The ESMO Congress 2026, held in Madrid from October 23–27, presented new Phase III findings and updated survival analyses across GI Oncology, including gastric and gastroesophageal, colorectal, and biliary tract cancers. Among the notable developments were advances in CLDN18.2- and HER2-directed therapies, new evidence for immunotherapy-based combinations, and randomized trials examining chemotherapy duration and scheduling. The findings included both superiority and noninferiority results, with implications for treatment selection and tolerability in different clinical settings.
CLDN18.2-Targeted ADCs in Gastric Cancer: G-HOPE-001 and CLARITY-Gastric01
At ESMO 2026, two Phase III trials evaluated CLDN18.2-directed antibody-drug conjugates (ADCs) in previously treated advanced gastric and gastroesophageal cancers.
In G-HOPE-001 (LBA77), presented by Kohei Shitara, arcotatug tavatecan (IBI343/TAK-921) was compared with physician’s choice of chemotherapy in patients with CLDN18.2-positive, HER2-negative advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had received two to four prior treatment regimens.
The study met both primary endpoints of overall survival (OS) and progression-free survival (PFS).
At the second prespecified interim analysis, with a September 3, 2026 data cutoff, median OS was 10.2 versus 6.9 months (HR 0.57; 95% CI 0.45–0.73; p<0.0001). Median PFS was 7.1 versus 3.1 months (HR 0.45; 95% CI 0.35–0.58), while the confirmed objective response rate (ORR) was 37.4% versus 7.7%.
The earlier first interim analysis, with a February 13, 2026 cutoff, had established a statistically significant PFS benefit of 5.5 versus 2.9 months (HR 0.47; 95% CI 0.34–0.65; p<0.0001).
Grade ≥3 treatment-related adverse events occurred in 47.4% of patients receiving arcotatug tavatecan compared with 55.9% receiving chemotherapy. One treatment-related fatal adverse event occurred in the arcotatug tavatecan group.
These findings provide randomized evidence for the efficacy of arcotatug tavatecan in later-line CLDN18.2-positive gastric/GEJ cancer. The trial was conducted in China and Japan, and broader implementation will depend on regulatory decisions and treatment availability.
The second study, CLARITY-Gastric01 (LBA7), presented by Rui-Hua Xu, evaluated sonesitatug vedotin, another CLDN18.2-directed ADC, versus investigator’s choice of therapy in patients with previously treated advanced gastric, gastroesophageal junction (GEJ), or oesophageal adenocarcinoma.
The trial had two primary endpoints: overall survival (OS) in the third-line-or-later population and progression-free survival (PFS) in the overall second-line-or-later population.
In the third-line-or-later population, sonesitatug vedotin significantly improved median OS to 10.0 months versus 5.0 months with investigator’s choice (HR 0.47; 95% CI 0.36–0.62; p<0.000001), meeting the prespecified primary OS endpoint. For the key secondary endpoint of OS in the overall second-line-or-later population, median survival was 10.6 versus 6.4 months (HR 0.58; 95% CI 0.47–0.73; p=0.000004).
However, the co-primary PFS endpoint in the overall population was not met. Median PFS was 4.2 versus 3.8 months (HR 0.77; 95% CI 0.62–0.96; p=0.053193), which did not reach the prespecified statistical significance threshold. Grade ≥3 treatment-related adverse events occurred in 36.4% of patients receiving sonesitatug vedotin versus 44.8% receiving investigator’s choice.
CLARITY-Gastric01 demonstrated a significant OS benefit in the third-line-or-later population, although the co-primary PFS endpoint was not met. The findings support further consideration of sonesitatug vedotin as a potential later-line treatment for CLDN18.2-positive advanced gastroesophageal cancer.
Both G-HOPE-001 and CLARITY-Gastric01 reported survival benefits with CLDN18.2-directed ADCs. However, differences in eligibility criteria, biomarker requirements, and primary endpoint outcomes prevent direct comparisons of efficacy between arcotatug tavatecan and sonesitatug vedotin.
HER2-Positive Gastroesophageal Cancer: HERIZON-GEA-01
The initial results of the Phase III HERIZON-GEA-01 trial were published in The New England Journal of Medicine on May 27, 2026, demonstrating improved progression-free survival (PFS) with zanidatamab plus chemotherapy, with or without tislelizumab, compared with trastuzumab plus chemotherapy in first-line HER2-positive advanced gastroesophageal adenocarcinoma.
