Immunotherapy has made significant strides in cancer treatment, but microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has long posed a challenge due to its resistance to immune-based therapies. However, promising results from a recent phase 2/3 trial have shown that the individualized neoantigen-directed immunotherapy, GRANITE, may change the outlook for patients with MSS mCRC. This innovative therapy, combined with atezolizumab (Tecentriq), fluoropyrimidine, bevacizumab (Avastin), and a single dose of ipilimumab (Yervoy), is offering hope by improving progression-free survival (PFS) in these patients.
What Makes GRANITE Immunotherapy Different?
GRANITE is an individualized neoantigen-targeting immunotherapy, designed to stimulate a patient’s immune system to specifically recognize and attack tumor cells based on unique tumor proteins called neoantigens. Unlike more generalized immunotherapies, which can struggle to target MSS mCRC (a tumor type known for being “cold” or less responsive to immune attacks), GRANITE is tailored to each patient’s tumor, enhancing the immune system’s ability to fight the cancer.
The phase 2/3 trial investigated whether adding GRANITE to standard maintenance therapy could improve outcomes for patients with MSS mCRC. Patients who received GRANITE showed a 21% reduction in the risk of disease progression or death compared to those who received standard therapy alone. While the trial was not statistically powered to detect PFS improvements, these early results are encouraging and indicate that this approach may offer significant benefits, particularly for patients with lower disease burden.
Promising Results for Patients with Low Disease Burden
One of the standout findings from the trial is the impact on patients with low circulating tumor DNA (ctDNA), a marker for low disease burden. In these patients, the risk of disease progression was reduced by 38%. The data suggest that patients with lower amounts of disease may derive the greatest benefit from this immunotherapy approach.
This could represent a shift in how we view and treat MSS mCRC. As Andrew Allen, MD, PhD, CEO of Gritstone bio, noted, “The potential PFS benefit observed in MSS CRC, a notoriously ‘cold’ tumor, suggests the opportunity for even greater effects in tumors more typically amenable to immunotherapy.”
How GRANITE Works
GRANITE uses a two-pronged prime/boost vaccine approach to activate the immune system. The regimen starts with GRT-C901, followed by GRT-R902, both of which work to prime and boost the immune response against tumor-specific neoantigens. These are combined with atezolizumab (an immune checkpoint inhibitor), fluoropyrimidine, bevacizumab, and a single dose of ipilimumab to enhance the immune system’s ability to attack the tumor.
Patients in the investigational arm received 24 weeks of induction therapy with standard chemotherapy (including oxaliplatin, irinotecan, and bevacizumab), followed by six doses of the GRANITE vaccines, with ipilimumabadministered alongside the first dose. This was coupled with maintenance therapy involving atezolizumab, fluoropyrimidine, and bevacizumab.
A Path Forward for MSS mCRC
The results from this trial mark an important development for MSS mCRC, which historically has not responded well to immunotherapy. The phase 2/3 trial showed that the GRANITE-based regimen not only delayed disease progression but also generated a strong immune response in all patients tested. Patients who exhibited stable ctDNA levels (a marker of minimal residual disease) experienced encouraging outcomes, suggesting that GRANITE could become a powerful new tool in controlling disease progression.
What’s Next for GRANITE?
The journey for GRANITE is far from over. Gritstone bio plans to continue working closely with the FDA to further investigate the benefits of this individualized therapy. Upcoming trials may focus on using ctDNA levels to better identify patients who are most likely to benefit from the treatment. Additionally, overall survival (OS) data is expected in the second half of 2025, which will shed more light on the long-term benefits of this treatment approach and future clinical trials. Further followup is definitively needed.
For patients with MSS mCRC, these early results are a source of optimism. Immunotherapy, once considered ineffective for this patient population, may soon become a key component of treatment, especially for those with lower disease burden.
Future for MSS mCRC Treatment
The recent phase 2/3 trial results for GRANITE immunotherapy are promising, offering new hope for patients with microsatellite stable metastatic colorectal cancer. By harnessing the power of neoantigen-directed immune responses and combining it with proven therapies like atezolizumab and bevacizumab, GRANITE has the potential to significantly improve outcomes for patients who currently have limited options.
As the trial data continue to mature and more patients are treated, GRANITE may become an important tool in the fight against MSS mCRC, providing a tailored, effective option for prolonging survival and enhancing quality of life. Further information can be found here!
About the Author
Dr. Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. With his many years of experience, he brings a wealth of expertise to the complex and challenging world of oncology. About Dr Thomas – MedOncMD