Cancer Updates GI and Breast Memphis: GI Cancer Updates with Dr Axel Grothey
Presenter:
Axel Grothey, MD, West Cancer Center
Conference:
2025 Cancer Updates GI and Breast, Memphis
A Paradigm Shift: Precision Medicine and Immunotherapy in GI Cancers
At the 2025 Cancer Updates GI and Breast Dinner Conference in Memphis, TN, Dr Axel Grothey from West Cancer Center presented updates across the gastrointestinal (GI) cancers, with a focus on emergent, biomarker-driven strategies which have been transformative across the spectrum of GI oncology. Highlighting how far the field has come, Dr Grothey emphasized, “Almost every three to four months, we see another marker or drug added to our portfolio”, pointing to the expanding universe of actionable targets such as mismatch repair (MMR) and microsatellite instability (MSI) status, Human epidermal growth factor receptor 2 (HER2), the BRAF and RAS signaling pathways, and more recently, Claudin 18.2 (CLDN18.2) expression. He noted that these biomarkers can now be used to guide therapy selection across the continuum of care for colorectal, gastric, and pancreatic cancers.
MSI-H/dMMR Colorectal Cancer: An Evolving Role for Immunotherapy
Dr Grothey highlighted the evolving role of the immunotherapy using immune checkpoint inhibitors (ICIs) for patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), where these agents have helped to redefine treatment outcomes. He noted findings from studies like CheckMate 8HW, which compared the efficacy of nivolumab alone, nivolumab with ipilimumab (NIVO+IPI), and chemotherapy, emphasizing the particularly robust efficacy of the ICI combination in this setting: “You can drive a truck through that progression-free survival difference… This already became a new standard of care…” He also contrasted the CheckMate 8HW results with those from another trial KEYNOTE-177 with a different ICI, pembrolizumab, noting: “the NIVO/IPI [combination] trends better than pembrolizumab alone… because there's no early crossing of the PFS curves…” Despite the absence of overall survival (OS) data with the NIVO/IPI combination as of yet, Dr Grothey noted: “When I have a patient with MSI-H/dMMR colorectal cancer Stage IV, the goal is cure—and that’s what I communicate to my patients…”
Neoadjuvant Immunotherapy: A Potential Game Changer
Dr Grothey further noted the use of ICI immunotherapy extending into early-stage MSI-H/dMMR colon cancer setting. He reviewed data from the NICHE-2 trial by Chalabi et al. that were, in his words, “unprecedented”. In patients who had received just two doses of immunotherapy prior to surgery, results from the trial showed that 67% of patients had a pathologic complete response (pCR), and 98% showed major regression of their tumor. “That’s not a waterfall plot—it’s Niagara Falls!” Dr Grothey commented, referring to the robust tumor regression results seen after only 2 cycles of immunotherapy. Moreover, at three years of follow up, none of the patients had recurred – a result to which Dr Grothey commented “I’ve never seen anything like it…” As such, Dr Grothey now urges his colleagues to engage surgeons for an early referral to medical oncology, stating: “Will surgeons listen and send patients before surgery? Because that's what we need…”
BRAF V600E in mCRC: Target Early
For patients with BRAF V600E mutant CRC, Dr Grothey noted this was a particularly poor prognostic factor. He reviewed results from the BREAKWATER trial, which evaluated the combination of encorafenib, a small molecule BRAF inhibitor, and cetuximab, and epidermal growth factor receptor (EGFR) directed therapy, with or without chemotherapy in the first-line setting. While the no-chemotherapy arm was halted due to underperformance, Dr Grothey noted that the combination arm demonstrated improved outcomes including overall response rate versus the standard of care arm (60.9% vs. 40.0%). Emphasizing the importance of early treatment for BRAF V600E, Dr Grothey noted “When you have a very bad prognostic marker, you don’t wait to target it—you hit early…” He also predicted that survival benefits, though not statistically significant as yet, are likely to emerge from the trial: “I’d bet a lot this will turn out to be significant…”
HER2 in CRC: Sequencing Strategies Emerge
Dr Grothey noted that HER2 amplification in mCRC, while comparatively rare (~3%), is nonetheless a clinically actionable target. He highlighted results from the DESTINY-CRC01 trial (investigating the efficacy of the antibody drug conjugate, trastuzumab deruxtecan, T-DXd) and the MOUNTAINEER trial (investigating the combination of trastuzumab and tucatinib). Based on the overall evidence from these trials, Dr Grothey notes he prefers starting with the trastuzumab and tucatinib combination: “We don’t have data for T-DXd working first, but we do have it working after trastuzumab-based therapy.” He also cited the major toxicity concern with T-DXd, interstitial lung disease, noting “There are toxicities we need to recognize and manage [with T-DXd]—especially pulmonary.” He also cited zanidatamab, a bispecific antibody, as an emerging HER2-targeted agent with promising applications across multiple GI tumors.