At ESMO 2026, Kohei Shitara presented the planned second interim overall survival (OS) analysis (LBA79), providing updated findings after longer follow-up. The trial randomized 914 patients to zanidatamab plus chemotherapy, zanidatamab plus tislelizumab and chemotherapy, or trastuzumab plus chemotherapy.
At the July 15, 2026 data cutoff, median follow-up was 35.3 months. Zanidatamab plus chemotherapy demonstrated a statistically significant OS benefit compared with trastuzumab plus chemotherapy, with median OS of 22.9 versus 19.6 months (HR 0.76; 95% CI 0.62–0.93; p=0.0088).
Median OS with zanidatamab plus tislelizumab and chemotherapy was 27.0 months versus 19.6 months with trastuzumab plus chemotherapy (HR 0.65; 95% CI 0.52–0.80), maintaining the previously demonstrated survival benefit. However, the direct comparison between the two zanidatamab-containing regimens did not show a statistically significant additional OS benefit from tislelizumab (27.0 vs 22.9 months; HR 0.81; 95% CI 0.65–1.00; p=0.0502).
Updated safety findings were consistent with the first interim analysis. The ESMO 2026 findings provide more mature survival evidence for zanidatamab-based first-line treatment, including a newly statistically significant OS benefit for zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy.
Updated Survival Results From KC-WISE
The Phase III KC-WISE trial (LBA80) provided updated efficacy data for anbenitamab plus chemotherapy in patients with HER2-positive advanced gastric or GEJ cancer following progression on trastuzumab-containing treatment.
Presented by Ruixing Zhang, the analysis included 246 randomized patients and reported updated OS and final PFS findings. At the July 15, 2026 data cutoff, median OS was 19.6 months with anbenitamab plus chemotherapy compared with 9.6 months with placebo plus chemotherapy (HR 0.39; 95% CI 0.28–0.54; p<0.0001).
Median PFS was 7.1 versus 2.7 months (HR 0.35; 95% CI 0.26–0.48; p<0.0001). The efficacy benefit was accompanied by greater toxicity. Grade ≥3 treatment-related adverse events occurred in 69.4% versus 47.9% of patients. Severe neutropenia, leukopenia, and anemia were among the most frequently reported events.
The updated results strengthen the evidence for anbenitamab plus chemotherapy in HER2-positive gastric/GEJ cancer after trastuzumab failure. However, the higher incidence of severe treatment-related adverse events is relevant when evaluating its potential position among available HER2-directed therapies. The ESMO presentation also represents updated survival evidence from a previously positive trial, rather than a first report of efficacy.
Biliary Tract Cancer: HARMONi-GI1 Evaluates Ivonescimab Against an Active 1L Comparator
In biliary tract cancer, HARMONi-GI1 (LBA8) investigated whether replacing durvalumab with ivonescimab could improve outcomes when combined with gemcitabine and cisplatin.
Presented by Jian Zhou, the randomized, double-blind Phase III trial enrolled 682 patients with previously untreated unresectable locally advanced or metastatic biliary tract cancer in China. Ivonescimab is a bispecific antibody targeting PD-1 and VEGF. The control group received durvalumab plus gemcitabine/cisplatin. At a median follow-up of 14.3 months, the trial met its primary endpoint.
Median OS was 14.9 months with ivonescimab plus chemotherapy versus 12.1 months with durvalumab plus chemotherapy (HR 0.75; 95% CI 0.61–0.92; one-sided p=0.0031). Median PFS was 8.4 versus 5.8 months (HR 0.61; 95% CI 0.51–0.72; p<0.0001), while ORR was 53.8% versus 32.5%.
Grade 3–4 treatment-emergent adverse events occurred in 82.0% versus 72.3% of patients. Serious treatment-emergent adverse events were reported in 43.4% versus 43.7%. HARMONi-GI1 is relevant because it demonstrated an OS advantage over an active immunochemotherapy regimen rather than chemotherapy alone.
The findings support ivonescimab plus chemotherapy as a potential first-line treatment option in advanced biliary tract cancer. Nevertheless, the results are from an interim analysis conducted in China, and the safety profile and applicability to broader populations require consideration.
