Results from the NICHE study show remarkable pathological response to neoadjuvant combination immunotherapy in patients with early colon cancer and mismatch repair deficient (dMMR) tumours. The study team also observed pathological responses in some cases with MMR proficient (pMMR) tumours. The findings are published by Myriam Chalabi and colleagues of the Netherlands Cancer Institute in Amsterdam, The Netherlands on 6 April 2020 in the Nature Medicine.
The authors wrote in the study background that combination of PD-1 and CTLA-4 immune checkpoints inhibitors is highly effective in patients with advanced dMMR colorectal cancer. However, the same regimens have shown poor response rates in patients with metastatic pMMR colorectal cancer. Such differential outcome has been attributed to the higher mutational burden of dMMR tumours, giving rise to more neoantigens.
As a possible result of higher neoantigen burden, dMMR tumours are also characterised by an increased density of intratumoral T cells. In several tumour types an increased T cell infiltration has been shown to increase the probability of response to immune checkpoint inhibitors, although there is no data available in colon cancer.
Recent studies in early stage melanoma, lung cancer and bladder cancer have shown high rate and deep pathological responses to neoadjuvant immune checkpoint inhibitors. The higher response rates in early disease compared with metastatic setting have been attributed to a difference in T cell infiltration, a lower degree of systemic immune suppression, absence of visceral metastases and a lower tumour burden.
In early stage pMMR colon cancer, a substantial proportion of tumours has a high T cell infiltration compared with metastatic pMMR colon cancer. This fact prompted Dutch investigators to investigate the activity of neoadjuvant immune checkpoint blockade in both, dMMR and pMMR early colon cancer.
Based on preclinical data and observation that majority of patients with metastatic pMMR colorectal cancer do not derive benefit from immune checkpoint inhibitors, the study team combined immune checkpoint blockade with the cyclooxygenase (COX)-2 inhibitor celecoxib.
The authors hypothesised a higher efficacy of neoadjuvant immunotherapy in patients with early stage colon cancer than in metastatic setting. In their exploratory NICHE study, patients with dMMR or pMMR tumours received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib.
The primary objective was safety and feasibility. In total, 40 patients with 21 dMMR and 20 pMMR tumours were treated, and 3 patients received nivolumab monotherapy in the safety run-in.
The treatment was well tolerated and all patients underwent radical resections without delay, thus meeting the study primary endpoint.
Among the patients who received ipilimumab plus nivolumab (20 dMMR and 15 pMMR tumours), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20 of 20 dMMR tumours (100%; 95% exact confidence interval [CI] 86–100%), with 19 major pathological responses (MPRs), defined as at least 10% residual viable tumour and 12 pathological complete responses.
In patients with pMMR tumours, 4 of 15 patients (27%; 95% exact CI 8–55%) showed pathological responses, with 3 MPRs and 1 partial response.
The investigators found that CD8-positive, PD-1-positive T cell infiltration was predictive of response in pMMR tumours.
The authors wrote that these results should be validated in larger studies with at least 3 years of disease-free survival data before neoadjuvant immunotherapy could be considered as a standard of care for a defined group of patients with early colon cancer.
The RNA- and DNA-sequencing data will be deposited into the European Genome–Phenome Archive under accession no. EGAS00001004160 and will be made available on reasonable request for academic use and within the limitations of the provided informed consent. Every request will be reviewed by the institutional review board of the Netherlands Cancer Institute. The TCR-sequencing data that support the findings of the study are available from Adaptive Biotechnologies. Restrictions apply to the availability of these data.
The study was funded by the BMS International Immuno-Oncology Network and sponsored by the Netherlands Cancer Institute. The funding source had no role in design and execution of the study, data analysis or writing of the manuscript.
Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nature Medicine 2020; 26:566-576.