A groundbreaking phase 1 clinical trial has demonstrated that a novel immunotherapy combination can successfully treat the most common form of colorectal cancer, potentially transforming treatment options for thousands of patients who previously had limited therapeutic alternatives.
The international study, published in Nature Medicine, evaluated the combination of botensilimab and balstilimab in 148 patients with microsatellite stable metastatic colorectal cancer (MSS mCRC), representing the first time immunotherapy has shown consistent efficacy against this prevalent cancer subtype.
Addressing an Unmet Medical Need
Colorectal cancer ranks as the second leading cause of cancer-related death in the United States after lung cancer, with an estimated 53,000 Americans expected to die from the disease this year. While immunotherapy has previously shown success in patients with mismatch repair deficient (dMMR) tumors, only a small percentage of colorectal cancer patients have this tumor type. The vast majority of patients have MSS mCRC tumors, which have historically been unresponsive to immunotherapy treatments.
"This was the first time immunotherapy has really been shown to be working in this most common type of colon cancer," said Dr. Sunil Sharma, Chief of Translational Oncology and Drug Development at HonorHealth Research Institute, one of the study's authors.
Promising Clinical Results
The three-year study revealed encouraging outcomes for patients treated with the dual immunotherapy approach. Of the 101 patients who completed a six-month follow-up, 61% experienced tumor shrinkage or stabilization after receiving the botensilimab and balstilimab combination.
The treatment demonstrated particular effectiveness in patients without liver metastases, showing higher response rates and prolonged intervals of stable response lasting several years in some cases, compared to those with liver metastases.
"For those patients without liver metastases, there appears to be a higher response rate and a prolonged interval of ongoing stable response lasting several years in some patients in contrast to those patients with liver metastases," explained Dr. Michael S. Gordon, Chief Medical Officer of HonorHealth Research Institute and co-author of the study.
Mechanism of Action
The combination therapy works by overcoming cancer's ability to evade the immune system. Both botensilimab and balstilimab are monoclonal antibodies that sidestep immune checkpoint blockades—natural elements that prevent immune cells from attacking healthy tissue but which cancer cells exploit to hide from immune detection.
"With this therapy, you wind up with larger numbers of highly effective immune T cells that can attack the cancer," Dr. Gordon explained. The treatment was well-tolerated by patients, with the most common side effects being diarrhea and fatigue.
Growing Concern Among Younger Adults
The study highlighted an alarming trend in colorectal cancer incidence among younger populations. According to the Nature Medicine publication, from 1995 to 2019, the number of patients under age 55 diagnosed with colorectal cancer in the United States nearly doubled.
"Oh my God, my whole clinic is full of younger people dying of colon cancer. It's a real tragedy," said Dr. Sharma, noting that younger patients often present with advanced or metastatic disease because their symptoms are frequently misdiagnosed as irritable bowel syndrome or hemorrhoids, and screening typically isn't recommended until after age 45.
Future Development and Regulatory Path
Professor Justin Stebbing of Anglia Ruskin University, a co-author who described the results as "potentially game changing," emphasized the significance of these findings for the broader colorectal cancer patient population.
"This is the first time there has been convincing evidence that immunotherapy can work in all forms of colorectal tumors, so this is potentially game changing," Stebbing stated.
Agenus Inc., the Lexington, Massachusetts-based sponsor of the clinical trial, is planning to seek FDA approval for the combination immunotherapy and has initiated a phase 3 clinical trial to further validate these promising results.
The research establishes a foundation for future immunotherapy development in colorectal cancer. "We've shown the proof of principle that immunotherapies can work against this disease. This creates a backbone upon which we can hopefully build even better immunotherapies," Dr. Sharma concluded.
