8MO - Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient and deficient colorectal cancer: NEST-1 clinical trial

Background

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 BOT plus PD-1 inhibitor BAL in pts with resectable CRC.

Methods

This single-armed study enrolled 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/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.

Results

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. 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 (Table). Table: 8MO

Changes in CD68, CD3, CD4, and CD8 ratios in patients with deeper responses (pathologic tumor reduction ≥50% versus ≤50%)

Conclusions

The NEST-1 clinical trial met its primary and secondary endpoints, supporting the expansion for pts with MSS tumors to examine a longer duration of exposure to immunotherapy (NEST-2 Cohort), ∼8 vs ∼4 weeks, and a watch-and-wait option for MSI-H pts. The study is open and accruing.

Clinical trial identification

NCT05571293.

Legal entity responsible for the study

The authors.

Funding

Agenus Inc.

Disclosure

P.M. Kasi: Financial Interests, Personal, Advisory Board, Consultancy/Advisory Board: Foundation Medicine, Natera Oncology, AstraZeneca, Merck MSD, Tempus, Bayer, Lilly, Delicath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, Eisai, Daiichi Sankyo/AstraZeneca, Seattle Genetics, SAGA Diagnostics, BostonGene, Illumina; Financial Interests, Personal, Advisory Board: NeoGenomics Laboratories, Guardant Health; Financial Interests, Personal, Other, Scientific Advisory Board Member: Elicio; Financial Interests, Personal, Other, Co-Founder: Precision BioSensors Inc. H. Yeo: Financial Interests, Personal, Advisory Board: SurvivorNet Inc. A. Ocean: Financial Interests, Personal, Speaker’s Bureau: Natera, Guardant Health, Daiichi Sankyo; Financial Interests, Personal, Member of Board of Directors: Novocure. M. Hidalgo: Financial Interests, Personal, Member of Board of Directors: BMS; Financial Interests, Personal, Leadership Role, Founder: Nelum; Financial Interests, Personal, Advisory Role, Scientific Advisory Board: MiNK, InxMed, Oncomatrix; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Peaches; Financial Interests, Personal, Invited Speaker, Scientific Advisory Board: Champions; Non-Financial Interests, Personal, Principal Investigator: Agenus. All other authors have declared no conflicts of interest.