Groundbreaking data from the Phase II NEOPRISM-CRC trial show that patients given pembrolizumab prior to surgery for certain types of high-risk, operable colorectal cancer (CRC) remain relapse-free for almost three years.
Furthermore, the response to treatment can be predicted by DNA and T cell biomarkers.
At present, the standard of care for people with high-risk stage II or III CRC with deficient DNA mismatch repair (dMMR) or microsatellite instability (MSI), like those included in the study, is surgery followed by chemotherapy, but relapse rates can range from 15% to 40% at three years.
Pembrolizumab is already given to patients with inoperable stage IV dMMR/MSI CRC to shrink the tumors and prolong life, but it is not yet available for patients with operable tumors.
The NEOPRISM-CRC trial investigated whether pembrolizumab could benefit such patients.
For the study, 32 people with large, high-risk stage II or III dMMR/MSI CRC were given three cycles of intravenous pembrolizumab 200 mg followed by surgery.
The researchers, led by Kai-Keen Shiu, from University College London (UCL) Cancer Institute, have previously reported that that 59% of participants had a pathologic complete response (pCR) to pembrolizumab, indicating that there were no cancer cells in tissue samples removed from these patients during surgery.
The data presented at the American Association for Cancer Research Annual Meeting 2026 by Yanrong Jiang, a PhD student at UCL Cancer Institute, focused on survival outcomes and whether biomarkers could predict which patients respond to pembrolizumab.
She reported that, after a mean of 33 months of follow-up, all patients were alive and relapse-free.
Shiu said: “Seeing that no patients have experienced a cancer recurrence after almost three years of follow-up is extremely encouraging and strengthens our confidence that pembrolizumab is a safe and highly effective treatment to improve outcomes in patients with high-risk bowel cancers.”
Blood samples taken throughout the study were assessed for circulating tumor (ct)DNA using the highly sensitive whole genome tumor-informed Personalis NeXT Personal assay, which can track up to 1800 patient-specific variants.
The team found that all 25 patients with evaluable data had detectable ctDNA at baseline.
Remarkably, after one round of treatment with pembrolizumab, 24% of participants no longer had detectable ctDNA. The proportion increased to 43% and 58% after rounds two and three, respectively. Post-surgery, ctDNA was undetectable in all 25 patients.
When the researchers analyzed the ctDNA clearance profiles, they identified three distinct patterns. They designated the first group “super molecular responders.” All six patients in this group had undetectable ctDNA after one cycle of pembrolizumab.
The “dynamic molecular responder” group included 11 patients who cleared ctDNA at different rates—four after cycle two of pembrolizumab, five after cycle three, and the remainder post-surgery, even though the level was decreasing rapidly during immunotherapy.
The final group, termed “poor molecular responders,” included eight patients who showed stable, high levels of ctDNA throughout immunotherapy, with levels only becoming undetectable post-surgery.
Interestingly, the pCR rate varied across the three groups: It was 100% among the super molecular responders and 82% among the dynamic molecular responders, but 0% among the poor molecular responders.
Shiu told Inside Precision Medicine that measuring ctDNA using the Next Personal assay could “potentially trump all standard tests when it comes to informing decision making.”
He suggested that the super molecular responders could potentially consider forgoing surgery altogether, while the poor molecular responders could be considered for treatment intensification, such as the addition of a second immunotherapy agent.
Although ctDNA gives information on how the tumor is responding to treatment, it doesn’t explain why some patients respond and others don’t.
The researchers, therefore, also carried out T cell receptor (TCR) sequencing, which provides a readout of the immune environment within the tumor, specifically whether there are expanded T cell populations that may recognize cancer, explained Marnix Jansen, MD, a clinician scientist and consultant histopathologist who led the translational research on the trial from UCL Cancer Institute.
“We found that patients who achieved a complete response had a higher proportion of expanded T cell clones in their tumors, suggesting a more focused and effective anti-tumor immune response at baseline,” he said.
When the team combined the ctDNA results with the TCR sequencing data, they improved the ability to predict outcomes compared with using either biomarker alone.
“The key implication is that integrating immune and tumor biomarkers in a dynamic model may allow early, data-driven treatment decisions, such as identifying patients who are highly likely to benefit or, conversely, those who may need a change in therapy,” Jansen told Inside Precision Medicine.
The post Presurgery Pembrolizumab May Be the Future for Some Operable CRCs appeared first on Inside Precision Medicine.