Neoadjuvant Botensilimab/Balstilimab Is Active in Resectable Colon Cancer, Despite MMR Status

The combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) showed clinical activity and was safe in both patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) and mismatch repair deficient (dMMR)/microsatellite instability–high (MSI-H) colon cancer, according to updated results of the phase 2 NEST-1 trial (NCT05571293) that were presented during the 2024 ESMO Gastrointestinal Cancers Congress.¹

The trial assessed different dosing ranges in the NEST-1 and NEST-2 cohorts. Specifically, results showed that 71% of patients with MSS colon cancer (n = 12/17) achieved 50% or greater pathological responses across the NEST-1 and NEST-2 cohorts, and 35% (n = 6/17) achieved a complete pathological response. In both cohorts, 100% of patients with MSI–H disease achieved a pathological response.

“Response rates increased with more doses of balstilimab in conjunction with increased interval to surgery, with up to 50% complete pathological response rate in pMMR colon cancer,” second author Mehraneh D. Jafari, MD, an associate professor of surgery of Weill Cornell Medicine, chief of colorectal surgery at NewYork Presbyterian Hospital, and director of clinical research in the Department of Surgery at Weill Cornell Medical Center in New York, New York said during the presentation. “We believe that downstaging and pathological response may reduce our eventual need and reliance on surgical resection and cytotoxic agents, and this is something looking forward to in future studies.”

Effective therapeutic options for patients with pMMR/MSS colorectal cancer (CRC) are lacking. Botensilimab is a multifunctional next-generation CTLA-4 inhibitor, and balstilimab is a PD-1 inhibitor. Earlier results with the combination of both agents, which were presented during the 2024 Gastrointestinal Cancers Symposium, showed that the pathologic response was 67% in patients with MSS CRC (n = 9), and 100% of all those with MSI-H CRC (n = 3) had a major pathologic response.²

The NEST-1 trial is the first study that is evaluating botensilimab plus balstilimab in the neoadjuvant setting for patients with resectable colon cancer. Broadly, the NEST protocol encompasses 2 cohorts: NEST-1, which is evaluating one 75-mg dose of botensilimab followed by two 240-mg doses of balstilimab 2 weeks apart prior to surgery; NEST-2 is evaluating one 75-mg dose of botensilimab plus up to four 240-mg doses of balstilimab 2 weeks apart before surgery.

To be eligible for enrollment, patients must have had resectable, nonmetastatic colon cancer with no contraindication to undergo immunotherapy. Surgical resection must have been able to occur within 1 to 6 weeks after completing therapy.

At the time of the presentation, 25 patients were enrolled on the NEST protocol, and 2 patients with rectal cancer were deemed ineligible. Twenty patients had MSS disease vs 3 with MSI-H disease; 20 patients had pathological results.

Regarding baseline characteristics in both NEST-1 (n = 10) and NEST-2 (n = 10), the median age was 67 years (range, 23-79) in both arms. In NEST-1, 70% of patients were female, the median time to operation from cycle 1, day 1 of therapy was 29.5 days (range, 21-38), and 70% had received adjuvant chemotherapy. In the NEST-2 cohort, 40% of patients were female, the median time to operation from cycle 1 day 1 of therapy was 57 days (range, 45-81), and Jafari noted it was too early to report adjuvant chemotherapy use.

No patients in either arm experienced unresolved immune-related adverse effects (AEs); 2 patients had grade 3 diarrhea and colitis that was managed with infliximab (Remicade) and a short course of steroids.

“In short, neoadjuvant botensilimab/balstilimab was safe and did not delay planned surgery,” Jafari said.

When responses were stratified by cohort, Jafari noted that of the 8 patients with MSS disease in NEST-1, the pathological response rate (≥50% tumor regression) was 63% (n = 5/8) with 1 complete pathological response; in the MSI-group (n = 2), these rates were 100% and 50%, respectively.

Of the 9 patients with MSS disease in NEST-2, the PR rate was 78% (n = 7/9) and the complete pathological response rate was 56% (n = 5/9). The 1 patient with MSI-H disease in this cohort had a complete pathological response.

Editor’s Note: Dr Jafari did not cite any relevant disclosures.

References

1. Kasi P, Jafari MD, Lowenfeld YL, et al. Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient and deficient colorectal cancer. Presented at: 2024 ESMO Gastrointestinal Cancers Congress; June 26-29, 2024; Munich, Germany. Abstract 8M0.
2. Kasi PM, Jafari MD, Yeo H, et al. Neoadjuvant botensilimab plus balstilimab in resectable mismatch repair proficient and deficient colorectal cancer: NEST-1 clinical trial. J Clin Oncol. 2024;42(suppl 3):117. doi:10.1200/JCO.2024.42.3_suppl.117