Zanzalintinib

Rectal cancer recurrence remains a major therapeutic challenge, particularly in patients unresponsive to conventional regimens. Tumors with mismatch-repair-proficient (pMMR) or microsatellite-stable (MSS) status represent the majority of colorectal cancers and are characteristically resistant to immune checkpoint inhibitors. We report a 50-year-old woman with recurrent metastatic KRAS-G12D mutant MSS rectal adenocarcinoma refractory to and with complications to standard chemotherapy regimens who achieved a complete and durable molecular response following initiation of the RIN protocol, a combination of regorafenib, ipilimumab, and nivolumab. A sustained decline in biomarker levels was observed, with both circulating tumor DNA and carcinoembryonic antigen becoming undetectable within 6 months, consistent with a complete molecular response accompanied by a marked interval decrease in FDG-avid disease and sustained radiologic and pathologic remission. This case illustrates the potential for multimodal immune modulation to overcome intrinsic resistance in pMMR/MSS in non-liver metastatic (NLM) colorectal cancer. While previous studies have demonstrated limited benefit of immunotherapy in this tumor subtype, the present findings suggest an emerging therapeutic opportunity that warrants prospective evaluation to confirm efficacy, explore the mechanistic basis, and identify biomarkers predictive of durable response beyond the absence of liver metastases. More effective combinatorial regimens like zanzalintinib and atezolizumb (STELLAR-303) trial, as well as newer generation of CTLA-4 inhibitors like botensilimab, vilastobart, and muzastotug are showing more promise for patients with MSS colorectal cancers in particular who do not have liver metastases (NLM).