precision oncology, the major challenge lies not only in developing more effective therapeutic regimens, but also in identifying the most appropriate treatment combinations for the right patients at the optimal stage of therapy.¹⁸ Studies such as this provide an important foundation for achieving that goal. In summary, Wang et al.⁷ conducted a timely and well-designed translational study that offers a promising neoadjuvant strategy and preliminary supportive evidence for HER2-overexpressing G/GEJ cancer. Although confirmation in larger randomized studies is still required, this work represents a meaningful advance in the perioperative and neoadjuvant management of this complex disease and further promotes the development of more effective, biomarker-guided and biologically rational treatment strategies (Figure 1).

Shulun Nie and Yu Wang jointly wrote the original draft. Cunliang Wang and Xiaolan Cao contributed to the review and editing of the final manuscript. Shuyi Song was responsible for figure preparation and layout. All authors reviewed and approved the final version of the manuscript.

The authors declare no conflicts of interest.

No external funding was received for this study.

This is an Invited Letter and does not involve original human or animal research.

Not applicable, as this manuscript does not contain any data from individual persons in any form.

No new data were generated or analysed in this study.