Botensilimab Plus Balstilimab Shows Durable Activity in Refractory CRC Across Lines of Therapy

As novel immunotherapeutic combinations continue to advance for the treatment of patients with microsatellite stable (MSS) metastatic colorectal cancer (CRC)—a historically immunoresistant population—emerging data with the CTLA-4 inhibitor botensilimab in combination with the PD-1 inhibitor balstilimab have demonstrated promising clinical activity across heavily pretreated subgroups, according to Benjamin L. Schlechter, MD.

During the 2025 ESMO Gastrointestinal Cancers Congress (ESMO GI), investigators presented updated findings from the phase 1 C-800-01 trial (NCT03860272), expanding on earlier data published in Nature Medicine in 2023.1 Among 123 patients with pretreated MSS metastatic CRC with no active liver metastases who received the combination, the overall response rate (ORR) was 20% (95% CI, 13%-28%) and the disease control rate (DCR) was 69% (95% CI, 60%-77%) at 6 weeks. The median progression-free survival (PFS) was 4.0 months (95% CI, 2.8-4.1), and median overall survival (OS) was 20.9 months (95% CI, 16.2-26.6). The regimen also produced a median duration of response (DOR) of 16.6 months (95% CI, 5.7–not reached [NR]), with a clinical benefit rate of 28% (95% CI, 20%-36%) at week 24.

“This is a [combination] which is working on the immune system and using it as an antineoplastic tool in a novel way,” Schlechter said in an interview with OncLive®. “As a consequence, chemorefractoriness doesn't matter, the line of therapy doesn't matter, the benefit of the agent is maintained, and the toxicity profile is similar across all lines of therapy, which is a novel and important finding in this combination of [botensilimab and balstilimab].”

Schlechter is a senior physician in the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts.

In the interview, Schlechter emphasized the consistency of response across treatment-refractory subsets, including a 37-patient cohort in the fourth- and later-line settings, where the ORR was 19% (95% CI, 8%-35%) and median OS reached 22.5 months (95% CI, 12.6-NR). He noted that outcomes were comparable regardless of prior therapy, reinforcing the immune-mediated mechanism of action of the regimen.

OncLive: What do these updated findings reveal about the clinical activity of botensilimab plus balstilimab and how do they inform its potential use across treatment-refractory subgroups?

Schlecter: This novel CTLA-4 inhibitor, botensilimab, is modified to achieve efficacy in very cold tumors such as CRC. These modifications enhance engagement with [antigen-presenting cells], but importantly, improve Treg [regulatory T cell] depletion and NK [natural killer cell] recruitment, and also prevent Fcγ receptor fixation, which mitigates toxicity.

[The initial report included] 77 patients [published a year ago], and here at ESMO GI, we presented [updated results from] 123 patients with 2 years of follow-up. The important findings are that the efficacy is deep and maintained in patients without hepatic disease or non–liver metastases. [Additionally], if we look at the different populations enrolled, patients who had prior fluoropyrimidine, oxaliplatin, irinotecan, and monoclonal antibody therapy were an important population.

But if you look at a subset analysis of the most refractory patients who have been exposed to trifluridine/tipiracil [Lonsurf] with bevacizumab [Avastin], fruquintinib [Fruzaqla], and regorafenib [Stivarga], we see identical efficacy and safety between that hyper-refractory population, the late-line population, and the advanced-line population.

What were the primary toxicities observed with balstilimab in this trial and how were they managed?

The principal toxicity [with] balstilimab was colitis. Immune-related diarrhea and colitis are [considered] a combined term, because sometimes [it is] coded as colitis and sometimes as diarrhea—they're the same thing.

What we learned in this trial is that early initiation of tumor necrosis factor [TNF] inhibition is critical to [ensuring] patient safety and [allowing patients to remain] on treatment. [Continuing] the PD-1 inhibitor after CTLA-4 [therapy] is very important for maintaining efficacy. That was demonstrated in a presentation by Marwan Fakih, MD PhD, at the 2025 ASCO Gastrointestinal Cancers Symposium, looking at the randomized phase 2 [evaluation] of this combination, where there was single-agent botensilimab vs botensilimab with balstilimab versus chemotherapy.

The combination [of botensilimab and balstilimab] produces better outcomes. Early initiation of TNF inhibitors such as infliximab [Remicade] is important, and a steroid-sparing approach [appears to be] better for patients and better for the immune response.

Where do you see this combination fitting within the current and future treatment paradigms for this patient population?

There are several ways that botensilimab has a future [in clinical practice]. Number one is in [patients with] refractory disease, and we need to push forward with approval of this agent through randomized trials in the refractory setting.

It’s very compelling that there are some early trials—[including] 2 trials in colon cancer, [NEST-1 (NCT05608044) and NEST-2 (NCT05571293)]—showing that in earlier stages of disease, there’s benefit [with this approach]. We have to move this forward in all lines of therapy, knowing that the most refractory and advanced disease [populations] have similar efficacy.

We’ve learned from the work of other investigators that the in-situ primary tumor and the in-situ lymph nodes provide a training ground for the immune system. That training ground is important for promoting immune responses in earlier-stage disease. This is hypothesis-generating but gives us the idea that these are agents that can be brought forward [into] early-line therapy as a nonoperative management strategy in immunologically cold tumors such as MSS CRC.

Botensilimab is [interesting]. It’s novel and not just a CTLA-4 inhibitor in the old sense, this is a new drug.

It’s also important to distinguish CTLA-4 [inhibitors], which are pro-inflammatory agents, from PD-1 [inhibitors], which are [agents that help maintain] inflammation. One of the important lessons here is that we can move beyond the first-generation CTLA-4 [inhibitors] and see benefit in diseases where we didn’t before, and that we still need PD-1 [inhibitors] to maintain that benefit.

We start the process [by] igniting the fire of the immune response and then we can maintain it using novel agents.

Reference

1. Schlechter BL, Fakih M, Tsimberidou, et al. Botensilimab plus balstilimab in an expanded cohort of 123 patients with metastatic microsatellite-stable colorectal cancer and no active liver metastases. Ann Oncol. 2025;36(suppl 1):S7-S8. doi:10.1016/j.annonc.2025.05.020