Neoadjuvant Immunotherapy and Short Treatment Courses Drive Paradigm Shifts in CRC Management

In this episode of Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Pashtoon Kasi, MD, MS, the medical director of GI Medical Oncology, the Rad Family Chair in Gastrointestinal Oncology, and an associate clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Orange County in Irvine, California.

Their discussion centered on the rapid rise of neoadjuvant immunotherapy in colorectal cancer (CRC) management, framing the shift in which immunotherapy is given upfront and surgery becomes the adjuvant step as a genuine paradigm change. Drs Park and Kasi grounded the conversation in the biology of mismatch repair–deficient (dMMR)/microsatellite instability–high tumors, which harbor a high neoantigen load, rendering them sensitive to checkpoint blockade.

A major focus was the treatment evolution that stemmed from data from the phase 3 ATOMIC trial (NCT02912559), which added atezolizumab (Tecentriq) to FOLFOX (leucovorin, fluorouracil, oxaliplatin) in stage III dMMR disease, to the NICHE clinical trial series from the Netherlands, in which brief neoadjuvant nivolumab (Opdivo) plus 1 dose of ipilimumab (Yervoy) produced near-universal responses. Dr Kasi then detailed his own NEST trials, which replicated this short-course design using the Fc-enhanced CTLA-4 inhibitor botensilimab plus balstilimab, notably extending activity into the larger mismatch repair–proficient/microsatellite stable (MSS) population with sustained disease-free survival.

Drs Park and Kasi explored mechanistic insights that have been seen with CRC drugs, including an "inside-out" serosal-to-mucosal response pattern, regulatory T cell depletion, and the rationale that an intact tumor and lymph nodes provide more antigens than the postsurgical setting. They also discussed circulating tumor DNA as an emerging surrogate end point, the implications of data from the phase 3 STELLAR-303 trial (NCT05425940) of an immunomodulatory TKI plus atezolizumab (Tecentriq) in patients with MSS disease, liver metastases as an immunosuppressive niche, and the alarming rise of early-onset CRC.