PD-1–Based Neoadjuvant Therapy Benefits Select Patients With pMMR Rectal Cancer

Published results from the phase 2 SILAR trial (NCT05450029) show that a novel neoadjuvant approach combining sintilimab (Tyvyt) PD-1 blockade plus neoadjuvant long-course chemoradiotherapy yielded positive clinical outcomes in patients with proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC), provided they exhibited a favorable immune microenvironment.¹

The trial’s primary end point of pathologic complete response (pCR) was met, with more than half of patients achieving pCR (65.2%; n = 30/46; 95% CI, 49.7%-78.6%). Notably, the response was even more pronounced in the subgroup with high Immunoscores (pCR rate, 85.7%).

Clinical activity was further supported by an objective response rate (ORR) of 93.5% and an R0 resection rate of 97.8%, indicating that the regimen effectively downstaged tumors to allow for successful surgical margins. Survival data were immature at the time of analysis.

The safety profile of the combination was manageable and consistent with the known toxicities of the individual agents. The most frequent treatment-related adverse event (TRAE) was leukopenia, occurring in approximately 70% of participants. Grade 3 TRAEs were reported in 15.2% of the cohort.

Importantly, the addition of sintilimab did not compromise surgical outcomes. Only 4 patients (8.7%) experienced postoperative complications, all of which were low-grade (≤ grade 2), highlighting the feasibility of the neoadjuvant regimen.

“This strategy may contribute to high CR and increased opportunities for organ preservation in this selected population,” wrote study authors Zheng et al in the Nature Communications publication. “A large clinical multicenter randomized trial of all comers stratified by Immunoscore is required.”

Identifying a “Hot” Subset: Clinical Implications

For years, pMMR LARC has been considered "cold" and largely nonresponsive to immunotherapy, leaving total neoadjuvant therapy or standard chemoradiotherapy as the only treatment options. The SILAR data introduce a potential paradigm shift by introducing a biomarker-driven selection process.

By identifying patients with intermediate or high Immunoscores—a measure of the density of CD3-positive and CD8-positive T cells in the tumor center and invasive margin—clinicians may be able to identify a subset of pMMR patients who can benefit from PD-1 inhibitors. If validated in larger, randomized trials, this strategy could pave the way for more personalized neoadjuvant protocols and potentially increase the number of patients eligible for "watch and wait" organ preservation strategies, given the high pCR rates observed.

SILAR Study Design and Methodology

The SILAR study was a single-arm, open-label phase 2 study conducted at the Sixth Affiliated Hospital of Sun Yat-sen University in Guangzhou, China.² The trial enrolled 46 treatment-naive adult patients with histologically confirmed T_3–4N₀M₀ or T_1–4N₊M₀ rectal adenocarcinoma. To be eligible, all patients were required to have pMMR status and an intermediate or high Immunoscore, as determined by biopsy.

The treatment protocol consisted of a robust total neoadjuvant framework:

• Induction: 6 cycles of mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil).
• Chemoradiotherapy: Long-course radiotherapy (50 Gy in 25 fractions).
• Immunotherapy: Sintilimab (3 mg/kg) administered every 2 weeks during the chemoradiotherapy phase (cycles 2 through 6).
• Surgery: Total mesorectal excision following completion of neoadjuvant therapy.

Primary analysis focused on the pCR rate, with secondary end points including safety, R0 resection, and 3-year survival metrics. While 3-year survival data remain immature, the high pCR rate may serve as a surrogate for long-term survival in this challenging patient population.

REFERENCES

1. Zheng X, Liu H, Shi L, et al. Neoadjuvant chemoradiotherapy plus sintilimab in proficient mismatch repair locally advanced rectal cancer with intermediate/high-immunoscore (SILAR): a single-arm phase II trial. Nat Commun. 2026;17(1). doi:10.1038/s41467-025-65162-8

2. Neoadjuvant chemoradiotherapy plus sintilimab for intermediate/high immunoscore locally advanced rectal cancer (SILAR). ClinicalTrials.gov. Updated September 26, 2023. Accessed January 28, 2026. https://clinicaltrials.gov/study/NCT05450029