Latest GI Cancer Trends From ASCO 2025: Molecular Testing, IO Strategies & Targeted Therapy
Key Points
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Circulating tumor DNA (ctDNA) is useful in stage II colon cancer, while its role in stage III remains investigational.
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The ATOMIC trial will clarify the role of adjuvant immunotherapy (IO) in colon cancer.
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BREAKWATER established a new standard in BRAF V600E-mutant colorectal cancer (CRC) with encorafenib and cetuximab (EC) plus chemotherapy.
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MATTERHORN supports the integration of perioperative durvalumab in upper gastrointestinal (GI) cancers.
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CheckMate 577 supports adjuvant nivolumab in esophageal cancer with residual disease.
Leading voices in GI oncology joined Rahul Gosain, MD, MBA, and Rohit Gosain, MD—the Oncology Brothers—at an Advancements in Oncology live event held alongside the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. Tanios Bekaii-Saab, MD, of Mayo Clinic, and Namrata Vijayvergia, MD, of Fox Chase Cancer Center, offered their perspectives on integrating emerging data into clinical care across colorectal, esophageal, gastric, gastroesophageal junction (GEJ), biliary, and neuroendocrine cancers.
Colorectal Cancer: Circulating Tumor DNA, Minimal Residual Disease, and Precision Therapy
Dr. Vijayvergia addressed the growing enthusiasm for circulating tumor DNA (ctDNA) testing in early-stage colon cancer, emphasizing that although patients increasingly request it, ctDNA currently serves a prognostic, not predictive, role. She likened this to “asking an astrologer to predict the future”—it offers insight but no way to alter outcomes. Data from the DYNAMIC-III trial confirmed that escalating adjuvant chemotherapy based on ctDNA positivity in stage III colon cancer did not improve overall survival (OS), reinforcing that such strategies should remain within clinical trials. For stage IIIA colon cancer—where recurrence risk is lower than in stage IIC—Drs. Vijayvergia and Bekaii-Saab noted that minimal residual disease (MRD) testing could support de-escalation decisions, particularly if MRD is negative. However, Dr. Bekaii-Saab cautioned that MRD is still more “art than science,” and while useful in shared decision-making, it may also induce unnecessary anxiety. He advised against MRD testing in stage I disease and recommended selective use in stage III patients after thorough discussion.
When asked about immunotherapy in stage III microsatellite instability (MSI)–high colon cancer, Dr. Vijayvergia reiterated that surgery followed by adjuvant chemotherapy remains standard care. Although the NICHE-2 data support the activity of immunotherapy in localized disease, it is not yet practice-changing outside of trials. She reserves agents like nivolumab plus ipilimumab for bulky or inoperable tumors, not up front for resectable cases. The upcoming ATOMIC trial will further clarify the role of chemoimmunotherapy in this setting.
In metastatic colorectal cancer (CRC), tumor biology and sidedness are central to decision-making. Dr. Bekaii-Saab underscored the importance of early, aggressive therapy, especially in BRAF V600E-mutated tumors. The BREAKWATER trial showed a doubling in median OS—from 15 to 30 months—when chemotherapy was added to encorafenib plus cetuximab (EC). Although EC alone offers some benefit, combining it with chemotherapy addresses tumor heterogeneity and sensitizes tumors to targeted agents. Dr. Bekaii-Saab noted that EC alone may be appropriate for older patients or those unfit for chemotherapy, but a chemotherapy backbone remains preferred when possible. Dr. Rahul Gosain stressed the importance of comprehensive upfront molecular profiling, including MSI, BRAF, KRAS/NRAS, HER2, and tumor sidedness, to guide therapy.
For HER2-negative, RAS wild-type patients, Dr. Vijayvergia prefers TAS-102 plus bevacizumab in the third-line setting, citing improved survival and tolerability from the SUNLIGHT study. In patients who develop cytopenias or cannot tolerate further chemotherapy, fruquintinib offers a chemo-free alternative. She rarely uses regorafenib due to poor tolerability.
For HER2-positive metastatic CRC, Dr. Bekaii-Saab outlined a sequencing strategy:
- First line: trastuzumab plus tucatinib, based on MOUNTAINEER, which showed an objective response rate of 38.1% and median OS of 24.1 months in HER2-amplified, RAS wild-type tumors
- Later lines: trastuzumab deruxtecan (T-DXd), especially in RAS-mutated tumors, due to its mechanism as a smart, receptor-targeted chemotherapeutic agent that does not require biologic signaling to be active
Dr. Bekaii-Saab emphasized that T-DXd relies on HER2 as a “docking station” rather than a biologic driver, making it effective in settings where traditional HER2-targeted therapies may fail due to pathway resistance in cases of RAS-mutant tumors. He noted ongoing trials evaluating combinations of FOLFOX (leucovorin [folinic acid], fluorouracil, and oxaliplatin), trastuzumab, and tucatinib in the first-line setting.
Overall, the panelists emphasized that timely, biology-driven, intervention and personalization of care remain key pillars in managing CRC. Although ctDNA and MRD are promising tools, their current use should be supportive, not directive, outside clinical trials.
