Neoadjuvant Botensilimab Combo Elicits High MPR Rates in MSS/MSI-H CRC

The major pathologic response rate improved with extended time to surgery using botensilimab plus balstilimab in resectable colorectal cancer.

Neoadjuvant botensilimab (AGEN-1181, BOT) plus balstilimab (AGEN-2034, BAL) elicited high major pathologic response (MPR) rates in a small cohort of patients with resectable mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR) colorectal cancer (CRC), according to data from the NEST trial (NCT05571293) presented at the 2025 ASCO Gastrointestinal Cancer Symposium.¹

Data from the study revealed that the complete MPR rate among patients classified as having microsatellite stable (MSS) disease treated with 2 balstilimab doses (NEST-1) vs up to 4 balstilimab doses (NEST-2) were 14% (95% CI, 0.4%-58%) and 40% (95% CI, 16%-68%), respectively. Additionally, among patients with microsatellite instability-high (MSI-H) CRC, the complete MPR rate was 75% (95% CI, 19%-99%). Additionally, the median days to surgery among patients treated in the NEST-1 arm, NEST-2 arm, and the MSI-H cohort were 29 (range, 21-37), 57 (range, 45-104), and 46 (34-78), respectively.

Additionally, an MPR of 90% or greater occurred in 29% (95% CI, 4%-71%) of the NEST-1 arm, 47% (95% CI^, 21%-73%) of the NEST-2 arm, and 100% (95% CI, 40%-100%) of patients with MSI-H disease. MPR of 50% or greater occurred in 57%, 60%, and 100% of the respective groups.

Median progression-free survival (PFS) was 18.2 months (IQR, 16.9-19.23) in the NEST-1 arm and 8.98 months (IQR, 8.07-9.37) in the NEST-2 arm. Additionally, circulating tumor DNA (ctDNA)–positive status was reported in 9 of 16 patients.

“Neoadjuvant BOT/BAL is safe and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date,” Erika Hissong, MD, gastrointestinal pathologist in the Department of Pathology and Laboratory Medicine at Weill Cornell Medicine, wrote in the study with coinvestigators.¹ “The [MPR] rate improved with extended time to surgery.”

The study examined the combination checkpoint inhibitor (CPI) therapy in patients with MSI-H and MSS localized CRC. A total of 24 patients were enrolled on study, including 10 in the NEST-1 arm and 14 in the NEST-2 arm; there was a total of 4 patients identified as having dMMR disease, including 3 NEST-1 patients and 1 NEST-2 patient.

Patients in the NEST-1 arm received 1 dose of botensilimab at 75 mg and 2 doses of balstilimab at 240 mg 2 weeks apart, followed by surgery. In the NEST-2 arm, patients received the same botensilimab regimen and received the same balstilimab dose but for up to 4 doses 2 weeks apart, followed by surgery.

Patients 18 years and older with cytologically, histologically, or clinically confirmed adenocarcinoma of the colon or rectal and no plans for neoadjuvant radiation for rectal cancer were eligible for enrollment on the NEST trial.²

The median patient age was 64 (IQR, 46-73) across all arms, 57 (IQR, 35-69) for NEST-1, and 69 (IQR, 59-75) for NEST-2. The male to female ratio was 13:11, 5:5, and 8:6 in respective arms. Most patients were White (n = 12, 5, and 7, respectively) and non-Hispanic (n = 21, 9, and 12, respectively). Additionally, 10 patients had a clinical stage of T1/T2, and 14 had a clinical stage of III or greater.

In the NEST-1 arm, there was a single grade 2 instance of fever and single grade 3 instances of fatigue and colitis or diarrhea. Additionally, the NEST-2 arm had 3 grade 2 instances of colitis or diarrhea, 2 grade 2 instances of fever, and single grade 2 instances of fatigue, anemia, nausea, and myositis. Additionally, there were 2 grade 3 instances of colitis or diarrhea in this arm.

A total of 7 patients did not complete the 4 cycles of balstilimab in the NEST-2 cohort. There were no grade 4 adverse events (AEs) or unresolved immune-mediated AEs. Furthermore, no delays in surgery due to immune-mediated AEs were observed.

References

1. Hissong E, Jafari D, Khan S, et al. Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC). J Clin Oncol. 2025;43(suppl 4):207. doi:10.1200/JCO.2025.43.4_suppl.207
2. Combination immunotherapy in colorectal cancer (NEST-1). ClinicalTrials.gov. Updated August 20, 2024. Accessed January 27, 2024. https://bit.ly/3CrbWaf