RAS-Targeted Therapies: A Reawakening
Dr Grothey was particularly enthusiastic about efforts underway to target patients with RAS mutations, which have, historically, been undruggable, but are now targetable in a small subset of patients, such as those with KRAS G12C. He noted findings from trials like CodeBreaK 100 and KRYSTAL-1 which have demonstrated modest efficacy of agents like sotorasib and adagrasib, respectively, but only when combined with EGFR inhibitors: “Combination therapy works better—similar to BRAF….” Dr Grothey expressed the greatest excitement, however, for the emergence of pan-RAS inhibitors, noting especially results for RMC-6236 in pancreatic ductal adenocarcinoma (PDAC): “This is the most RAS-driven tumor type we have, and in second-line pancreatic cancer, we’re seeing 36% response and 14-month OS… remarkable…” He further noted the unique mechanism of action of this agent for blocking RAS: “Sterically blocking RAS activation via Cyclophilin A—it’s a brilliant strategy.”
CLDN18.2: A Rising Star in Gastric Cancer
Dr Grothey concluded his presentation with a discussion of gastric cancer and a new biomarker, Claudin 18.2 (CLDN18.2), a tight junction protein aberrantly expressed on tumor cell surfaces. He noted results from the SPOTLIGHT trial, which led to the approval of zolbetuximab, a CLDN18.2-targeted antibody, in combination with mFOLFOX, as a first-line treatment for patients with CLDN18.2-positive gastric cancer. Notably, the median overall survival (OS) in the trial was 18.2 months, which Dr Grothey commented was both “easy to remember… and impressive” for this patient population. With regard to the rather unique toxicities of this agent seen in the SPOTLIGHT trial, Dr Grothey noted the incidence of vomiting in the absence of nausea: “Projectile vomiting without nausea—this is something we haven't seen in a while…” As such, he suggested that proper education for both the nursing team and the patients is essential, particularly during the first cycle. He further noted that the treatment appears to be better tolerated in patients post-gastrectomy. Looking forward, Dr Grothey expects a wave of CLDN18.2-directed antibody drug conjugates to follow: “This is just the beginning. We have a new target, and it’s going to reshape the treatment landscape.”
GI Cancer Updates with Dr Grothey: Quick Summary
In MSI-H/dMMR mCRC: Combination immunotherapy with NIVO+IPI may be more effective than single-agent PD-1 blockade; this is now a frontline option.
In Early-Stage CRC: Neoadjuvant immunotherapy may eliminate the need for surgery in selected MSI-H/dMMR patients.
For BRAF V600E mCRC: There is a need to target this poor prognostic factor early; results from BREAKWATER support encorafenib + cetuximab use as a first-line triplet therapy.
In HER2+ mCRC: The sequence of therapy matters; consider trastuzumab/tucatinib before using T-DXd.
In RAS Mutated Tumors: Novel Pan-RAS inhibitors, like RMC-6236 are showing early promise, especially in PDAC.
In Gastric Cancer: Zolbetuximab, targeting CLDN18.2, represents a novel first-line option in gastric/GEJ cancer, with careful toxicity management.
Speaker Disclosure Information: Dr Grothey reported no relevant disclosures for this presentation.