Upper Gastrointestinal Cancers: Integrating Immunotherapy Into Perioperative Care
Drs. Vijayvergia and Bekaii-Saab also discussed significant updates in gastric, GEJ, and esophageal cancers. Dr. Rohit Gosain opened the segment by noting how recent trials, including ESOPEC and MATTERHORN, are reshaping perioperative treatment paradigms.
Dr. Vijayvergia explained that GEJ and gastric adenocarcinomas now rely more on perioperative chemotherapy, such as FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel), with limited roles for radiation. The MATTERHORN trial, which added durvalumab to perioperative FLOT, demonstrated positive results with significantly better event-free survival outcomes than FLOT alone among participants with resectable gastric or GEJ adenocarcinoma. These findings point toward a future sandwich model of immunotherapy—preop, surgery, postop—mirroring evolving strategies in lung and breast cancer.
For esophageal squamous cell carcinoma and upper esophageal adenocarcinoma, especially in PD-L1–positive tumors, the CheckMate 577 regimen remains standard: neoadjuvant chemoradiation followed by adjuvant nivolumab for patients with residual disease. Dr. Vijayvergia emphasized restricting this approach to patients with higher risk, PD-L1–positive disease not treated with immunotherapy preoperatively. Decisions remain complex for PD-L1–negative or chemo-ineligible patients. In those who progress after chemoradiation but cannot undergo surgery, Dr. Bekaii-Saab favors combining chemotherapy and immunotherapy (eg, FOLFOX plus IO), particularly in cases of macroscopic residual disease. He noted that FLOT is not necessary in these unresectable settings and that management should reflect disease biology and patient condition.
In the metastatic setting, Dr. Rahul Gosain reiterated the need for biomarker testing—MSI, PD-L1, HER2, and CLDN18.2—to tailor treatment. Dr. Vijayvergia discussed DESTINY-Gastric04, which established T-DXd as the standard second-line therapy for HER2-positive gastric and GEJ cancer. However, she emphasized the need to reconfirm HER2 status at progression, given the approximately 14% risk of interstitial lung disease with T-DXd and the possibility of HER2 loss in 20% of cases, as seen in breast cancer. While immunohistochemistry (IHC)–based biopsy remains the standard, ctDNA and RNA expression profiling may play a future role. The panel agreed that upper gastrointestinal cancer care is shifting toward biomarker-driven treatment, with a growing role for perioperative immunotherapy and evolving standards in HER2-targeted approaches.
Neuroendocrine Tumors: Choosing Wisely in a Chronic Disease
Turning to neuroendocrine tumors (NETs), Dr. Vijayvergia highlighted that sequencing is less critical than in other cancers because patients often live long enough to receive multiple therapies. She recommends starting with somatostatin analogues, followed by radioligand therapy (peptide receptor radionuclide therapy [PRRT]), particularly in pancreatic NETs. She cautioned against using PRRT in patients with low-volume disease, renal impairment, significant peritoneal involvement, or bowel obstruction, who are at higher risk of complications such as frozen abdomen and show reduced efficacy. Practical issues like caregiver burden can also influence timing.
For lung NETs, which express somatostatin receptors in only about 40% of cases, PRRT is often not feasible. Instead, Dr. Vijayvergia uses cabozantinib or everolimus. Everolimus may cause hyperglycemia and mucositis, while cabozantinib may lead to hypertension and hand-foot syndrome. Dr. Bekaii-Saab noted that many clinicians start cabozantinib at 40 mg, rather than the 60 mg used in trials, because of better tolerability. He emphasized that early, consistent dosing is crucial across targeted therapies. Dr. Vijayvergia added that the average dose in the CABINET trial was 39 mg, supporting this approach.
Biliary Tract Cancers: Target-Rich and Rapidly Advancing
Biliary tract cancers (BTCs) remain aggressive, with a poor prognosis. Dr. Gosain reviewed the standard approach: surgery with adjuvant capecitabine for resectable disease and chemotherapy plus immunotherapy for unresectable or metastatic cases. Dr. Bekaii-Saab emphasized that 30% to 40% of biliary cancers harbor targetable alterations, including HER2 amplification, most often in extrahepatic and gallbladder cancers. He described a tiered treatment strategy:
- For IHC 3+ tumors, zanidatamab offers the strongest data and is FDA approved. The HERIZON-BTC-01 trial showed an objective response rate of 41.3% with rapid and durable response with zanidatamab as monotherapy in patients with HER2-positive BTC.
- For IHC 2+/fluorescence in situ hybridization–positive tumors, he uses tucatinib plus trastuzumab, supported by data from the SGNTUC-019 basket trial.
- For patients who progress, T-DXd is reserved as a later-line option due to its mechanism as a HER2-targeted antibody-drug conjugate.
Finally, Dr. Gosain noted that zanidatamab, although structurally a bispecific antibody, functions similarly to trastuzumab plus pertuzumab and has a favorable adverse effect profile. Dr. Bekaii-Saab added that it outperforms traditional HER2 combinations, enhances immune response, and reduces resistance by targeting 2 distinct HER2 epitopes. Dr. Vijayvergia echoed this, noting the clinical benefit of dual epitope targeting.