2026 Cancer Updates GI and Lung Denver: GI Cancer Updates and Panel Discussion
Presenter:
· Sunnie Kim, MD, University of Colorado Comprehensive Cancer Center
Discussion Panelists:
· Sunnie Kim, MD, University of Colorado Comprehensive Cancer Center (Moderator)
· Sujatha Nallapareddy, MD, Rocky Mountain Cancer Center
· Julie Elliott, MS, PA-C, Rocky Mountain Cancer Center
Overview
At the 2026 GI and Lung Cancer Updates program in Denver, Colorado, Dr Sunnie Kim from University of Colorado Comprehensive Cancer Center provided an overview of the evolving landscape in gastrointestinal (GI) oncology, with a clear emphasis on the growing centrality of biomarker-directed treatment strategies. Drawing heavily from data presented at the 2026 ASCO Gastrointestinal Cancers Symposium, Dr Kim framed her discussion around two key practice-changing trials, HERIZON-GEA01 and BREAKWATER, while also highlighting emerging therapeutic targets that are poised to further reshape care in pancreatic and biliary tract cancers. Across disease types, Dr Kim emphasized the increasing complexity, and opportunity, associated with precision oncology.
HERIZON-GEA01 (HER2+ Gastroesophageal Cancer)
In gastroesophageal cancer, Dr Kim focused on the HERIZON-GEA01 trial, which evaluated zanidatamab, a novel bispecific HER2-targeted antibody, in combination with chemotherapy with or without the programmed death receptor (PD-1) inhibitor tislelizumab in the first line setting for HER2-positive metastatic disease. She noted that zanidatamab represents a mechanistically distinct approach to HER2 targeting, binding simultaneously to two extracellular domains of the receptor, promoting receptor clustering and immune-mediated cytotoxicity. This dual-binding strategy appears to translate into meaningful clinical benefit. The trial demonstrated a progression-free survival (PFS) advantage of approximately four months for zanidatamab-containing regimens as compared with trastuzumab-based therapy, alongside a striking overall survival (OS) improvement of 26.4 months versus 19.2 months in the quadruplet arm. Dr Kim underscored the clinical significance of these findings, noting that, in the context of gastroesophageal cancer, such survival gains are rarely observed. “To reach over two years in a phase three study is a landmark… and to reach over seven months of survival benefit is… unprecedented for us.” Dr Kim noted.
The benefit of zanidatamab appeared most pronounced in patients with high HER2 expression (IHC3+), which is consistent with prior experience in this disease. One of the more intriguing findings, however, was the observation that patients with programmed death ligand 1 (PD-L1)-negative tumors derived substantial benefit from the zanidatamab-containing regimen, a departure from historical expectations with immune checkpoint inhibitors. As such, Dr Kim noted that the findings raise important biological questions regarding the interplay between HER2 targeting and immune modulation that remain to be fully elucidated.
Despite the strength of the data, Dr Kim acknowledged several limitations that must be considered when interpreting the results. For example, the study did not include a direct comparison to the current standard of care in the United States, as established by KEYNOTE-811 – a regimen which incorporates pembrolizumab with trastuzumab and chemotherapy. Additionally, Dr Kim noted the trial was conducted entirely outside the United States, which introduces uncertainty regarding its true efficacy in a US population and toxicity management in routine US practice. Among the most clinically relevant adverse events observed was diarrhea, with nearly one-quarter of patients in the quadruplet arm experiencing grade 3 or higher symptoms despite mandated diarrhea prophylaxis. Dr Kim emphasized the importance of proactive management, particularly for vulnerable populations, noting that “grade 3 and higher is very uncomfortable… we’re really going to have to make sure that they’re okay when they’re on this treatment.” Taken together, the magnitude of benefit observed in HERIZON-GEA01 led Dr Kim to suggest that zanidatamab-based therapy is likely to become a new standard of care in the first-line treatment of HER2-positive gastroesophageal cancer, pending regulatory approval.
BREAKWATER (BRAF V600E mCRC)
Dr Kim’s presentation then shifted to metastatic colorectal cancer (mCRC), wherein Dr Kim reviewed updated findings from the BREAKWATER trial, a study which has redefined the management of BRAF V600E–mutated metastatic disease. She noted that this molecular subset has historically been associated with poor outcomes, but the integration of targeted therapy with chemotherapy has significantly improved response rates and survival. Prior data from BREAKWATER demonstrated that the combination of encorafenib, cetuximab, and FOLFOX chemotherapy resulted in an overall response rate (ORR) of approximately 60%, with median OS exceeding 30 months, as compared with roughly 15 months for standard chemotherapy alone.
Dr Kim also noted recent data evaluating an alternative chemotherapy backbone using FOLFIRI in combination with encorafenib and cetuximab. Although the dataset remains immature with respect to the OS endpoint, the observed response rate of over 60% and the consistent magnitude of benefit relative to standard therapy suggested that this regimen is a viable option, particularly for patients who are not candidates for oxaliplatin due to baseline neuropathy. Dr Kim highlighted the clinical relevance of this flexibility, emphasizing that treatment personalization should extend beyond molecular targeting to include tolerability considerations and patient-specific factors.
