Early Efficacy Induced by Neoadjuvant Botensilimab/Balstilimab Combination in pMMR/dMMR Colorectal Cancer

Stomach and intestine with organs anterior view: © 7activestudio - stock.adobe.com

The administration of neoadjuvant botensilimab (AGEN1181) alongside balstilimab (AGEN2034) resulted in strong responses and extended circulating tumor DNA (ctDNA)/minimal residual disease (MRD) negativity in individuals with resectable mismatch repair–proficient (pMMR) and mismatch repair–deficient (dMMR) colorectal cancer (CRC). This achievement met the primary endpoint of the phase 2 NEST-1 trial (NCT05571293), findings from which were presented at the 2024 Gastrointestinal Cancers Symposium.¹

A total of 67% of patients with microsatellite stable (MSS) CRC (n = 9) experienced pathologic responses, defined as tumor reduction of at least 50%, and 100% of patients with microsatellite instability–high (MSI-H) CRC (n = 3) experienced major pathologic responses, defined as tumor reduction of at least 90%. In the MSS population, tumor reductions of 100% (complete response [CR]; n = 2), 90% (n = 1), 85% (n = 1), 50% (n = 2), 25% (n = 1), and 10% (n = 1) were observed. In the MSI-H population, tumor reductions of 100% (CR; n = 2) and 98% (n = 1) were observed.

“Neoadjuvant botensilimab/balstilimab is a safe and active regimen in both pMMR/MSS and dMMR/MSI-H CRC,” lead study author Pashtoon Murtaza Kasi, MD, MS, of Weill Cornell Medicine and NewYork Presbyterian Hospital in New York, New York, and colleagues, wrote in a poster of the data.

Previously, a phase 1a/1b trial (NCT03860272) showed that the Fc-enhanced, next-generation CTLA-4 inhibitor botensilimab in combination with the PD-1 inhibitor balstilimab generated a response rate of 23% (95% CI, 14%-34%) in patients with heavily pretreated pMMR/MSS metastatic CRC.²

The single-arm NEST-1 trial evaluated botensilimab plus balstilimab in the neoadjuvant setting in 12 patients with colon and rectal cancer who were eligible for surgery.¹ All patients received 1 fixed dose of botensilimab at 75 mg plus 2 fixed doses of balstilimab at 240 mg 2 weeks apart. Patients were permitted to proceed to surgery 1 week after completing the second dose of balstilimab. Less than 25% of patients were permitted to have dMMR/MSI-H disease.

Among the 12 patients enrolled in the trial, 6 were male and 6 were female. Most patients (n = 4) were Caucasian, followed by African American patients (n = 3), Southeast Asian patients (n = 2), Arab/Middle Eastern patients (n = 2), and Hispanic/Mexican patients (n = 1). Pre-treatment disease stages included stage I (n = 1), stage IIIA (n = 1), stage IIIB (n = 5), and stage IIIC (n = 4). One patient had TXN0 disease.

Post-treatment disease stages included no tumor (n = 4), stage I (n = 3), stage IIA (n = 2), stage IIIA (n = 1), stage IIIB (n = 1), and stage IIIC (n = 1). From day 1 of cycle 1, patients waited 21, 24, 27, 29, 29, 30, 34, 36, 38, 42, 57, and 64 days until surgery.

Disease mutations, which were evaluable in 11 patients, were present in KRAS A146 (n = 2), HER2(n = 1), TP53 (n = 7), APC (n = 4), CTNNB1 (n = 2), KRAS G12V (n = 1), ATM (n = 1), KRAS A146 (n = 1), BRAF K483T (n = 1), KRAS G12D (n = 2), MSH2 (n = 2), BRCA2 (n = 1), KRAS G12S (n = 1), and KRAS G12D (n = 1). Of 10 patients evaluable for tumor mutational burden (TMB), the TMB levels were 3.1 ,4.7, 4.7, 4.7, 5.5, 6.4, 7.1, 8.6, 9.4, and 105. Two patients had TMB levels that were not available.

All patients enrolled in NEST-1 safely received botensilimab/balstilimab without surgical delay or increased risk of severe adverse effects (AEs). Six patients experienced no AEs. The remaining 6 patients experienced grade 3 diarrhea; grade 1 chills/fever; grade 1 chills/headache and grade 2 fever; grade 1 chills, headache, dizziness, and grade 3 fatigue; grade 1 flu-like symptoms and grade 1 fever; and grade 1 fatigue, rash, and headache.

Investigators assessed tissue immune microenvironment correlates on colon and rectal samples before and after immunotherapy using the RareCyte Inc. 13-marker immune-oncology panel. This analysis demonstrated a robust immunogenic pathologic response known as the “inside-out” phenomenon, a serosa-to-mucosa response pattern. Contrary to the pattern of response observed with neoadjuvant chemotherapy, targeted therapy, and/or radiation, during the “inside-out” response, immune cells penetrate the cancer cells from layers deep within the body.

“Analyses show a significant increase and a diverse array of immune cells in more than 1 instance, shedding novel insights into the mechanism and pattern of immune responses,” the study authors noted in the poster.

Additionally, 100% of patients who were positive for ctDNA at screening (n = 7) cleared ctDNA. Furthermore, 100% of patients who were tested for ctDNA after surgery (n = 11) remained ctDNA/MRD negative for more than 30 cumulative blood draws.

Posttreatment immunohistochemistry/immunofluorescence showed that botensilimab/balstilimab elicited robust T-cell infiltration, Treg depletion, and dendritic cell/myeloid repolarization.

“Clinical downstaging and deep pathological responses provide a framework for reduced reliance on surgery and/or adjuvant chemotherapy in future studies,” the study authors concluded in the poster.

NEST-1 has expanded enrollment to investigate an 8-week treatment course of balstilimab/botensilimab instead of the current minimum 3-week course for patients with MSS CRC. This expansion portion of the trial will also evaluate the necessity of surgery for patients with MSI-H disease.

Editor’s Note: Dr Kasi has disclosed having a leadership role with Precision Biosensors; having stock and other ownership interests with Elicio Therapeutics; having consulting or advisory roles with Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Systems, Eisai, Elicio Therapeutics, Exact Sciences, Foundation Medicine, Guardant Health, Illumina, Ipsen (Inst), Lilly, MSD Oncology, Natera, NeoGenomics Laboratories, QED Therapeutics, SAGA Diagnostics, Seagen, SERVIER, Taiho Oncology, Taiho Pharmaceutical (Inst), and Tempus; receiving research funding from Advanced Accelerator Applications (Inst), Boston Scientific (Inst), and Tersera (Inst); and receiving travel, accommodations, and expenses from AstraZeneca.

The NEST-1 trial received research funding from Agenus, Inc.

REFERENCES:

1. 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

2. El-Khoueiry AB, Fakih MG, Gordon MS, et al. Results from a phase 1a/1b study of botensilimab (BOT), a novel innate/adaptive immune activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer (MSS CRC). J Clin Oncol. 2023;41(suppl 4):LBA8. doi:10.1200/JCO.2023.41.4_suppl.LBA8