A phase 2 adaptive trial has demonstrated promising results for neoadjuvant immunotherapy without chemotherapy in early-stage triple-negative breast cancer (TNBC). The BELLINI trial, conducted at the Netherlands Cancer Institute, explored the use of the PD-1 inhibitor nivolumab alone or in combination with the CTLA-4 inhibitor ipilimumab in patients with TNBC. The study was funded by Bristol Myers Squibb and published in November 2024 in Nature Medicine.
The purpose of the study was to evaluate whether short-term immune checkpoint inhibition could induce immune activation and potentially pathological responses in early TNBC without concurrent chemotherapy. This approach aimed to explore options for chemotherapy de-escalation in select patients.
The trial enrolled a total of 46 patients across three cohorts. Cohorts A and B included 31 patients with stage I-III TNBC and ≥5% tumor-infiltrating lymphocytes (TILs). Cohort A received 4 weeks of nivolumab monotherapy, while cohort B received 4 weeks of nivolumab plus ipilimumab. Cohort C enrolled 15 patients with stage I-II node-negative TNBC and ≥50% TILs, who received 6 weeks of nivolumab plus ipilimumab.
Key inclusion criteria were newly diagnosed, previously untreated TNBC with estrogen receptor expression <10% and HER2-negative status. Patients were required to have adequate organ function and an ECOG performance status of 0-1. Exclusion criteria included a history of autoimmune disease, immunodeficiency, or conditions requiring immunosuppression.
The median age of participants was approximately 50 years. Most patients had T1-T2 tumors, with cohort C restricted to node-negative disease. About 20-25% of patients carried germline BRCA1/2 mutations.
In cohorts A and B, immune activation (defined as a ≥2-fold increase in CD8+ T cells or IFNG expression) was achieved in 53% and 60% of patients, respectively. Clinical responses were observed in 38.7% of patients. Notably, all clinical responses occurred in patients with ≥30% TILs and PD-L1 combined positive score ≥20%.
In cohort C, which focused on patients with high TILs, 33.3% of patients achieved a pathological complete response (pCR) and 53% had a major pathological response (≤10% residual viable tumor). This pCR rate is notable considering the short 6-week treatment duration without chemotherapy, compared to standard 5-month chemo-immunotherapy regimens that typically yield 63% pCR rates.
Translational analyses revealed that clinical responders had higher pretreatment levels of TILs, PD-L1 expression, and inflammatory gene signatures. Single-cell RNA sequencing demonstrated that responders had higher fractions of tumor-specific CD8+ T cells and follicular helper T cells before treatment. Conversely, non-responders showed increased regulatory T cells after treatment, suggesting a potential mechanism of resistance.
Circulating tumor DNA (ctDNA) analysis showed that all clinical responders in cohorts A and B and patients with pCR/major pathological response in cohort C had at least a 50% drop in ctDNA or were negative at baseline. This supports the potential use of ctDNA as a biomarker for early response assessment.
The safety profile was generally manageable, with grade ≥3 treatment-related adverse events occurring in 17% of patients. However, there was a notably high rate of immune-related endocrinopathies, with 41% of patients developing hypothyroidism and 13% experiencing adrenal insufficiency. These rates were higher than typically observed in similar immunotherapy trials for other cancer types.
The study has several limitations. As a small phase 2 trial, it was not powered to assess long-term outcomes. The follow-up period was relatively short, with a median of 32.5 months for cohorts A and B and 17.6 months for cohort C. Additionally, the non-randomized design and lack of a control arm limit direct comparisons to standard chemo-immunotherapy approaches.
The authors conclude that neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy in early TNBC, particularly in patients with high TILs. They suggest that this approach warrants further investigation as a potential de-escalation strategy for select patients.
The potential clinical impact of this study is significant. It provides early evidence that some patients with TNBC may achieve meaningful responses to short-term immunotherapy alone, potentially sparing them from the toxicities of chemotherapy. The identification of pretreatment biomarkers associated with response, such as high TILs and inflammatory gene signatures, could help guide patient selection for this approach in future studies.
However, the high rate of endocrinopathies observed is a concern that requires careful consideration, especially given the relatively good prognosis of patients with high-TIL TNBC. Future studies will need to weigh the potential benefits of chemotherapy de-escalation against the risk of long-term endocrine complications.
This trial also highlights the potential of adaptive platform designs in efficiently exploring novel treatment strategies. The ability to open new cohorts based on signals from previous cohorts allowed for rapid iteration and exploration of promising approaches.
In conclusion, while these results are promising, larger randomized trials with longer follow-up will be necessary to definitively establish the role of chemotherapy-free immunotherapy regimens in early TNBC. Ongoing and planned studies, including some using TILs as inclusion criteria, will help further elucidate the optimal patient population and treatment approach for this strategy.
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. Nat Med. 2024;30(11):3223-3235. doi:10.1038/s41591-024-03249-3