Emerging Targets and Early-Phase Data
Beyond these two practice-changing trials, Dr Kim devoted attention to emerging therapies targeting KRAS G12D and FGFR2 alterations, which represent important unmet needs in other GI cancers, including pancreatic cancer and cholangiocarcinoma. She described the phase 1 data for the KRAS G12D inhibitor INCB161734 as encouraging, with an ORR of approximately 37% and effective disease control being observed in most patients. While toxicity was generally manageable and consistent with expectations, Dr Kim noted the combination of this agent with chemotherapy was associated with frequent treatment interruptions, underscoring the challenges of integrating novel targeted therapies into existing regimens. Nevertheless, the visual impact of the response data was notable, prompting Dr Kim to remark that the waterfall plot “does show that this is a very active drug in this disease.”
Similarly, Dr Kim noted that the development of fibroblast growth factor receptor 2 (FGFR2)-selective inhibition in cholangiocarcinoma continues to gain momentum. Data presented for lirafugratinib demonstrated a response rate approaching 50% and a disease control rate exceeding 90% in a pretreated population, with a median OS nearing two years. Dr Kim noted that these results reinforce the importance of molecular testing in this disease and suggest that increased selectivity may offer both efficacy and tolerability advantages over earlier FGFR inhibitors.
Panel Discussion: Real-World Implementation
Dr Kim then moderated a panel discussion with Dr Sujatha Nallapareddy and Julie Elliott, MS, PA-C, which provided some important insight on how these advances are being translated into clinical practice. A recurring theme was the logistical complexity of biomarker testing, which has become a critical determinant of treatment decision-making. Overall, the panelists described a pragmatic approach in which patients with symptomatic disease are often initiated on chemotherapy while awaiting molecular results, with subsequent modification of therapy based on biomarker status. As one panelist explained, “At least we are not delaying the treatment… we start with FOLFOX or CAPOX and then add depending on biomarker positivity.” The process of obtaining timely and comprehensive biomarker data, however, remains challenging. Panelists noted delays related to tissue acquisition, institutional workflows, and testing logistics as common barriers. In some cases, these challenges have been significant enough to prompt repeat biopsies, highlighting the distinction between optimal workflows and real-world clinical practice.
The panel also explored how clinicians are preparing their teams to manage the growing complexity of treatment-related toxicities associated with novel agents. Some of the institutional strategies cited include dedicated nursing education programs, pharmacist-led training sessions, and the development of multidisciplinary partnerships, particularly with ophthalmology in the context of FGFR inhibitor-associated ocular toxicities. These efforts underscore the importance of infrastructure workflows and education to ensure the safe implementation of new therapies.
Another evolving area discussed by the panel was the incorporation of DPYD testing to mitigate the risk of severe fluoropyrimidine toxicity. They noted that, with increasing recognition of its importance and improved access through next-generation sequencing platforms, DPYD assessment is becoming more routinely integrated into baseline evaluations. Ensuring that results are consistently reviewed and acted upon, however, remains an ongoing challenge, particularly in the absence of standardized electronic medical record-based alerts.
Treatment Sequencing and Ongoing Clinical Questions
The panelist’s discussion also highlighted several unresolved questions, particularly regarding treatment sequencing and resistance mechanisms in HER2-positive gastroesophageal cancer. The phenomenon of HER2 tumor heterogeneity, as well as loss of expression following trastuzumab-based therapy were noted to complicate subsequent treatment decisions, reinforcing the importance of re-biopsy upon progression. “Many patients can lose that HER2 clone after trastuzumab, so it is important to re-biopsy to re-assess HER2 status,” one panelist noted, underscoring a critical consideration in the era of targeted therapy. Some of the additional open questions that were considered included the relative contribution of immune checkpoint inhibition within zanidatamab-based regimens, optimal sequencing strategies following progression, and the overall generalizability and applicability of trial results in US practice settings.
Conclusions and Clinical Implications
In summary, Dr Kim’s GI cancers presentation reflected a field in transition, where advances in biomarker-driven therapy are rapidly expanding treatment options across GI malignancies. HERIZON-GEA01, for example, introduces a potentially practice-changing approach for HER2-positive gastroesophageal cancer, particularly in patient populations that have historically derived limited benefit from immunotherapy. Meanwhile, results from BREAKWATER have reinforced the importance of integrating targeted therapy early in the treatment course for BRAF-mutated colorectal cancer, with an increasing flexibility in the chemotherapy backbone selection.
At the same time, the GI cancer panel discussion highlights the fact that successful implementation of these advances will depend on continued improvements in biomarker testing infrastructure, toxicity management strategies, and multidisciplinary care coordination. As the therapeutic landscape becomes more complex, ensuring equitable access to testing and treatment will also remain essential, particularly for patients in community settings or underserved populations, where logistical barriers may limit the full realization and implementation of precision oncology.
Speaker Disclosure information: Dr Kim reported the following disclosures for her presentation: Advisory boards: BeOne; Consultant: Jazz Pharmaceuticals.
