Insights From ASCO 2026: Evolving Treatment Strategies in Gastrointestinal Malignancies

Gastrointestinal (GI) malignancy experts reviewed several key studies presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting during a panel discussion focused on how new data may influence daily practice in the management of GI cancers. 

The Role of ctDNA in Early-Stage Colon Cancer

One of the most discussed studies at ASCO 2026 was the phase 3 CIRCULATE trial, which evaluated whether postoperative ctDNA testing could guide adjuvant treatment decisions in patients with stage II colon cancer. Results showed that ctDNA was highly prognostic in stage II colon cancer, with inferior 3-year disease-free survival (DFS) and overall survival (OS) among ctDNA-positive patients. 

Although the use of ctDNA has increased in recent years, experts emphasized that its integration into routine practice remains nuanced. Despite its promising clinical implications, experts highlighted the importance of patient-centered decision-making and noted that negative ctDNA testing may provide reassurance for some patients. However, positive ctDNA results can create additional anxiety and uncertainty, particularly given a lack of clearly established intervention guidelines. The use of ctDNA remains one of the most closely watched developments in oncology, with ongoing studies expected to define its clinical utility further, especially in early-stage settings.

Immunotherapy-Driven Shifts in dMMR/MSI-H Colon Cancer 

Current standard treatment of stage III colon cancer continues to be based on results from the IDEA trial. However, promising immunotherapy data have been challenging traditional chemotherapy-based approaches for patients with dMMR/MSI-H colon cancer. Panelists highlighted findings from the phase 3 ATOMIC trial, which demonstrated a DFS benefit with the addition of atezolizumab to adjuvant treatment. This breakthrough study is now raising another challenging question: how much benefit does chemotherapy truly contribute to colon cancer known to be highly responsive to immunotherapy? Experts suggested that future treatment strategies may increasingly favor immunotherapy while reducing chemotherapy intensity, particularly for MSI-high disease.

Perhaps one of the most challenging discussions was the role of neoadjuvant immunotherapy and whether surgery could ultimately be avoided in selected patients. Panelists shared their own experiences in clinical practice with remarkable results after neoadjuvant treatment with immune checkpoint inhibitors similar to the phase 2 NICHE-2 trial results, raising the possibility of nonoperative management approaches in the future. At the same time, panelists acknowledged important limitations. Including the risk of overtreatment. In the metastatic MSI-H CRC setting, panelists noted that the choice between single-agent and combination immunotherapy often depends on disease burden, the need for rapid tumor reduction, and patient tolerance of additional toxicity.

Advances in Metastatic Colorectal Cancer

For first-line treatment, anti-EGFR therapy remains an important option for RAS wild-type patients and particularly for left-sided disease, following evidence from the PARADIGM trial demonstrating improved outcomes. However, experts noted that treatment decisions frequently extend beyond efficacy data. Quality-of-life considerations and tolerability of side effects play an essential role in shared decision-making with patients. 

For further lines, there are several treatment options. Fruquintinib was highlighted as an increasingly attractive option because of its more manageable safety profile and flexibility in dose adjustment, whereas regorafenib continues to benefit from dose-escalation approaches established by the ReDOS study. Experts also recommended increased use of DPYD testing before initiating fluoropyrimidine-based therapy, reflecting recent updates to FDA and National Comprehensive Cancer Network guidelines aimed at reducing severe treatment-related toxicity.

Biomarker-Driven Strategies in Gastroesophageal Cancer

Results from the phase 3 MATTERHORN trial reinforced the growing role of immunotherapy among patients with resectable gastric and gastroesophageal junction adenocarcinoma. The addition of perioperative durvalumab to FLOT (fluorouracil [5-FU], leucovorin [folinic acid], oxaliplatin, and docetaxel) chemotherapy has rapidly become a new standard of care, given significantly better event-free survival (EFS) outcomes. 

Updated data presented at ASCO 2026 (Abstract 4070) demonstrated that patients who completed the full treatment course—including neoadjuvant therapy, surgery, adjuvant therapy, and maintenance durvalumab—had the most favorable EFS outcomes compared with patients who discontinued treatments prematurely.

Experts also discussed promising results from the HERIZON-GEA-01 trial for HER2-positive metastatic gastroesophageal adenocarcinoma, which compared first-line zanidatamab (a dual HER2-targeted bispecific antibody) plus chemotherapy with or without tislelizumab (anti–PD-1) versus trastuzumab plus chemotherapy. Experts described the findings as potentially transformational with improvements in progression-free survival (12.4 months vs 8.1 months) and OS (26.4 months vs 19.2 months) with zanidatamab-based therapy compared with standard treatment. The importance of early prophylactic intervention for diarrhea was also highlighted to minimize side effects.

For patients with CLDN18.2-positive gastroesophageal cancers, experts generally favored prioritizing zolbetuximab-containing regimens in patients with lower PD-L1 expression, while reserving immunotherapy for later lines in refractory settings.

Emerging Targeted Approaches in Pancreatic Cancer

Pancreatic cancer has historically lacked effective targeted treatment options. While treatment remains a multidisciplinary approach for resectable disease, we have only a few options for metastatic disease including modified FOLFIRINOX (folinic acid, 5-FU, irinotecan, and oxaliplatin), NALIRIFOX (nanoliposomal irinotecan, oxaliplatin, 5-FU, and folinic acid), gemcitabine and nab-paclitaxel (Gem/Nab-Paclitaxel) or single agent chemotherapy. Although NAPOLI 3 trial showed slight superiority of NALIRIFOX compared with Gem/Nab-Paclitaxel, experts noted that there is no significant difference between regimens, given the lower tolerability of NALIRIFOX and modest improvement in OS by 1.9 months. 

RASolute 302 trial results were the most anticipated and exciting presentation at ASCO 2026. This study evaluated the role of the multi-RAS inhibitor daraxonrasib in previously treated metastatic pancreatic cancer. Early results generated tremendous excitement and hope, with survival outcomes almost doubling compared with current standard therapies. Ongoing studies are already exploring the role of daraxonrasib as a frontline treatment and in the neoadjuvant and adjuvant settings.

Overall, the panel highlighted a clear transition in the management of GI cancers from traditional chemotherapy-based approaches toward more biomarker-driven strategies.