Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC): NEST clinical trial update.
Authors: Erika Hissong, Mehraneh D. Jafari, Sahrish Khan, Pashtoon Murtaza Kasi, Preethi Guniganti, Allyson J. Ocean, Despina Siolas, Heather Yeo, Uqba Khan, Alessio Pigazzi, Areeb Lutfi, Zhengming Chen, Manish A. Shah, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2025)

207 Background: Checkpoint inhibitors (CPI) have been transformative for localized dMMR CRC (microsatellite instability-high [MSI-H]), but not for localized pMMR CRC (microsatellite stable [MSS]). The combination of BOT, a novel Fc-enhanced multifunctional CTLA-4 antibody, and BAL, an anti-PD-1 antibody, has demonstrated significant activity in metastatic CRC. We examined this novel dual CPI therapy in patients with MSI-H and MSS localized CRC. Methods: This is a single arm trial of neoadjuvant BOT 75 mg/m 2 (day 1) and BAL 240 mg/m 2 every 2 weeks x2 (NEST1) or x4 (NEST2) in patients with localized CRC who were candidates for surgery. The primary endpoint was major pathologic response (MPR), defined as ≥90% pathologic tumor regression. The 95% confidence interval (CI) was computed based on exact method for binomial distribution. Results: NEST1 (n=12: 9 MSS / 3 MSI-H) accrued from 3/21/23 to 9/25/23 and NEST2 (n=14: 13 MSS / 1 MSI-H; 2 MSS patients had synchronous CRC) accrued from 2/15/24 to 5/6/24; 2 patients in NEST1 were not evaluable (1 with rectal cancer not resected [ypT0N0 on local excision] and 1 patient with occult lung metastasis). In total, 7 MSS CRC tumors were evaluable from NEST1 and 15 from NEST2; and 3 MSI-H tumors were evaluable from NEST1 and 1 from NEST2, leaving a final evaluable study population of 24 patients (20 MSS / 4 MSI-H) and 26 tumors (22 MSS / 4 MSI-H). The Table provides pathologic response rates across NEST1, NEST2, and MSI-H. With a median follow-up of 13.1 months (NEST1) and 4.8 months (NEST2), no patients have recurred and ctDNA testing remains negative. No grade 4 toxicities were observed and the only treatment-related grade 3 toxicity was diarrhea/colitis in 15% and fever in 4%. Treatment-related grade 2 diarrhea/colitis occurred in 8%, grade 2 fever in 15%, and grade 2 fatigue in 4% of patients. Diarrhea/colitis resolved in all cases with steroids ± anti-TNFα therapy. All patients underwent laparoscopic resection, with 1 conversion to open. No surgeries were delayed due to treatment-related adverse events. Median length of stay was 2 days (range 1-14). Translational data including pathologic evaluation of tumor infiltrate and response will be presented. Conclusions: Neoadjuvant BOT/BAL is safe, with no delays to surgery, and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date. The MPR and pCR rate improved with extended time to surgery. Clinical trial information: NCT05571293 . Pathologic response to neoadjuvant BOT/BAL in localized CRC. Pathologic Response NEST 1n=7 MSS tumors NEST 2n=15 MSS tumors MSI-H (3 NEST1, 1 NEST2) 100% (CR%, 95%CI) 1 (14%, 0.4-58%) 6* (40%, 16-68%) 3** (75%, 19-99%) ≥ 90% (MPR%, 95%CI) 2 (29%, 4-71%) 7 (47%, 21-73%) 4^ (100%, 40-100%) ≥ 50% 4 (57%) 9 (60%) 4 (100%) Median days to Surgery (range) 29 (21-37) 57 (45-104) 46 (34-78) *2 with carcinoma in situ , no tumor bed. ^MPR was in NEST1. **1 was rectal.