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Neoadjuvant checkpoint blockade in MSI-H/dMMR CRC

Conference
ASCO 2024
Trial
Phase 1/2, NICHE-2, NEOPRISM-CRC
Doi
https://doi.org/10.55788/de6c796d
In patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal tumours, the efficacy of (adjuvant) chemotherapy is limited. Now, several trials demonstrated high response rates with neoadjuvant immune checkpoint blockade.

Previously, the phase 2 NICHE-2 trial demonstrated that neoadjuvant nivolumab/ipilimumab induced a high rate (95%) of pathological complete response (pCR) in patients with locally advanced MSI-H/dMMR colon cancer [1,2]. At ASCO 2024, 3 additional trials reported comparable results.

Prof. Rui-Hua Xu (Sun Yat-sen University Cancer Center, China) presented results from a randomised, open-label, phase 1b study (NCT05890742) evaluating neoadjuvant treatment in patients with stage III MSI-H/dMMR colon cancer [3]. The study randomised 101 participants 1:1 to receive sintilimab (an anti-PD-1 antibody) or sintilimab plus IBI310 (an anti-CTLA-4 antibody). Following radical surgery, pCR rates were 80% in participants treated with sintilimab plus IBI310 and 47.7% in those treated with sintilimab monotherapy. All participants achieved R0 resection. With a median follow-up of 5.7 months, none of the participants experienced disease recurrence.

Dr Andrea Cercek (Memorial Sloan Kettering Cancer Center, NY, USA) presented the results of a phase 2 trial (NCT04165772) evaluating neoadjuvant PD-1 blockade with dostarlimab in patients with locally advanced, dMMR rectal cancer [4]. In total, 42 participants were treated with dostarlimab every 3 weeks for 6 months. All participants achieved a pCR, 24 sustained pCR over 2 years (i.e. until data of cut-off).

In addition, Dr Kai-Keen Shiu (University College Londen, UK) presented results from the phase 2 NEOPRISM-CRC trial (NCT05197322), which showed a pCR in 59% of participants with high-risk MSI-H/dMMR colorectal cancer after 3 courses of neoadjuvant pembrolizumab monotherapy [5]. No participants had relapsed disease at a median follow-up of 9.7 months.

  1. Chalabi M, et al. Ann Oncol 2022;33 (suppl_7): S808-S869.
  2. Chalabi M, et al. N Engl J Med 2024;390:949-1958.
  3. Xu R-H, et al. Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: Results from a randomized, open-labeled, phase Ib study. Abstract 3505, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.
  4. Cercek A, et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. Abstract LBA3512, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.
  5. Shiu K-K, et al. Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer: the multicentre phase 2 NEOPRISM-CRC trial. Abstract LBA3504, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.

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