For years, microsatellite-stable (MSS) colorectal cancer has remained one of immunotherapy’s most difficult challenges. While immune checkpoint inhibitors have transformed treatment for patients with mismatch repair-deficient tumors, most patients with colorectal cancer have seen little benefit from these therapies.
Now, new findings from Agenus suggest that a next-generation immunotherapy combination may offer a different outlook for some patients who have already exhausted multiple treatment options.
On November 6, 2026, Agenus announced that 51% of patients with heavily pretreated MSS metastatic colorectal cancer without active liver metastases survived at least 18 months after starting botensilimab plus balstilimab (BOT+BAL).
The findings, from a post hoc analysis of the Phase 1b C-800-01 trial, were released ahead of a poster presentation scheduled for November 7 at the Society for Immunotherapy of Cancer (SITC) 2026 Annual Meeting in Phoenix, Arizona.
Perhaps most notably, nearly one-quarter of the long-term survivors were alive without receiving any further anticancer treatment at their last follow-up.
BOT+BAL in MSS Colorectal Cancer: What Did the Study Find?
The analysis included 123 patients with refractory MSS metastatic colorectal cancer without active liver metastases, all previously treated with multiple lines of therapy.
Patients received botensilimab, an Fc-enhanced anti-CTLA-4 antibody, in combination with balstilimab, an anti-PD-1 antibody.
Long-term survival was defined as surviving at least 18 months after treatment initiation.
The analysis identified several important findings:
- 51% (63 of 123 patients) survived at least 18 months after starting treatment.
- Among these 63 long-term survivors, an estimated 59% were alive at three years.
- 35% (22 of 63) achieved a confirmed objective tumor response, including three complete responses.
- Median duration of response among long-term survivors had not been reached, with responses lasting at least 37.4 months and 10 still ongoing.
- 24% (15 of 63) were alive and off all anticancer therapy at their last follow-up.
These findings build on previously reported results from the entire 123-patient cohort, which demonstrated a median overall survival of 21.2 months and an estimated three-year overall survival rate of 33%.
The full-cohort findings were presented at ESMO Gastrointestinal Cancers Congress 2026 and subsequently published in Clinical Cancer Research.
Importantly, the 59% three-year survival estimate refers specifically to the subgroup that had already survived 18 months, rather than the entire treated population.
Who Were the Patients Who Survived Longer?
One of the most interesting aspects of the new analysis was the attempt to understand whether patients experiencing prolonged survival shared identifiable clinical characteristics. Investigators compared the 63 patients who survived at least 18 months with 60 patients who survived less than 18 months.
The groups were generally similar in several assessed characteristics, including performance status, previous immunotherapy exposure, metastatic disease characteristics, and selected prognostic biomarkers.
However, differences emerged in their treatment histories. Among long-term survivors, 56% had received at least three previous lines of therapy, compared with 78% of those who survived less than 18 months.
This association raises the possibility that patients receiving BOT+BAL earlier in their treatment course may have a greater chance of achieving prolonged survival, although the retrospective analysis cannot establish that earlier treatment caused better outcomes.
Thomas U. Marron, MD, PhD, of the Tisch Cancer Center at Mount Sinai and presenting author of the SITC study, said:
“These findings suggest the potential to meaningfully change the course of disease and provide a compelling rationale for evaluating this approach earlier in treatment.”
He also highlighted that durable outcomes occurred in some patients previously exposed to immunotherapy, suggesting that prolonged benefit was not restricted to a narrowly defined group of patients.
Why Does This Matter for MSS Colorectal Cancer?
Approximately 95% of metastatic colorectal cancers are microsatellite-stable or mismatch repair-proficient, a biological characteristic frequently associated with limited responsiveness to conventional immune checkpoint blockade.
Unlike MSI-high tumors, which often contain large numbers of mutations capable of generating recognizable neoantigens, MSS tumors generally have a more immunosuppressive tumor microenvironment. This has made extending immunotherapy benefits to MSS colorectal cancer a major research priority.
Botensilimab is designed to address some of these barriers through enhanced CTLA-4-directed immune activation. Its Fc-enhanced structure is intended to promote T-cell priming, modulate regulatory T cells within tumors, and activate innate immune responses.
Balstilimab simultaneously blocks PD-1 signaling, supporting antitumor T-cell activity.
Together, the agents aim to generate immune responses in tumors traditionally considered immunologically resistant.
The previously published Phase 1b findings reported a confirmed objective response rate of 21% in the full cohort, including activity in some tumors with low tumor mutational burden or absent PD-L1 expression.
However, the absence of a randomized control group means these results cannot yet demonstrate that BOT+BAL improves survival compared with established later-line treatments. The exclusion of patients with active liver metastases also limits how broadly the outcomes can be generalized.
Durable Responses, but Safety Remains Important
The new analysis also provides further information about the treatment’s safety profile. No treatment-related deaths were reported.
Immune-mediated adverse events were more frequent among patients classified as long-term survivors than in the overall cohort. Immune-mediated diarrhea or colitis remained the most frequently reported immune-related complication.Among long-term survivors who developed this toxicity, 97% (33 of 34 patients) experienced resolution, with a median time to resolution of 13 days.
Management included early corticosteroid treatment and tumor necrosis factor-alpha-directed therapy when clinically appropriate. Although these findings suggest that many immune-related complications were manageable, they also underline the importance of careful patient selection and monitoring when using combinations targeting CTLA-4 and PD-1.
From Advanced Disease to Earlier Treatment: What Comes Next?
The latest findings arrive as Agenus is expanding its clinical development strategy for BOT+BAL beyond refractory metastatic disease.
The company is preparing the randomized Phase 3 ROBBIN trial, which will evaluate short-course neoadjuvant botensilimab plus balstilimab in patients with high-risk Stage II and Stage III MSS colon cancer.
The strategy is supported by encouraging findings from two earlier neoadjuvant studies, NEST and UNICORN, which reported pathologic complete response rates of approximately 30% in MSS colon cancer cohorts treated with BOT+BAL before surgery.
Unlike the metastatic C-800-01 study, ROBBIN will investigate whether introducing immunotherapy before surgery can improve longer-term outcomes in patients being treated with curative intent.
The company expects the first patient to be enrolled in the first quarter of 2027.
Steven J. O’Day, MD, Chief Medical Officer of Agenus, said:
“The significance of these data extends beyond the survival milestone itself.”
He explained that the durability of responses and the association between fewer previous treatments and longer survival reinforce the rationale for investigating BOT+BAL earlier in the disease course.
Meanwhile, the combination has received its first marketing authorizations in Armenia for eligible previously treated adults with MSS metastatic colorectal cancer without active liver metastases. It remains investigational outside Armenia and is not approved by the U.S. Food and Drug Administration.
A New Possibility for a Historically Immunotherapy-Resistant Cancer
The findings represent another encouraging signal for immunotherapy in a disease that has largely remained resistant to conventional checkpoint inhibition.
The most notable observation is not simply that 51% of patients reached the 18-month survival milestone. It is that a subset experienced prolonged tumor responses, and some remained alive without additional anticancer treatment.
Nevertheless, the findings come from a single-arm Phase 1b cohort and a retrospective survivor analysis. Randomized trials will be essential to determine how much of the observed survival can be attributed to treatment, which patients are most likely to benefit, and whether the strategy can improve outcomes earlier in the disease course.
For MSS colorectal cancer, the next question is no longer only whether immunotherapy can generate responses, but whether these responses can be reproduced, predicted, and translated into meaningful survival benefits for a broader patient population.
Read further on OncoDaily: UNICORN Challenges Immunotherapy Resistance in MSS Colon Cancer
