Clinical data from the 2026 European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancers reveals a shifting landscape in GI oncology, marked by the failure of the KRYSTAL-10 trial to improve outcomes in colorectal cancer and emerging success for RAS(ON) inhibitors in pancreatic cancer. These findings highlight a move toward more selective, targeted therapies while underscoring the persistent efficacy of traditional chemotherapy regimens.
Why did the KRYSTAL-10 trial fail to meet endpoints?
The phase 3 KRYSTAL-10 trial, which evaluated the combination of adagrasib and cetuximab, did not demonstrate a survival benefit over standard chemotherapy in patients with KRAS G12C-mutated metastatic colorectal cancer. According to final trial data presented at the meeting, median progression-free survival (PFS) was 7.5 months in the experimental arm compared with 8.1 months in the chemotherapy group (HR, 0.89; P = .3241).
Pfeiffer, MD, of the University of Southern Denmark and Odense University Hospital, noted that the chemotherapy arm performed unexpectedly well. While historical expectations for this patient population suggest a median overall survival (OS) of 12 to 14 months, the chemotherapy cohort in this trial reached 21.7 months. Pfeiffer also suggested that the higher crossover rate—where 30% of patients in the chemotherapy arm later received a KRAS G12C inhibitor compared with 4% in the experimental arm—may have confounded the survival results.
How is zoldonrasib changing pancreatic cancer treatment?
Early-phase data for the RAS(ON) G12D-selective inhibitor zoldonrasib suggest it can be safely combined with standard-of-care chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC). In the RMC-GI-102 trial, patients treated with zoldonrasib plus mFOLFIRINOX achieved an objective response rate (ORR) of 82%, while those receiving the drug with gemcitabine and nab-paclitaxel (GnP) reached an ORR of 61%, according to findings reported at the congress.
Teresa Macarulla, MD, head of the medical oncology department at Hospital Clínic Barcelona and congress co-chair, stated that the ability to combine these agents without introducing unexpected safety issues is a positive signal for the field. The study also showed significant molecular activity, with 47% to 71% of patients achieving complete clearance of RAS G12D-mutant circulating tumor DNA (ctDNA).
What are the latest developments in TACE combinations for HCC?
The role of immunotherapy combined with transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) remains uncertain following mixed results from the EMERALD-1 and EMERALD-3 trials. Data from EMERALD-1 showed that adding durvalumab, with or without bevacizumab, to TACE failed to improve overall survival compared to TACE alone. Jens Ricke, MD, of University Hospital, LMU Munich, described these results as “disappointing,” noting that early PFS benefits did not translate into long-term survival gains.
Conversely, EMERALD-3 provided more optimistic data. The trial, which tested the STRIDE regimen (tremelimumab and durvalumab) with or without lenvatinib, showed a continued PFS benefit (HR, 0.70) and improved response rates compared to TACE alone. Ricke suggested that while toxicity is a concern, the potential survival benefit makes the combination a candidate for further study, particularly if it allows for the preservation of lenvatinib for later lines of therapy.
Can immunotherapy provide durable survival in MSS CRC?
Long-term follow-up from a phase 1b study indicates that the combination of botensilimab and balstilimab may offer durable survival for patients with refractory microsatellite-stable (MSS) metastatic colorectal cancer. According to data presented by Benjamin L. Schlechter, MD, of Dana-Farber Cancer Institute, the 3-year OS rate was 33% for patients without active liver metastases.
Notably, 17% of the 123 enrolled patients remained alive and off all systemic therapy at the time of the latest follow-up. These results are significant because durable responses in this heavily pretreated, MSS-stable population have historically been rare. These findings have informed the design of the ongoing phase 3 BATTMAN trial.
Frequently Asked Questions
- Did the adagrasib and cetuximab combination meet its primary endpoints? No. According to the KRYSTAL-10 trial, the combination did not outperform chemotherapy in PFS or OS in patients with KRAS G12C-mutated colorectal cancer.
- Is zoldonrasib effective in previously treated pancreatic cancer? Yes, phase 1 data from the RMC-9805-001 trial showed an ORR of 50% in the second-line setting and 47% in the third-line-or-later setting.
- What is the main concern with TACE-based immunotherapy for HCC? Treatment-related toxicity is a significant factor. In the EMERALD-1 trial, grade 3 or 4 adverse events were reported in 47% of the triple-therapy arm compared to 25% in the TACE-alone arm.
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