Colorectal Cancer: PRABITAS Supports a Modified Treatment Schedule
The Phase III PRABITAS trial (LBA31) evaluated whether a simplified schedule of trifluridine/tipiracil plus bevacizumab could reduce toxicity while maintaining overall survival in patients with refractory metastatic colorectal cancer. Presented by Hiroya Taniguchi and simultaneously published in The Lancet on October 24, 2026, PRABITAS was a pragmatic, randomized, open-label noninferiority trial conducted across 178 hospitals in Japan.
The study randomized 972 patients to a 14-day or conventional 28-day treatment schedule, with 970 included in the intention-to-treat analysis. The primary endpoint was overall survival (OS), with a prespecified noninferiority margin of 1.25 for the hazard ratio.
After a median follow-up of 17.9 months, median OS was 11.3 months with the 14-day schedule versus 10.3 months with the conventional 28-day schedule (HR 0.93; 95% CI 0.80–1.08), meeting the prespecified noninferiority criterion. However, the 14-day schedule did not demonstrate OS superiority (p=0.35).
Median progression-free survival (PFS) was 3.9 months in both groups (HR 0.93; 95% CI 0.81–1.06). The modified schedule was associated with lower rates of several treatment-related adverse events. Grade ≥3 neutropenia occurred in 13% versus 39% of patients, while febrile neutropenia was reported in 1% versus 5%. Grade ≥2 anorexia was also less frequent with the 14-day schedule (15% vs 26%).
However, two treatment-related deaths occurred in the 14-day group, one due to gastrointestinal hemorrhage and another due to gastrointestinal perforation, both attributed to bevacizumab. No treatment-related deaths were reported in the conventional group. PRABITAS demonstrated that the 14-day schedule maintained OS within the prespecified noninferiority margin while reducing clinically relevant hematological and gastrointestinal toxicities.
The findings support the modified schedule as an alternative to conventional administration of trifluridine/tipiracil plus bevacizumab in refractory metastatic colorectal cancer. However, the study was conducted exclusively in Japan, and patient-reported quality of life was not formally assessed. These factors should be considered when interpreting the clinical implications of the observed toxicity reductions.
Adjuvant Gastric Cancer: LOMAC Examines Shorter XELOX Duration
The Phase III LOMAC trial (LBA81), presented by Dazhi Xu, investigated whether four months of adjuvant capecitabine plus oxaliplatin (XELOX) could provide outcomes noninferior to six months of treatment in patients with stage II–IIIB gastric cancer following curative D2 gastrectomy.
The randomized, open-label study included 1,023 patients, assigned to receive either four or six months of XELOX. The primary endpoint was three-year disease-free survival (DFS), with a prespecified noninferiority margin of 1.33 for the hazard ratio. At a median follow-up of 52.8 months, three-year DFS was 69.2% with four months of XELOX versus 70.8% with six months (HR 1.01; 95% CI 0.82–1.25; one-sided p=0.006 for noninferiority), meeting the primary endpoint in the modified intention-to-treat population.
The findings were consistent in the per-protocol population, with a DFS HR of 0.96 (95% CI 0.75–1.25; one-sided p=0.007 for noninferiority). For overall survival (OS), the HR was 1.06 (95% CI 0.84–1.34) in the modified intention-to-treat population and 0.95 (95% CI 0.71–1.27) in the per-protocol population. These analyses did not demonstrate an OS advantage for either treatment duration.
Shorter treatment was associated with lower toxicity. Grade ≥3 adverse events occurred in 8.4% of patients receiving four months of XELOX compared with 15.0% receiving six months. Grade ≥3 peripheral sensory neuropathy was reported in 0.4% versus 5.9%, respectively. Treatment completion was also higher in the four-month group, at 83.6% versus 60.4%.
LOMAC demonstrated that four months of adjuvant XELOX was noninferior to six months for DFS, with fewer severe adverse events and a higher treatment completion rate.
These findings support consideration of shorter adjuvant XELOX treatment in appropriately selected patients with stage II–IIIB gastric cancer following D2 gastrectomy. However, the trial established DFS noninferiority, not OS noninferiority, and its results should not be generalized to other perioperative treatment strategies.
