Neoadjuvant SCRT Plus Cadonilimab/Chemo Meets pCR End Point in pMMR/MSS Rectal Cancer

Pathological complete responses (pCR) and an acceptable safety profile were demonstrated with neoadjuvant short-course radiation therapy (SCRT) followed by cadonilimab (AK104) and chemotherapy for the treatment of patients with mismatch repair–proficient (pMMR) or microsatellite stable (MSS) locally advanced rectal cancer (LARC), according to data from the open-label, single-arm phase 2 NeoCaCRT trial (NCT05792735) presented at the 2025 Gastrointestinal Cancers Symposium.1

At the October 20, 2024, data cutoff, with a median follow-up of 9.7 months, the pCR rate was 37.0% (95% CI, 19.4%-57.6%); the clinical major pathological response rate (MPR) was 55.6% (95% CI, 35.3%-74.5%); and the clinical complete response rate (cCR) was 22.2% (95% CI, 8.6%-42.2%), and among those who achieved a cCR, 83.3% received local excisions.

The investigators also noted that radiological tumor shrinkage underestimated the degree of pathological regression.

“In patients with pMMR/MSS LARC, neoadjuvant SCRT with cadonilimab plus [chemotherapy] resulted in promising pCR rates with a manageable safety profile,” Wan He, a researcher in the Department of Oncology at Shenzhen People’s Hospital in Shenzhen, China, and lead study investigator, stated in the poster. “These data deserve further investigations in a phase 3 randomized trial.”

A total of 27 patients between 18 and 79 years of age with pMMR/MSS stage II to III (cT3-4 or N1) rectal adenocarcinoma located below the peritoneal reflection were enrolled in the trial. Additionally, patients were required to have histologically confirmed disease with an ECOG performance status of 0 or 1 and adequate organ and bone marrow function.

Patients received 5 Gy of SCRT in 5 fractions, then 6 mg/kg of cadonilimab every 2 weeks plus mFOLFOX6 chemotherapy (85 mg/m2 of oxaliplatin, 400 mg/m2 of leucovorin, 400 mg/m2 of 5-fluorouracil bolus on day 1, and 2400 mg/m2 of 5-fluorouracil infusion for 48 hours) for 6 preoperative cycles.2 They then underwent either total mesorectal excision or transanal local excision, and those who did not have a pCR received the adjuvant cadonilimab with chemotherapy for 6 cycles and those who did have a pCR were given the opportunity to choose between the adjuvant treatment or observation. Patients who had a cCR chose between surgery or the “watch and wait” method.

The median age of patients was 58 years (range, 33-71), the majority were male (n = 18), and an ECOG performance status of 0 was most common (n = 24). Twenty-four patients had clinical stage III disease, 15 were extramural venous invasion positive, and 14 had positive mesorectal facia involvement. cT3 disease was most common (n = 15), followed by cT4 (n = 12) and cT3a-b (n = 11); and cN2 (n = 13) and cN1(n = 11) disease were also observed. A distance to the anal verge of 5cm or less was identified in 15 patients and 5.1-10cm in 12.

The trial’s primary end point was pCR. Secondary end points included cCR, MPR, overall response rate, R0 resection rate, disease-free survival, overall survival, safety, and quality of life.

Regarding safety, treatment-related adverse events (TRAEs) of any grade and grade 3/4 in 88.9% and 22.2% of patients, respectively; drug-related AEs in 85.2% and 14.8%; and immune-mediated AEs in 66.7% and 11.1%. TRAEs led to treatment discontinuation in 18.5% of patients, and there were no treatment-related deaths. Grade 3/4 TRAEs include diarrhea (14.8%), neutropenia (3.7%), liver dysfunction (3.7%), type 2 diabetes (3.7%), pneumonia (3.7%), and infusion-related reaction (3.7%).

The most common TRAEs were diarrhea (37%), nausea (37%), fatigue (37%), and neutropenia (26%).

References

1. He W, Huang J, Liao G, et al. Short-course radiation (SCRT) followed by 6 cycles of cadonilimab plus mFOLFOX6 as neoadjuvant therapy for patients with locally advanced rectal cancer (LARC): A multicenter, single arm phase 2 trial (NeoCaCRT). J Clin Oncol. 2025;43(4):LBA210. doi:10.1200/JCO.2025.43.4_suppl.LBA210
2. Neoadjuvant cadonilimab plus chemotherapy following short-course radiotherapy in locally advanced rectal cancer (NeoCaCRT). ClinicalTrials.gov. Updated June 29, 2023. Accessed January 25, 2025. https://tinyurl.com/es8en7nk