In an adaptive platform BELLINI study, the researchers demonstrates that neoadjuvant treatment with immune checkpoint inhibitor (ICI) nivolumab, with or without ipilimumab, is a feasible chemotherapy-free regimen for patients with early-stage triple negative breast cancer (TNBC). They showed that nivolumab with or without ipilimumab induces immune activation in the majority of patients and can result in pathological complete response (pCR) and circulating tumour DNA (ctDNA) clearance. Pre-existing inflammatory features such as higher tumour infiltrating lymphocytes (TILs), shorter distances from CD8-positive T-cells to the tumour and higher baseline fractions of tumour specific CD8-positive T-cells were associated with response.
However, the rate of endocrinopathies (40% hypothyroidism and 20% adrenal gland insufficiencies) is a serious concern, especially considering the relatively good prognosis of patients with TNBC with high TILs according to Dr. Marleen Kok of The Netherlands Cancer Institute in Amsterdam, the Netherlands, and colleagues, who presented the results at the ESMO Congress 2024 along with a simultaneous publication on 16 September 2024 in the Nature Medicine.
The authors wrote in the background that adding anti-PD-(L)1 to neoadjuvant chemotherapy has changed the treatment landscape for patients with early-stage (II–III) TNBC; however, all trials evaluating the efficacy of anti-PD-(L)1 in TNBC combined it with chemotherapy. This chemotherapy backbone inevitably results in a high rate of adverse events (AEs), affects quality-of-life, and could diminish T-cell activity.
So far, no biomarkers have been established to predict which patients with early-stage TNBC will benefit from anti-PD1. Treatment is currently given for a total duration of 1 year, although data in other tumour types have shown that a pCR can be reached after only a few weeks of treatment with ICI.
While numerous studies have integrated anti-PD-(L)1 with chemotherapy in early-stage TNBC, data on combination ICIs are limited. ICIs targeting CTLA4 have revolutionised treatment for non-small cell lung cancer and melanoma. Additionally, neoadjuvant trials across various tumour types have shown impressive major pathological response (MPR) rates when combining anti-PD-(L)1 with low-dose anti-CTLA4. A study in metastatic breast cancer revealed long-lasting responses after combining low-dose anti-CTLA4 with anti-PD1, which are infrequently observed with anti-PD-(L)1 alone. These findings provide a rationale to test low-dose anti-CTLA4 in combination with anti-PD-(L)1 in early TNBC.
Simultaneously with the advent of ICI, TILs have emerged as a putative prognostic and predictive biomarker.
The BELLINI is an adaptive platform trial exploring the effect of ICI without chemotherapy starting with window-of-opportunity (WOO) cohorts with a biological endpoint followed by neoadjuvant cohorts with a pCR endpoint. It consists of sequential, single-cohort, phase II studies, where new cohorts can be opened based on signals obtained in previous cohorts.
The first two cohorts evaluated whether 4 weeks of nivolumab (cohort A) or nivolumab and low-dose ipilimumab (cohort B) can lead to immune activation which was primary endpoint. This 4-week regimen was scheduled before the start of regular therapy and therefore the effect of ICI could be assessed independently of chemotherapy. Promising results in cohorts A and B among patients with high TIL levels (≥50%) led to the initiation of cohort C. In cohort C, the study team used a neoadjuvant design with 6 weeks of nivolumab plus low-dose ipilimumab followed by surgery to assess the pCR rate.
In WOO cohorts A and B, the researchers observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients. High levels of TILs correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumour-reactive CD8-positive T-cells, follicular helper T-cells and shorter distances between tumour and CD8-positive T-cells correlated with response. Higher levels of regulatory T-cells after treatment were associated with nonresponse.
Based on these data, the study team opened cohort C for patients with high levels of TILs (≥50%) who received 6 weeks of neoadjuvant anti-PD1 plus anti-CTLA4 followed by surgery with pCR as primary endpoint. Overall, 53% (8 of 15) of patients had a MPR (<10% viable tumour) at resection, with 33% (5 of 15) having a pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II.
Complete and near-complete pathological responses after only 6 weeks of treatment with ICI in patients with high TILs suggest that a subgroup of TNBC could be treated with chemotherapy-free regimens if further research powered for long-term outcome analysis will confirm these results. More research is needed on the optimal selection strategy and treatment regimen, especially in view of the observed high endocrinopathy rate. Grade ≥3 AEs were observed in 17% of patients, as well as a high rate (57%) of immune-mediated endocrinopathies.
The authors commented that it remains unknown whether pCR after immunotherapy has the same prognostic value as pCR after chemotherapy. Therefore, larger trials are needed to validate the pCR rate after short-term ICI alone and to determine whether this results in excellent survival rates, as seen in other cancers.
pCR might not be the optimal endpoint as KEYNOTE-522 and GeparNUEVO have indicated that the benefit of PD1 blockade is not exclusively seen in patients with pCR. Establishing the feasibility of patient inclusion based on TIL opens the door for more immune biomarker-driven trials, which is particularly important in diseases such as TNBC that include both inflamed and non-inflamed tumours. The potential integration of additional inflammation analyses, for example, using IFNG gene expression as well as TILs as suggested by BELLINI data, may optimise patient selection, increase pCR rates for ICI-only approaches and could help treatment personalisation in the future.
In BELLINI, a substantial fraction of patients achieved ctDNA clearance after short-term ICI. Given the strong prognostic value of early ctDNA decrease, as shown by the I-SPY trial, future studies are needed to investigate the feasibility and reliability of TIL-informed patient inclusion and the potential of ctDNA-informed therapy adjustments.
The study costs were supported by Bristol Myers Squibb.
References
- Nederlof I, Isaeva OI, de Graaf M, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial. Nature Medicine; Published online 16 September 2024; DOI: https://doi.org/10.1038/s41591-024-03249-3
- LBA11 – Nederlof I, Rolfes AL, Gielen RC, et al. Neoadjuvant nivolumab/relatlimab or nivolumab/ipilimumab in triple negative breast cancer with high tumor-infiltrating lymphocytes (TILs). Annals of Oncology 2024;35(Suppl 2):S1206.