While both are used, some oncologists consider Next-Generation Sequencing (NGS) the gold standard over Immunohistochemistry (IHC) for MSI testing. NGS provides tumor mutation burden (TMB) data, which can identify rare, ultra-hypermutated but technically microsatellite-stable (MSS) tumors that are likely to respond to immunotherapy but would be missed by IHC alone.
While the STELLAR-303 trial was positive, experts are concerned about the toxicity of the zenzalintinib/atezolizumab combination. The side effect profile and high rate of dose modifications raise questions about the real-world risk-benefit ratio for what is still an incremental, non-curative improvement in survival for refractory metastatic colorectal cancer.
Unlike the 100% complete clinical response seen in some rectal cancer trials, studies like NICHE-2 for MSI-high colon cancer show a lower pathologic complete response rate (around 68%). This crucial difference suggests non-operative management is far riskier in colon cancer and requires a distinct clinical approach.
A positive ctDNA (MRD) test after surgery is seen as a stronger predictor of recurrence than traditional histopathological features. This result pushes clinicians to recommend more aggressive adjuvant chemotherapy, such as extending the duration to a full six months, and to increase the frequency of surveillance imaging.
Despite the excellent prognosis associated with a negative post-operative MRD test, oncologists are not yet comfortable omitting adjuvant chemotherapy for younger, high-risk stage II colon cancer patients. The current data is not considered sufficient to justify de-escalation based on a negative ctDNA result alone outside of a clinical trial setting.
Experts overwhelmingly favor tissue-based testing (IHC or NGS) to determine MSI status in localized colorectal cancer. They express concern that liquid biopsies (ctDNA) may produce false negatives because smaller, localized tumors might not shed enough DNA into the bloodstream for reliable detection.
An MSK trial of neoadjuvant dostarlumab for MSI-high locally advanced rectal cancer showed a 100% complete clinical response rate. This groundbreaking result allows for non-operative management, sparing patients from chemotherapy, radiation, and life-altering surgery, potentially representing a cure with immunotherapy alone.
Analysis across multiple studies suggests that longer treatment durations with neoadjuvant immunotherapy, up to six months, are associated with higher rates of complete pathologic response in localized MSI-high colorectal cancer. This indicates that treatment duration is a critical variable for optimizing patient outcomes and designing future trials.
After numerous failures to make immunotherapy effective in microsatellite-stable (MSS) metastatic colorectal cancer, the STELLAR-303 trial shows a statistically significant survival benefit for zenzalintinib plus atezolizumab over regorafenib. This marks a potential breakthrough, offering a new IO-based option for this large patient population.
In metastatic colorectal cancer, clinicians are using ctDNA MRD testing to help guide the decision to stop immunotherapy. For patients who have been on treatment for 1.5-2 years with a complete or durable radiographic response, a negative ctDNA result provides an additional layer of confidence to discontinue therapy.