Unpacking the Latest Research in Gastrointestinal Cancers

In Season 4, Episode 1 of Targeted Talks, Benjamin L. Schlechter, MD, chief physician at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, discusses new studies in the field of gastrointestinal cancer. Worse explains how these studies may influence future research.

Initially, a phase 1a/1b study (NCT03860272) of botensilimab (AGEN1181) plus balstilimab (AGEN2034) demonstrated promising clinical activity and durable responses in patients with heavily pretreated metastatic microsatellite stable (MSS) colorectal cancer (CRC). The results were presented at the American Society of Clinical Oncology (ASCO GI) Gastrointestinal Cancers Symposium. Schlecter explains that botensilimab is a first-in-class drug that targets the CTLA-4 protein receptor and therefore offers something different than currently available anti-CTLA-4 therapies.¹

“I don’t think anybody expected things like this to work because there has been so much failure in this area. I think it emphasizes that this isn’t just a CTLA-4 inhibitor and it’s not just a checkpoint inhibitor. The behavior of this agent is fundamentally different. We see that in the efficacy profile and toxicity profile. And I think it’s easy to put this in the same basket as tremelimumab [Imjudo]or ipilimumab [Yervoy], and I don’t think that’s a fair assessment. It’s a next-class drug, and it’s really its own thing,” Schlechter says.

In another early-stage study (TACTIC-02; NCT04727151), researchers are investigating the use of autologous T cells expressing T cell antigen pairs (TAC) that target HER2 in patients with solid tumors. Schlechter says T-cell therapy is difficult in solid tumors, but if successful, this study will create opportunities for other targeted therapy trials in the future.²

Schlechter says: “I think that’s a really important start. If we can safely and successfully target HER2, it will really open the door to a number of targets that are currently taboo. There are so many cancers right now that we know have a target, but we can’t pursue that target because so many target normal tissue that it would be dangerous to do so. This is an important innovation in both T cell therapy and HER2. But this is also an important innovation for cell therapy in oncology, because products like these would allow us to target far more targets than we can currently with existing technology.”

Worse also discusses later-stage studies that appear to be changing practice. The SUNLIGHT study (NCT04737187), for example, may have global implications for adding Bevacizumab (Avastin) in combination with trifluridine/tipiracil (Lonsurf) for the treatment of metastatic CRC. This strategy is already standard in the USA. Additionally, the addition of liposomal irinotecan to 5-fluorouracil with leucovorin plus oxaliplatin (NALIRIFOX) may potentially yield better efficacy compared to standard treatment, as shown in FIG NAPOLI-3 study (NCT04083235) in patients with ductal adenocarcinoma of the pancreas.

_REFERENCES:

_{1. El-Khoueiry AB, Fakih M, Gordon MS, et al. Results of a phase 1a/1b study of botenlimab (BOT), a novel innate/adaptive immune system activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic, heavily pretreated, microsatellite stable colorectal cancer (MSS CRC). J Clin Oncol. 2023; 41 (Supplement 4): LBA8. doi: 10.1200/JCO.2023.41.3_suppl.LBA8}

_{2. Poor BL, Olson D, Sailbil S, et al. A phase I/II study to evaluate the safety and efficacy of autologous TAC-T cells targeting HER2 in relapsed or refractory solid tumors. J Clin Oncol. 2023;41 (Supplement 4): TPS816. doi: 10.1200/JCO.2023.41.4_suppl}