New Study Identifies Molecular Clues Behind Mixed Immunotherapy Response in Colon Cancer Patients

Patients with a particularly aggressive form of metastatic colorectal cancer may benefit from a novel combination of targeted therapy and immunotherapy, according to a Houston-led phase 1/2 clinical trial that offers new insights into why some patients benefit while others don’t.

The multi-institutional clinical trial showed significantly better outcomes from a three-drug regimen of encorafenib, cetuximab and the immune checkpoint inhibitor nivolumab in patients with microsatellite-stable (MSS) colorectal cancer harboring the BRAFV600E mutation than is typically seen in either approach alone. The subgroup is known for its poor prognosis and has shown a decidedly limited response to just immunotherapy.

“This was a very successful clinical trial, but the real question in immunotherapy is always why some patients respond and others don’t,” said Dr. Kyuson Yun, a study co-author and a Houston Methodist professor of neurology and cancer researcher.

The study, published in Cancer Cell in November, was led by clinician scientists at MD Anderson GI oncology group. Houston Methodist scientists conducted the research’s cellular analysis.

Study design

Among 26 patients enrolled, investigators reported an overall response rate of 50% and a median overall survival of 22 months — more than double the outcomes historically seen with standard targeted therapies.

The results address a long-standing gap in colorectal cancer treatment. While immunotherapy has transformed care for a subset of patients with microsatellite instability–high (MSI-high) tumors, single-agent PD-1 blockade has consistently failed in patients with MSS colorectal cancer.

Within this already difficult-to-treat population, BRAFV600E mutant MSS tumors — representing approximately 10% of cases — are associated with particularly aggressive biology and significantly worse outcomes.

Against that backdrop, researchers say the new study demonstrates how targeting the mitogen-activated protein kinase (MAPK) pathway in combination with immunotherapy can help “reprogram” immunologically cold tumors toward immune responsiveness.

Decoding treatment response

While the clinical results were encouraging, a major advance of the study lies in its correlative science — the detailed molecular analysis led by Dr. Yun and her team. It aimed at unraveling why some tumors responded dramatically while others resisted treatment.

The team used cutting-edge techniques in novel 3D modeling, transcriptomic profiling of paired tumor biopsies and extracellular vesicle RNA (evRNA) isolated from blood, involving collaborators from multiple academic institutions and industry partners.

Tumors from non-responders exhibited heightened activation of the complement cascade and enrichment of innate immune and myeloid-related pathways. Rather than promoting tumor clearance, this immune state appeared to reinforce immune suppression and resistance to checkpoint blockade.

“The complement pathway stood out as a very strong signal in patients who did not respond,” Dr. Yun explained. “That tells us these tumors may actively maintain an immune-suppressive environment, even when we’re giving immunotherapy designed to overcome that barrier.”

Promising results for some

Importantly, these biological distinctions were not static. Longitudinal analysis of evRNA revealed that responders showed dynamic immune reprogramming over time, with rising inflammatory and interferon-related signals during therapy, while non-responders failed to mount similar changes. Two patients with particularly robust immune activation experienced durable responses lasting nearly two years — an uncommon outcome in this disease population.

The findings have practical implications for both clinical care and drug development, Dr. Yun said. By identifying molecular features associated with response or resistance early in treatment, clinicians may be able to better tailor therapies and avoid ineffective combinations.

“More than 90% of clinical trials fail late in development, after years of work and enormous cost,” Dr. Yun said. “If we can understand success and failure at the molecular level, we can design smarter trials and deliver more personalized care for patients.”

Next steps

The study also underscores the growing role of liquid biopsy approaches as noninvasive tools for monitoring treatment response and immune dynamics in real time.

The findings are already influencing next steps. A randomized phase 2 trial is underway to further test the combination therapy, and Dr. Yun’s group continues to investigate how immune-suppressive pathways — including complement signaling and myeloid cell activity — might be therapeutically targeted to extend benefit to a broader group of patients.

“Our long-term focus is reprogramming the tumor microenvironment,” Dr. Yun said. “If you can change the environment so immune cells can actually do their job, you open the door to much more effective cancer therapies.”