• NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer.

Background: The prognostic advantage of early stage deficient-MMR/MSI-High colorectal cancer (CRC) is lost after relapse. Hence, there is a clinical imperative to maximise the chance of cure in early-stage disease. Tumour mutation burden (TMB) is an emerging biomarker for response and clinical benefit to immunotherapy in the advanced setting. NEOPRISM-CRC (Neoadjuvant PembRolizumab In Stratified Medicine – ColoReCtal) is the first multicentre Phase II Trial to determine if neoadjuvant pembrolizumab is efficacious and safe, prospectively stratified to TMB. Methods: The trial population included patients (pts) with operable high-risk stage 2 or stage 3 dMMR/MSI-High CRC. Pts with tumours that were TMB high or medium (≥6 mutations/Mb on FoundationOneCDx test) received 3 cycles of pembrolizumab (200mg every 3 weeks) and underwent surgery within 4-6 weeks of last cycle. Pts with TMB low tumours (≤5 mutations/Mb) underwent surgery 4-6 weeks after 1 cycle of pembrolizumab. The primary end point was pathological complete response rate (pCR). Secondary endpoints included 3-year relapse free survival, overall survival, safety, and health-related quality of life. The trial also incorporated translational endpoints to explore relationships between possible predictive novel biomarkers and response to pembrolizumab in blood, tumour tissue and microbiome. We required 19 pts with TMB high or medium tumours to detect a pCR after 3 cycles of neoadjuvant pembrolizumab of 33% (minimum of 10%), with one-sided 5% significance level and 80% power (A’Hern single stage). The trial would be considered a success if ³5/19 of those pts achieved pCR. To achieve this number, we aimed to recruit 32 patients in total. Results: The trial opened on 20th July 2022 and 32 pts were rapidly enrolled. The pCR primary endpoint analysis was performed on 1st March 2024. The primary endpoint was exceeded with the pCR in the intent to treat pts (N=32) as well as the pCR in evaluable tumours shown in Table 1. Median TMB was 42 mutations/Mb (4-82). There was only 1 TMB low tumour and no TMB medium tumours. In the TMB high-medium cohort there were 32 evaluable resected tumours as 1 pt had 3 synchronous primaries, and 1 pt did not undergo surgery due to toxicity as well as pt choice. There were no immune-related toxicities >Grade 3. At a median follow-up of 6 months (range 2-15), no pts have had disease recurrence. Conclusions: Neoadjuvant pembrolizumab for early stage deficient-MMR/MSI-High CRC is highly efficacious and safe. Longer follow up is needed to assess relapse free survival and translational biomarker work is ongoing. Clinical trial information: NCT05197322.