Neoadjuvant Pembrolizumab Challenges Standard of Care in High-Risk Colorectal Cancer

Nine weeks of treatment with immunotherapy prior to surgery led to strong, lasting responses in patients with colorectal cancer (CRC). The breakthrough data from the NEOPRISM-CRC study (NCT05197322) may challenge the standard of care—chemotherapy following surgery—given that approximately 25% of patients have cancer recurrence within 3 years.¹

"Seeing that no patients have experienced a cancer recurrence after almost 3 years of follow-up is extremely encouraging and strengthens our confidence that pembrolizumab [Keytruda; Merck] is a safe and highly effective treatment to improve outcomes in patients with high-risk bowel cancers,” said Kai-Keen Shiu, MD, chief investigator of the trial from University College London (UCL) Cancer Institute and a consultant medical oncologist at University College London Hospital (UCLH).¹

Treating Colorectal Cancer

CRC is the second-leading cause of cancer-related deaths in men and women in the United States, according to the American Cancer Society. With an estimated 108,860 new diagnoses in 2026 alone, CRC represents a significant burden with incidence rates decreasing in older adults but rising in those younger than 50 years of age.²

The standard of care for patients with stage 3 CRC is partial colectomy followed by adjuvant chemotherapy—typically FOLFOX (5-FU, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). However, emerging data from the NEOPRISM-CRC trial suggest a different approach may yield superior survival outcomes.³

Pembrolizumab Reduced Risk of Relapse

Researchers from UCL and UCLH reported that 59% of patients treated with 9 weeks of pembrolizumab prior to surgical resection were disease-free at 3 years. At the 33-month follow up, they reported that none of the patients have relapsed.¹

The phase 2 trial enrolled 32 patients with operable high-risk stage 2 or stage 3 mismatch repair-deficient/microsatellite instability-high (MSI-High) CRC. Treatment allocation was stratified by tumor mutational burden (TMB). Patients with TMB-high or TMB-medium tumors (≥ 6 mutations/Mb) received 3 cycles of pembrolizumab (200 mg every 3 weeks) prior to surgery, which was performed within 4 to 6 weeks of the final cycle. Those with TMB-low tumors (≤ 5 mutations/Mb) proceeded to surgery 4 to 6 weeks after a single cycle of pembrolizumab.⁴

The primary end point was pathological complete response rate (pCR). Secondary end points included 3-year relapse-free survival, overall survival, safety, and health-related quality of life. The trial also incorporated translational endpoints to investigate the relationship between novel predictive biomarkers—in blood, tumor tissue, and the microbiome—and response to pembrolizumab.⁴

The trial met and exceeded its primary end point, with pCR rates observed in both the intent-to-treat population and among evaluable tumors.⁴

Personalized Blood Tests Helped Determine Responses

Alongside the clinical outcomes, the study yielded important new insights into the mechanisms underlying the durable responses observed with immunotherapy. A key finding concerned the use of personalized circulating tumor DNA blood tests.¹

"As a research team, we were thrilled to be able to follow patients very closely using the personalized blood tests,” explained Yanrong Jiang, PhD student at UCL and first author of the study. “When tumor DNA disappeared from the blood, patients were much more likely to have no cancer remaining, and this matched the long-term results we're now seeing.”¹

Researchers also investigated the factors underpinning treatment efficacy and explored approaches to identifying patients most likely to benefit. Through serial blood sample analysis, the team developed personalized tests capable of detecting residual cancer DNA in the circulation, potentially enabling earlier determination of treatment success.¹

"What is particularly exciting is that we now may be able to predict who will respond to the treatment using personalized blood tests and immune profiling,” said Shiu. “These tools could help us tailor our approach, identifying patients who are doing well and may need less therapy before and after surgery versus patients at higher risk of disease progression or relapse who need additional treatment."¹

REFERENCES

1. Colon cancer breakthrough keeps patients cancer-free for nearly 3 years. ScienceDaily. News release. May 6, 2026. Accessed May 14, 2026. https://www.sciencedaily.com/releases/2026/05/260505234618.htm

2. Key statistics for colorectal cancer. American Cancer Society. January 14, 2026. Accessed May 14, 2026. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
3. Treatment of colon cancer, by stage. American Cancer Society. December 27, 2024. Accessed May 14, 2026. https://www.cancer.org/cancer/types/colon-rectal-cancer/treating/by-stage-colon.html

4. Shui KK, Jiang Y, Saunders M, et al. NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer. Presented at: 2024 ASCO Annual Meeting. May 31-June 3, 2026. Chiacgo, IL.