KEY TAKEAWAYS
- The NEOPRISM-CRC phase 2 trial aimed to investigate the efficacy and safety of neoadjuvant pembrolizumab in patients with MMR/MSI-High CRC.
- The primary endpoint was to determine pCR.
- Researchers noticed that neoadjuvant pembrolizumab is highly efficacious and safe; further investigation is ongoing.
The prognostic advantage of early-stage deficient-MMR/MSI-High colorectal cancer (CRC) is lost after relapse. Hence, there is a clinical imperative to maximize 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.
Kai-Keen Shiu and the team aimed to assess the efficacy and safety of neoadjuvant pembrolizumab in early-stage deficient-MMR/MSI-High CRC, stratified by TMB.
They performed an inclusive analysis involving patients with operable high-risk stage 2 or stage 3 deficient-MMR/MSI-High CRC. The trial population included patients with tumors categorized by TMB using the FoundationOneCDx test. Patients with TMB high or medium (≥6 mutations/Mb) received 3 cycles of pembrolizumab (200mg every 3 weeks) and underwent surgery within 4-6 weeks of the last cycle. Those with TMB low tumors (≤5 mutations/Mb) underwent surgery 4-6 weeks after 1 cycle of pembrolizumab.
The primary endpoint was the pathological complete response rate (pCR), while secondary endpoints included 3-year relapse-free survival, overall survival, safety, and health-related quality of life (QoL). The trial also incorporated translational endpoints to explore relationships between possible predictive novel biomarkers and response to pembrolizumab in blood, tumor tissue, and microbiome.
The study required 19 patients with TMB high or medium tumors to detect a pCR after 3 cycles of neoadjuvant pembrolizumab of 33% (minimum of 10%), with a one-sided 5% significance level and 80% power (A’Hern single stage). The trial would be considered a success if 35/19 of these patients achieved pCR. To achieve this number, the researchers aimed to recruit a total of 32 patients.
About 32 patients were rapidly enrolled after the trial opened on 20th July 2022. The pCR primary endpoint analysis was performed on 1st March 2024. The primary endpoint was exceeded with the pCR in the intent-to-treat patients (N=32) as well as the pCR in evaluable tumors. Median TMB was 42 mutations/Mb (range 4-82). There was only 1 TMB low tumor and no TMB medium tumors.
In the TMB high-medium cohort, there were 32 evaluable resected tumors, as 1 patient had 3 synchronous primaries, and 1 patient did not undergo surgery due to toxicity and patient choice. There were no immune-related toxicities > Grade 3. At a median follow-up of 6 months (range 2-15), no patients have had disease recurrence.
The study concluded that 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 ongoing translational biomarker work will provide further insights.
The trial was sponsored by the University College, London.
Source: https://meetings.asco.org/abstracts-presentations/234190
Clinical Trial: https://clinicaltrials.gov/study/NCT05197322
Shiu K K, Jiang Y, Saunders M, et al. (2024). “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 ASCO 2024. J Clin Oncol 42, 2024 (suppl 17; abstr LBA3504), 10.1200/JCO.2024.42.17_suppl.LBA3504
