The first half of 2025 has marked a transformative period in gastrointestinal oncology, with the FDA granting five landmark approvals that are reshaping treatment paradigms across colorectal, gastric, hepatocellular, and anal cancers. These new indications reflect accelerating momentum in precision medicine, immunotherapy combinations, and biomarker-driven strategies for GI cancers.
First Targeted Therapy for KRAS G12C-Mutated Colorectal Cancer
On January 16, 2025, the FDA approved sotorasib in combination with panitumumab for adults with KRAS G12C-mutated metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This marks the first targeted regimen for KRAS G12C-mutated CRC, validating a strategy long considered "undruggable."
The approval was based on the CodeBreaK 300 trial, a randomized phase III study comparing sotorasib plus panitumumab with standard therapy (trifluridine/tipiracil or regorafenib). The combination doubled median progression-free survival to 5.6 months versus 2 months with standard care (HR 0.48; p = 0.005) and achieved an overall response rate of 26% compared with 0% in the control arm. Median duration of response was 4.4 months.
Common side effects include rash, diarrhea, stomatitis, and fatigue. This breakthrough offers new hope for refractory patients with this specific mutation.
Pembrolizumab Gains Full Approval for HER2-Positive Gastric Cancer
On March 19, 2025, the FDA granted full approval to pembrolizumab in combination with trastuzumab and chemotherapy for adults with HER2-positive, PD-L1 CPS ≥ 1 locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
The decision was supported by the KEYNOTE-811 trial, which enrolled 698 patients, 85% of whom had PD-L1 CPS ≥ 1 tumors. Pembrolizumab plus trastuzumab plus chemotherapy led to a median overall survival of 20.1 months versus 15.7 months with placebo (HR 0.79) and a median PFS of 10.9 versus 7.3 months (HR 0.72). The response rate reached 73%, significantly higher than the 58% achieved with the control regimen.
This approval establishes checkpoint inhibition as part of first-line HER2-positive gastric cancer therapy, combining HER2-targeted and PD-1-directed strategies for greater efficacy.
Dual Checkpoint Blockade for MSI-H/dMMR Colorectal Cancer
On April 8, 2025, the FDA approved nivolumab with ipilimumab for adults and pediatric patients ≥ 12 years with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch-repair-deficient (dMMR) colorectal cancer. The agency also converted nivolumab monotherapy from accelerated to full approval for this population.
The pivotal CheckMate-8HW trial compared nivolumab plus ipilimumab versus chemotherapy in first-line MSI-H/dMMR CRC. Median progression-free survival was not reached in the combination arm versus 5.8 months with chemotherapy (HR 0.21; p < 0.0001).
In a broader analysis including all treatment lines, dual therapy produced PFS not reached versus 39.3 months with nivolumab alone (HR 0.62; p = 0.0003) and an overall response rate of 71% compared with 58%. This approval reinforces dual checkpoint blockade as a cornerstone of care for MSI-H/dMMR colorectal cancer, offering deep and durable responses that exceed those seen with standard regimens.
New First-Line Option for Hepatocellular Carcinoma
On April 11, 2025, the FDA approved the combination of nivolumab and ipilimumab for the first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC). The CheckMate-9DW trial enrolled 668 patients with advanced HCC and no prior systemic therapy.
Nivolumab plus ipilimumab achieved a median overall survival of 23.7 months, compared with 20.6 months for lenvatinib or sorafenib (HR 0.79; p < 0.018), and an overall response rate of 36% versus 13%. This review was conducted under Project Orbis, allowing concurrent evaluation by multiple international agencies.
The approval adds a new immune-checkpoint combination to the HCC landscape, providing a VEGF-independent first-line option for patients with good hepatic reserve (Child-Pugh A).
Breakthrough for Rare Anal Canal Carcinoma
On May 15, 2025, the FDA approved retifanlimab-dlwr (Zynyz, Incyte) with carboplatin and paclitaxel for adults with inoperable, locally recurrent, or metastatic squamous cell carcinoma of the anal canal (SCAC). It also approved retifanlimab as a single agent for platinum-refractory or intolerant disease.
In POD1UM-303/InterAACT 2, combination therapy improved median PFS to 9.3 months versus 7.4 months (HR 0.63; p = 0.0006) and produced a response rate of 56% versus 44%. The single-agent study POD1UM-202 reported a 14% response rate and median duration of response of 9.5 months in previously treated patients.
The therapy, granted orphan drug, fast-track, and priority review status, represents a long-awaited advance in a rare and understudied GI malignancy, offering both first-line and salvage options for SCAC.
Clinical Impact and Future Directions
For clinicians, researchers, and patients alike, these advances bring both hope and new complexities in patient selection, sequencing, and safety management. The approvals demonstrate the growing sophistication of biomarker-driven treatment strategies and the expanding role of immunotherapy across GI malignancies.
These five approvals collectively represent a paradigm shift in GI oncology, moving beyond traditional chemotherapy approaches toward precision medicine and immunotherapy combinations tailored to specific tumor characteristics and patient populations.
