NEOPRISM-CRC: Neoadjuvant Pembrolizumab for Early-Stage Deficient-MMR/MSI-High CRC

Neoadjuvant pembrolizumab may be effective and safe for early-stage deficient mismatch repair (dMMR)/microsatellite instability (MSI)-high colorectal cancer (CRC), according to results of the NEOPRISM-CRC study presented as a late-breaking abstract at the 2024 American Society of Clinical Oncology Annual Meeting.

Tumor mutation burden (TMB) is an emerging biomarker for response and clinical benefit to immunotherapy in advanced-stage dMMR/MSI-high CRC. NEOPRISM-CRC is the first multicenter. phase 2 trial designed to determine the safety and effectiveness of neoadjuvant pembrolizumab when stratified by TMB for high-risk stage II-III disease.

Kai-Keen Shiu, MD, PhD, of University College Hospital, and colleagues sampled patients with operable high-risk stage II or III dMMR/MSI-high CRC. Those with TMB high or medium tumors received 3 cycles of pembrolizumab (200 mg every 3 weeks) and underwent surgery within 4 to 6 weeks of the last treatment cycle. Those with TMB low tumors underwent surgery 4 to 6 weeks after 1 cycle of pembrolizumab.

The primary end point of the study is pathological complete response rate (pCR), and secondary end points include 3-year relapse-free survival, overall survival, safety, and health-related quality of life.

Additionally, the researchers incorporated translational end points to investigate the relationships between possible predictive novel biomarkers and response to pembrolizumab in blood, tumor tissue, and the microbiome. They needed 19 patients with TMB high or medium tumors to detect a pCR of 33% (minimum 10%) after 3 cycles of neoadjuvant pembrolizumab. Researchers determined that the trial would be a success if 5 patients achieved pCR.

A total of 32 patients were enrolled, and the pCR rate in the intent-to-treat population and the evaluable tumor population was 53% and 58%, respectively (95% CI). Similarly, for patients with TMB high or medium tumors, the pCR rate was 55% and 59%, respectively.

There have been no immune-related toxicities greater than grade 3, Dr. Shiu and colleagues reported, and at a median follow-up of 6 months, no patients have had disease recurrence.

“Neoadjuvant pembrolizumab for early-stage dMMR/MSI-high CRC is highly efficacious and safe,” they concluded. “Longer follow-up is needed to assess relapse-free survival and translational biomarker work is ongoing.”