On August 26, 2026 Agenus Inc. (Nasdaq: AGEN), a leader in immuno-oncology innovation, reported the peer-reviewed publication of updated results from the investigator-sponsored Phase 2 NEST trial evaluating neoadjuvant botensilimab (BOT), Agenus’ multifunctional, Fc-enhanced anti-CTLA-4 antibody, and balstilimab (BAL), Agenus’ anti-PD-1 antibody, in patients with resectable colon cancer. The manuscript, titled "Neoadjuvant botensilimab/balstilimab for localized mismatch repair proficient and deficient colon cancer: Results of the NEST phase 2 clinical trial," was published in Clinical Cancer Research and is available here.
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Earlier findings from NEST were presented at the 2025 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium. The publication provides longer follow-up and a fuller peer-reviewed analysis of tumor responses, circulating tumor DNA (ctDNA) dynamics, disease-free follow-up and immune changes in the tumor microenvironment.
At the March 31, 2026 data cutoff, no colorectal cancer recurrences had been observed, with median follow-up of 32.2 months in NEST-1 and 23.5 months in NEST-2. Among 22 mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors, 59% achieved a pathologic response, including 41% with a major pathologic response and 32% with a pathologic complete response.
MSS/pMMR tumors represent approximately 85% of early-stage colorectal cancers and have historically derived limited benefit from conventional immunotherapy treatment, particularly in metastatic disease.i,ii In localized colon cancer, treatment remains centered on surgery and chemotherapy, creating a need for approaches that may deepen response and reduce recurrence risk. Administering immunotherapy before surgery offers a distinct biological opportunity to activate the immune system while the primary tumor, tumor-draining lymph nodes and surrounding immune microenvironment remain intact.
The publication adds peer-reviewed clinical and biological support for Agenus’ previously announced decision to prioritize BOT+BAL in earlier-stage, curative-intent MSS colon cancer. Agenus is advancing ROBBIN, a planned global randomized Phase 3 trial evaluating neoadjuvant BOT+BAL followed by standard of care versus standard of care alone in previously untreated patients with high-risk Stage II or Stage III MSS colon cancer, with event-free survival as the primary endpoint. NEST’s deep tumor regression, pre-surgical ctDNA clearance, preserved surgical timing and no observed recurrences at longer follow-up supports the clinical hypothesis ROBBIN is designed to test.
"NEST provides important context for Agenus’ strategic focus on neoadjuvant BOT+BAL in MSS colon cancer," said Steven O’Day, M.D., Chief Medical Officer of Agenus. "With longer follow-up now extending beyond two years across both NEST cohorts, the findings show BOT+BAL can generate deep tumor responses and immune activation before surgery, without delaying surgery. These results strengthen the rationale for our phase 3 ROBBIN trial and for evaluating BOT+BAL in a curative-intent setting, where the goal is to reduce the risk of recurrence and improve long-term outcomes."
NEST was a single-center, open-label, single-arm Phase 2 study that enrolled 24 eligible patients with 26 resectable colorectal tumors, including 22 pMMR/MSS tumors and four dMMR/MSI-H tumors. The study evaluated two pre-surgical treatment intervals; approximately four weeks in NEST-1 and approximately eight weeks in NEST-2. Patients in both cohorts proceeded to planned surgical resection without treatment-related delays.
NEST Results
Tumor responses in pMMR/MSS disease
Among 22 pMMR/MSS tumors, neoadjuvant BOT+BAL achieved:
59% pathologic response rate (pOR): defined as pathologic complete response, major pathologic response or partial response
41% major pathologic response rate (MPR): 10% or less viable tumor remaining
32% pathologic complete response rate (pCR): no viable tumor or adjacent lymph nodes found at surgery
The manuscript cites previously reported MPR rates of approximately 19% to 20%, including pCR of approximately 10%, with first-generation CTLA-4/PD-1 combination therapy in pMMR colon cancer. Cross-trial comparisons should be interpreted cautiously because of differences in study design, patient population and follow-up.
