Pipeline across gastrointestinal tumours

This overview outlines emerging therapeutic developments across gastrointestinal cancers. In hepatocellular carcinoma (HCC), treatment has evolved from reliance on oral targeted agents such as sorafenib, regorafenib, and lenvatinib to multiple effective immunotherapy-based combinations. The established regimen of atezolizumab plus bevacizumab has been followed by additional options, including durvalumab combined with tremelimumab and, more recently, nivolumab with ipilimumab. These regimens demonstrate meaningful clinical activity, but their use requires careful attention to toxicity, particularly immune-mediated hepatitis in a population already susceptible to liver dysfunction. Despite the heterogeneity of HCC, immunotherapy combinations appear poised to remain central in future management strategies.

In colorectal cancer, the most transformative developments involve MSI-high disease, where pembrolizumab became an early standard and has since been joined by nivolumab plus ipilimumab. A major advance is the movement of immunotherapy into the neoadjuvant setting. Trials such as the NICHE studies demonstrated near 100% response rate in MSI-high tumours treated before surgery. This raises the prospect that neoadjuvant immunotherapy could eventually be explored in microsatellite-stable colorectal cancer, although evidence is not yet available.

Gastric cancer has also seen a rapid expansion of targeted and immune-based options. Claudin 18.2–directed agents, HER2-targeted therapies, and various immunotherapy combinations are producing new treatment avenues. The field is becoming increasingly driven by biomarker-selected strategies, reflecting the molecular heterogeneity of gastric tumours. 

An up-and-coming area across gastrointestinal oncology is the development of RAS-directed therapies. After decades in which KRAS was considered undruggable, inhibitors of KRAS G12C and, more recently, G12D have emerged. Furthermore, pan-RAS inhibitors are entering clinical trials. These agents could be especially relevant for pancreatic cancer, where RAS mutations are present in the majority of cases, and for subsets of colorectal cancer.

Another broad area of innovation includes antibody–drug conjugates, which are rapidly proliferating across tumour types, and bispecific antibodies, including those targeting PD-1 together with VEGF pathways. These modalities aim to produce more potent and selective antitumour responses.

Finally, PRMT5 inhibitors represent an emerging targeted approach, particularly for tumors with MTAP deletion. Around 20% of pancreatic cancers harbor this alteration, and ongoing trials are evaluating PRMT5 inhibition in combination with chemotherapy. Similar strategies are being explored in other MTAP-deleted malignancies.

Overall, the pipeline in gastrointestinal oncology is expanding rapidly, driven by advances in immunotherapy, targeted agents, and molecularly defined patient subgroups.