Late toxicity after peposertib-enhanced chemoradiation in rectal cancer patients managed with organ preservation.

Background and purpose: Combining peposertib, a DNA-PK inhibitor, with capecitabine-based chemoradiation may improve tumor response and organ preservation in rectal cancer. We assessed how adding peposertib to chemoradiation impacts organ preservation-specific outcomes and toxicities. Materials and methods: In a recent phase Ib trial, rectal cancer patients underwent neoadjuvant capecitabine-based chemoradiation with peposertib. Patients were then restaged: those with clinical complete responses (cCRs) were offered "watch-and-wait" (WW), while those with non-cCRs (near complete and incomplete responses) were recommended surgery, although most opted for consolidation chemotherapy. Six patients were selected for this post-hoc analysis with primary endpoints of organ preservation rate, tumor response rates, and characterization of late grade 3 + toxicities. Results: Tumor response rates showed 50 % of patients (3/6) achieved cCR and entered WW. Additionally, the frequency of late grade 3 + toxicity was 50 % (3/6). Late grade 3 + toxicity was exclusively observed in patients with cCR entering WW, and all toxicities were specific to the rectum (severe proctitis and bowel fistulization). In contrast, no late grade 3 + toxicities were seen when disease was managed by oncologic surgical resection. Finally, while overall three-year organ preservation rate was 60 % (3/5), patients with organ preservation also had increased rates of late grade 3 + rectal toxicities (66 %, 2/3). Conclusion: Combining peposertib with capecitabine-based chemoradiation was associated with disproportionately high risks of severe late rectal toxicities, particularly in patients entering WW. Thus, careful assessment of the toxicity and response profiles of novel neoadjuvant regimens is critically important in future clinical trials focused on organ preservation and the nonoperative management of rectal cancer.