Clinical Implications of the ESMO 2026 Findings
The seven studies provide evidence relevant to different treatment settings and clinical decisions. In previously treated gastric and GEJ cancer, G-HOPE-001 and CLARITY-Gastric01 demonstrated OS improvements with CLDN18.2-directed ADCs. However, their primary endpoint findings differed, and neither trial provides a direct comparison between the two agents.
In first-line HER2-positive gastroesophageal adenocarcinoma, HERIZON-GEA-01 demonstrated a statistically significant OS benefit with zanidatamab plus chemotherapy compared with trastuzumab plus chemotherapy. However, the addition of tislelizumab did not demonstrate a statistically significant additional OS benefit in the direct comparison.
KC-WISE reported a significant survival benefit with anbenitamab plus chemotherapy following trastuzumab failure, accompanied by increased severe toxicity. In advanced biliary tract cancer, HARMONi-GI1 demonstrated improved OS compared with durvalumab plus chemotherapy, supporting further evaluation of ivonescimab-based treatment as a first-line option.
PRABITAS and LOMAC addressed treatment duration and scheduling. Both met their prespecified noninferiority endpoints and demonstrated reductions in toxicity, providing evidence for alternative approaches to established chemotherapy regimens. The implications of these findings differ. New treatment combinations require assessment of efficacy, safety, and regulatory availability, whereas noninferiority studies may support changes in treatment delivery within the populations studied.
The Bottom Line
ESMO 2026 presented important Phase III evidence across GI oncology, with several trials demonstrating survival benefits and others supporting modifications to established treatment regimens.
In advanced gastric and gastroesophageal cancer, G-HOPE-001 and CLARITY-Gastric01 reported significant OS benefits with CLDN18.2-directed ADCs, although only G-HOPE-001 met both primary endpoints. Updated findings from HERIZON-GEA-01 and KC-WISE provided additional survival evidence for HER2-directed treatment in different clinical settings, while HARMONi-GI1 demonstrated a statistically significant OS benefit compared with durvalumab-based first-line therapy in advanced biliary tract cancer.
PRABITAS and LOMAC provided evidence for treatment optimization. PRABITAS demonstrated OS noninferiority with a modified trifluridine/tipiracil plus bevacizumab schedule, while LOMAC established DFS noninferiority with a shorter course of adjuvant XELOX. Both approaches were associated with lower rates of several adverse events, supporting their consideration in the patient populations studied.
These findings provide evidence for new treatment approaches and modifications to established regimens in selected GI cancer populations. Their application in clinical practice will depend on the endpoints achieved, safety profiles, patient selection, regulatory status, and treatment availability.
Read more about ESMO 2026 Presidential Symposia: From Trial Results to Clinical Implications on OncoDaily.
Sources
- Selected ESMO Congress 2026 presentations, Madrid, Spain, October 23–27, 2026:
- Shitara K, et al. G-HOPE-001, LBA77. Phase III results of arcotatug tavatecan in previously treated CLDN18.2-positive gastric/GEJ cancer.
- Xu R-H, et al. CLARITY-Gastric01, LBA7. Sonesitatug vedotin versus investigator’s choice in CLDN18.2-positive advanced gastroesophageal cancer.
- Shitara K, et al. HERIZON-GEA-01, LBA79. Planned second interim overall survival analysis of zanidatamab plus chemotherapy, with or without tislelizumab, in first-line HER2-positive advanced gastroesophageal adenocarcinoma. ESMO Congress 2026.
- Zhang R, et al. KC-WISE, LBA80. Updated overall survival results with anbenitamab plus chemotherapy in HER2-positive gastric/GEJ cancer.
- Zhou J, et al. HARMONi-GI1, LBA8. Ivonescimab plus chemotherapy versus durvalumab plus chemotherapy in advanced biliary tract cancer.
- Sakakida T, Taniguchi H, Asayama M, et al. PRABITAS: 14-day versus 28-day trifluridine–tipiracil plus bevacizumab for refractory metastatic colorectal cancer. The Lancet. Published online October 24, 2026. doi:10.1016/S0140-6736(26)01782-4.
- Xu D, et al. LOMAC, LBA81. Four versus six months of adjuvant XELOX after D2 gastrectomy.
