The Top GI Cancer News of 2025

The landscape of gastrointestinal (GI) cancer treatment in 2025 has been defined by breakthrough clinical data. Advancements in treating pancreatic, colorectal, and other GI malignancies driven by immunotherapy and smarter chemotherapy application have offered patients more promising therapies. Here, we highlight these transformative developments shaping patient care this year.

Daraxonrasib Earns FDA Breakthrough Status in Pancreatic Cancer

In July, daraxonrasib (RMC-6236), an oral, direct RAS(ON) multiselective inhibitor, received FDA breakthrough therapy designation for treating previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) harboring KRAS G12X mutations.

This designation was based on promising findings from the phase 1 RMC-6236-001 trial. Updated results showed encouraging efficacy, including a median progression-free survival (PFS) of 8.8 months in patients with KRAS G12X-mutant PDAC receiving the 300-mg daily dose.

A global phase 3 trial (RASolute-302) is currently underway to further compare daraxonrasib against standard chemotherapy in this patient population, with results expected in 2026. The breakthrough status highlights the drug's potential role in addressing the significant unmet need for new pancreatic cancer treatments.

Aspirin Halves Recurrence Risk in 3 Years in PIK3CA-Mutated Colorectal Cancer

Data from the phase 3 ALASCCA trial presented at the ASCO Gastrointestinal Cancers Symposium in January demonstrated that aspirin significantly reduces the risk of disease recurrence in patients with nonmetastatic colorectal cancer (CRC) harboring alterations in the PI3K pathway, including PIK3CA mutations.

Patients who took aspirin for 3 years showed a 51% reduction in recurrence risk for PIK3CA exon 9/20 mutations and a 58% reduction for other PI3K pathway alterations compared with placebo.

The study confirms that these genetic alterations can predict a patient's response to aspirin, expanding the target population to nearly 40% of patients with CRC. Researchers highlight this as an example of repurposing an inexpensive, safe, and globally available drug, underscoring the importance of genomic testing.

Leronlimab Gets FDA Nod for Phase 2 Microsatellite-Stable CRC Trial

The FDA cleared the start of a phase 2 clinical trial to evaluate leronlimab, an investigational monoclonal antibody that targets CCR5 markers on tumor cells, in patients with relapsed/refractory microsatellite-stable CRC.

This open-label, randomized, 2-arm study will assess the drug's safety and efficacy when combined with standard treatments, trifluridine and tipiracil (TAS-102), and bevacizumab (Avastin). The trial aims to enroll approximately 60 patients who are positive for CCR5 expression. The primary end points include overall response rate, with secondary end points focusing on overall survival and safety. The estimated primary completion date for this study is June 2028.

Neoadjuvant PAXG Outperforms mFOLFIRINOX in Resectable and Borderline Resectable PDAC

Final results from the phase 3 CASSANDRA trial presented at the 2025 ASCO Meeting show that the neoadjuvant chemotherapy regimen PAXG (cisplatin, nab-paclitaxel, gemcitabine, and capecitabine) is superior to modified FOLFIRINOX (mFOLFIRINOX) for treating resectable or borderline resectable PDAC.

PAXG significantly improved event-free survival (EFS), with a median EFS of 16.0 months vs 10.2 months for mFOLFIRINOX. The 3-year EFS rate more than doubled with PAXG (31% vs 13%). PAXG also yielded better tumor response metrics, including a higher disease control rate and more favorable pathological outcomes, positioning it as the preferred neoadjuvant regimen.

First-in-Human Data Highlight Potential of Intracellular Checkpoint Inhibition in Metastatic Colorectal Cancer

First-in-human data from a phase 1 study demonstrates the feasibility and potential efficacy of targeting the intracellular immune checkpoint CISH in heavily pretreated metastatic CRC.

Researchers administered autologous tumor-infiltrating lymphocytes with the CISH gene knocked out using CRISPR/Cas9. This approach aims to enhance T-cell antitumor immunity by overcoming limitations of traditional cell-surface checkpoints. The treatment showed a favorable safety profile and resulted in an exceptional, long-term complete response in one patient. This marks a significant clinical validation for targeting intracellular checkpoints, suggesting a new, potentially broad-acting strategy beyond the current PD-1/PD-L1 immunotherapy paradigm.