By Elsa Lankford, Fight CRC Research Advocacy Trainings and Support (RATS) Program Member & Clinical Trial Curator

If you’re living with or caring for someone with microsatellite stable (MSS) stage IV colorectal cancer, you’ve probably heard this frustrating line before:
“Immunotherapy doesn’t work for MSS.”

That’s been the reality for years. While immunotherapy has made a huge difference for a small group of patients with MSI-high colorectal cancer, the vast majority —over 95%—are MSS. And they’ve had very few options once standard treatments stop working.

But some exciting new research presented at the ESMO GI 2025 conference is giving reason to hope.

At the conference, a group of respected researchers—including Dr. Benjamin Schlechter from Dana-Farber—shared results from a clinical trial testing an immunotherapy combination:

• Botensilimab (Bot): a newer kind of checkpoint inhibitor that helps kickstart the immune system
• Balstilimab (Bal): a checkpoint inhibitor that helps keep that immune response going

Together, they aim to turn “cold” tumors, like most MSS tumors, into “hot” ones that the immune system can recognize and attack.

The researchers looked at patients who had already been through many treatments. Some were on their third, fourth, or even fifth line of therapy. Many had already tried chemotherapy like regorafenib or TAS-102, and some had even tried other immunotherapies.

Here’s a simple snapshot of the patients in this study:

• 123 total patients with MSS colorectal cancer
• All had no active liver metastases, which can help immunotherapy work better
• About 30% had tried four or more treatments
• Around 15–30% had already tried immunotherapy
• None had high tumor mutation burden (TMB), which sometimes helps immunotherapy work better

These were patients who were running out of options—and looking for hope.

The results were surprisingly encouraging for a group of patients who’ve often been told “there’s nothing left.”

• 20% of patients had their tumors shrink by at least 30%
  • That’s 1 in 5 people seeing a meaningful response.
  • 3 people had a complete response (tumors disappeared), including one person in the most heavily treated group
• 50% of patients had stable disease
  • That means their cancer didn’t shrink, but it also didn’t grow
• About 70% of patients got some form of disease control
• For those who responded, the benefit lasted a long time—over 16 months
• Median overall survival was almost 21 months—even in patients who had already been through 4 or more treatments

For MSS colorectal cancer patients, these results are some of the most promising seen with immunotherapy.

All cancer treatments come with side effects, and this one is no different. But overall, they were manageable:

• About 6 in 10 patients had some side effects related to the immune system
• The most common side effect was diarrhea or colitis (inflammation of the colon)
• About 3 in 10 patients had more serious side effects (grade 3)
• Only one person had a very serious (grade 4) side effect
• No one died from treatment-related side effects

The more serious side effects were seen more often with higher doses. Doctors are learning more about how to manage this as the trials continue.

If you or your loved one has MSS colorectal cancer and has already tried multiple treatments, this trial offers something rare—hope.

These results show that immunotherapy might finally be on the horizon for MSS patients, especially those without active liver metastases. Even stable disease gives patients time: time to enter another trial, explore a new option, or even return to a treatment that may now work better because the immune system has been “revved up.”

Because the early results were so strong, the drug maker (Agenus) plans to start a Phase 3 trial by the end of 2025. This larger trial could bring botensilimab + balstilimab one step closer to FDA approval.

Right now, this drug combo is only available in clinical trials. But trials are open, and there may be one that’s a match for you or someone you care for.

You can search for trials using this combo on the Fight CRC Clinical Trial Finder: https://fightcolorectalcancer.org/resource/trial-results/?drug%5B0%5D=botensilimab

My name is Elsa, and I’ve been a caregiver, trial curator, and proud member of Fight CRC’s Research Advocacy Trainings and Support (RATS) Program for several years.

This trial stood out—not just for the science, but because it represents real progress for patients who’ve had very few options. I’ve seen firsthand how much every extra month, every slowed scan, every new option matters to patients and their families.

This is why research matters. This is why funding matters. And this is why we advocate.

Poster from ESMO GI 2025:
Download PDF

Trial Registration – NCT03860272:
ClinicalTrials.gov listing

Background on MSS and TMB:
Yaeger, R., et al. (2018). Clinical Cancer Research, 24(19), 4691–4703.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087857/