A short neoadjuvant regimen of nivolumab/relatlimab is highly effective in patients with locally advanced mismatch repair (MMR)-deficient colon cancer, resulting in a pathologic response rate of 97% and a pathologic complete response (pCR) rate of 68%.
NICHE-3 is the first study to report on the efficacy of neoadjuvant PD1 plus LAG3 inhibition in patients with colorectal cancer, demonstrating robust antitumour activity according to Dr. Myriam Chalabi of the Netherlands Cancer Institute in Amsterdam, The Netherlands and colleagues who presented the findings at the ESMO Congress 2024 along with a simultaneous publication on 15 September 2024 in the Nature Medicine.
The authors wrote in the background that MMR deficiency is found in approximately 15% of non-metastatic colon cancers and is characterised by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumours. Although patients with MMR-deficient colon cancer have limited benefit from chemotherapy, these tumours have been shown to respond exceptionally well to neoadjuvant anti-PD1 plus anti-CTLA4 therapy, with high rates of pathologic responses.
Recent data from the NICHE-2 study, in which patients with locally advanced MMR-deficient colon cancer were treated with neoadjuvant nivolumab/ipilimumab, demonstrated an exceptional pathologic response rate of 98% in 111 patients, including a pCR rate of 68% and no recurrences at median follow-up of 26 months.
Several smaller studies provided further evidence in support of neoadjuvant immune checkpoint blockade for patients with MMR-deficient colorectal cancer, as demonstrated by high pathologic and clinical complete response rates. Conversely, the FOxTROT study showed a pathologic response rate of only 7% in MMR-deficient tumours after neoadjuvant chemotherapy.
In melanoma, efficacy of nivolumab/relatlimab has been shown in both advanced and early-stage disease, in addition to a favourable toxicity profile compared to studies with other combination regimens. In MMR-deficient colon cancer, previous studies showed a high expression of LAG3 in tumour infiltrating lymphocytes. Based on these data, the NICHE-3 investigators hypothesised a high efficacy profile and potentially improved safety profile of neoadjuvant nivolumab/relatlimab in patients with MMR-deficient locally advanced resectable colon cancer.
In the NICHE-3 study, patients were treated with a short regimen of two cycles of nivolumab 480 mg plus relatlimab 480 mg on day 1 and day 29, followed by surgery within 8 weeks of enrolment. The primary endpoint was pathologic response; it was defined as ≤50% residual viable tumour (RVT). The study would be considered successful if a pathologic response was observed in at least 47 out of 59 patients.
Secondary endpoints included safety, major pathologic response (MPR; ≤10% RVT) and pCR (0% RVT) as well as disease-free survival (DFS) and overall survival. Additional planned secondary endpoints not reported in the article are circulating tumour DNA (ctDNA), transcriptomics and genomics analyses, as well as radiographic and metabolic response assessment.
Pathologic response was observed in 57 of 59 patients (97%; 95% confidence interval [CI] 88–100%), meeting the study primary endpoint. Responses included 54 (92%; 95% CI 81–97%) MPRs and 40 (68%; 95% CI 54–79%) pCRs. With a median follow-up of 8 months (range, 2–19), one patient had recurrence of disease.
Although pCR was observed across tumour stages, patients with cT4 tumours and/or higher CEA levels at baseline had a numerically lower pCR rate, suggesting a possible relation between tumour burden and pathologic response. Although speculative, the high rates of MPR observed also hint toward a possible dynamic effect and that a longer time to surgery may have led to a higher pCR rate in more advanced tumours.
The treatment had an acceptable safety profile, with all-grade and grade 3–4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). irAEs profile in the current study suggest a higher rate of thyroid dysfunction, adrenal insufficiency and colitis compared to the nivolumab/ipilimumab regimen in the NICHE-2, as well as in previous studies with nivolumab/relatlimab. This may, at least in part, be related to the higher dose of relatlimab at 480 mg compared to previous studies using 80 mg or 160 mg.
Future cohorts within the NICHE platform are currently underway and will include alternative treatment schedules of nivolumab/relatlimab with the aim of decreasing irAEs while maintaining similar efficacy. Data emerging from these studies will inform the design of a large international study testing nivolumab/relatlimab in patients with locally advanced MMR-deficient colon cancer.
The authors concluded that NICHE-3 findings add to the compelling body of evidence in support of neoadjuvant immune checkpoint blockade for MMR-deficient colon cancer, with responses to mono and dual immunotherapy regimens all vastly exceeding the pathologic responses observed after neoadjuvant chemotherapy.
They commented that at present, pathologic response after neoadjuvant treatment is not yet an accepted surrogate endpoint for colon cancer, unlike the situation in other tumour types, such as triple-negative breast cancer. The NICHE-2 is the first study in MMR-deficient colon cancer to provide correlative data on pathologic response to neoadjuvant immunotherapy and the widely accepted endpoint of 3-year DFS.
At the ESMO Congress 2024, Dr. Chalabi and colleagues showed a 100% 3-year DFS in patients with MMR-deficient colon cancer treated with one dose of ipilimumab and two doses of nivolumab prior to surgery in the NICHE-2 study. The survival data are also supported by negative ctDNA at the minimal residual disease timepoint in all patients, while on-treatment ctDNA dynamics provide an additional monitoring instrument for future trials on organ preservation for patients with MMR-deficient colon cancer.
The NICHE-3 and NICHE-2 studies were funded by Bristol Myers Squibb and sponsored by the Netherlands Cancer Institute.
References
- de Gooyer PGM, Verschoor YL, van den Dungen LDW, et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nature Medicine; Published online 15 September 2024. DOI: https://doi.org/10.1038/s41591-024-03250-w
- 503O - de Gooyer PGM, Verschoor YL, van den Dungen LDW, et al. Neoadjuvant nivolumab (nivo) plus relatlimab (rela) in MMR-deficient colon cancer: Results of the NICHE-3 study. Annals of Oncology 2024;35(Suppl 2):S428-429.
- LBA24 – Chalabi M, van den Dungen LDW, Verschoor YL, et al. Neoadjuvant immunotherapy in locally advanced MMR-deficient colon cancer: 3-year disease-free survival from NICHE-2. Annals of Oncology 2024;35(Suppl 2):S1217-1218.