Tumor responses in dMMR/MSI-H disease
All four dMMR/MSI-H tumors achieved an MPR, including two pCR and two additional tumors with near-complete tumor regression of 98% and 99%.
ctDNA clearance before surgery
Among patients with detectable circulating tumor DNA (ctDNA) at baseline and available pre-surgical samples, 88% cleared ctDNA prior to surgery. ctDNA remained undetectable following resection in all patients evaluated.
No observed recurrences at longer follow-up
At the March 31, 2026 data cutoff, no colorectal cancer recurrences had been observed. Median follow-up was 32.2 months in NEST-1 and 23.5 months in NEST-2. For external context, the FOxTROT study of neoadjuvant chemotherapy reported a two-year recurrence rate of 16.9%. Cross-trial comparisons should be interpreted cautiously.
Immune remodeling and activation in the tumor microenvironment
Analyses of paired tumor samples showed coordinated remodeling of the tumor immune microenvironment in responding tumors, characterized by increased CD8+ T-cell infiltration, reduced FOXP3+ regulatory T cells, increased CD8+/Treg ratios and spatial reorganization of immune cells within the tumor.
These findings provide biological support for BOT’s multifunctional, Fc-enhanced mechanism, which extends beyond conventional checkpoint blockade to actively remodel the immunosuppressive tumor microenvironment, and establishes a mechanistic basis for activity in historically immunotherapy-resistant pMMR/MSS tumors.
Surgical feasibility and safety
Patients proceeded to planned surgery without treatment-related delays. No Grade 4 treatment-related adverse events, treatment-related deaths or study discontinuations were observed.
"The NEST results reinforce a major opportunity in colorectal cancer to use immunotherapy earlier, before surgery, when the primary tumor and immune system are still positioned to generate a coordinated anti-tumor response," said Pashtoon M. Kasi, M.D., M.S., Medical Director of GI Medical Oncology at City of Hope Orange County, Rad Family Chair in Gastrointestinal Oncology, and originator of the NEST study. "For pMMR/MSS disease, where immunotherapy has historically had limited impact, the combination of pathologic responses, ctDNA clearance, no observed colorectal cancer recurrences at longer follow-up and immune remodeling is highly encouraging, particularly when viewed against historical benchmarks. These findings provide a strong foundation for continued study of neoadjuvant BOT+BAL, including NEST3, our enrolling multicenter Phase 2 investigator-sponsored study."
About the NEST and NEST 3 Studies
NEST (NCT05571293) was an investigator-initiated, single-center, open-label Phase 2 study evaluating neoadjuvant BOT+BAL in patients with resectable colorectal cancer. The study enrolled 24 eligible patients with 26 resectable colorectal tumors, including 22 with mismatch repair proficient/microsatellite stable and four mismatch repair deficient/microsatellite instability-high tumors. Patients received neoadjuvant BOT+BAL before planned surgical resection. The primary objectives were to assess safety, feasibility and anti-tumor activity, with exploratory analyses evaluating treatment-associated changes in the tumor immune microenvironment. Agenus supported the study and provided BOT and BAL.
NEST3 (NCT07595874) is an open and actively enrolling multicenter Phase 2 investigator-sponsored study evaluating neoadjuvant BOT+BAL in advanced resectable colorectal cancer. The study is sponsored by City of Hope Medical Center, led by Pashtoon M. Kasi, M.D., M.S., as overall principal investigator, and designed to enroll approximately 100 patients across 11 U.S. sites. The first patient was dosed in July 2026. NEST3 is being conducted through City of Hope’s National Clinical Trials Model, a centralized research framework designed to expand patient access to clinical trials across multiple City of Hope locations. More information is available at ClinicalTrials.gov.
(Press release, Agenus, AUG 26, 2026, View Source [SID1234670355])