KEY TAKEAWAYS
- The NEST-1 phase 2 trial aimed to investigate the safety and efficacy of a single dose of BOT plus BAL in pts with resectable CRC.
- Researchers noticed significant efficacy and safety of the BOT plus BAL combination in resectable CRC; further investigation is ongoing.
There is an unmet need for effective immunotherapy options for patients (pts) with colorectal cancer (CRC). The NEST-1 trial is the first neoadjuvant trial to explore the safety and efficacy of a single dose of a novel immune activator/Fc-enhanced CTLA-4 inhibitor botensilimab (BOT) plus PD-1 inhibitor balstilimab (BAL) in pts with resectable CRC.
Mehraneh Dorna Jafari and the team aimed to investigate the safety and efficacy of a single dose of BOT plus BAL in pts with resectable CRC.
They performed an inclusive analysis in this single-armed study, enrolling 12 CRC pts (4 with rectal cancer) — 9 microsatellite stable (MSS) and 3 microsatellite instability-high (MSI-H) tumors — to determine the feasibility, safety, and efficacy of neoadjuvant BOT/BAL to inform a larger trial. Blood and tissue-based correlatives pre- and post-treatment were assessed using RareCyte, Inc. and next-generation sequencing/minimal residual disease (MRD) circulating tumor DNA (ctDNA) assays.
Neoadjuvant BOT/BAL was safe and did not delay planned surgery in any patient. 6/9 (67%) pts with MSS had a ≥50% pathologic response; 2/9 with pathologic complete responses (pCR). 3/3 (100%) of pts with MSI-H had a major pathologic response (≥90% pathologic reduction). As of March 18, 2024, with a median follow-up of 8 months (mos) (range 6-12 mos), no pts had clinical or molecular recurrence. 39 MRD-assay timepoints are negative, showing sustained ctDNA clearance. 6/12 (50%) were KRAS-mutant.
In MSS tumors, the median TMB was 3.7 Mut/Mb (range 2.6-6 Mut/Mb). Post-treatment resection specimens revealed a significant increase in T cell infiltration, characterized by elevated CD8+/Treg ratios and a higher proportion of activated macrophages than pre-treatment biopsies. The depth of pathologic responses correlated with the time from immunotherapy initiation to surgery.
The study concluded that neoadjuvant BOT/BAL demonstrated significant safety and efficacy in resectable CRC, with notable pathologic responses in both MSS and MSI-H tumors. These results support further investigation in the NEST-2 cohort to assess longer exposure to immunotherapy and a watch-and-wait strategy for MSI-H pts.
The trial was sponsored by the Weill Medical College of Cornell University.
Source: https://cslide.ctimeetingtech.com/esmogi24hybrid/attendee/confcal/show/session/28
Clinical Trial: https://clinicaltrials.gov/study/NCT05571293
Jafari M.D., Kasi P.M., Jafari M.D., et al. (2024). “8MO – Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient and deficient colorectal cancer: NEST-1 clinical trial.” Presented at ESMO-GI 2024 (Abstract 8MO).
