A phase 2 trial, known as BELLINI, is evaluating the use of short-term neoadjuvant immunotherapy in patients with early-stage triple-negative breast cancer (TNBC). The study investigates the feasibility and efficacy of checkpoint inhibition using nivolumab, both as a monotherapy and in combination with ipilimumab, prior to standard neoadjuvant therapy or surgery. This approach aims to prime the immune system and potentially improve outcomes for TNBC patients, who often face aggressive disease and limited treatment options.
The BELLINI trial is a single-center, non-blinded, non-randomized study conducted at the Netherlands Cancer Institute (NKI). The trial enrolled patients with stage I-III TNBC, with specific cohorts receiving either nivolumab alone (cohort A) or nivolumab plus ipilimumab for 4 (cohort B) or 6 (cohort C) weeks. Regular therapy, consisting of neoadjuvant chemotherapy or primary surgery, started on D29 and onwards. The primary endpoint for cohorts A and B was immune activation, while for cohort C it was pathological complete response (pCR).
Study Design and Patient Population
Eligible patients were at least 18 years old with newly diagnosed, previously untreated TNBC. Key inclusion criteria included confirmation of estrogen receptor (ER) negativity (<10%) and HER2 negativity, a WHO performance status score of 0 or 1, and adequate organ function. A critical factor was the level of tumor-infiltrating lymphocytes (TILs), with patients required to have at least 5% TILs to ensure the exclusion of true immune-deserted tumors. Cohort C specifically targeted patients with clinically node-negative disease and TIL levels of 50% or higher, exploring the potential for chemotherapy de-escalation in this subgroup.
Exclusion criteria encompassed a history of immunodeficiency, autoimmune disease, conditions requiring immunosuppression, active hepatitis B or C infection, clinically overt cardiovascular disease, or previous systemic anticancer treatment.
Treatment Regimens
In cohort A, patients received nivolumab monotherapy at a dose of 240 mg on days 1 and 15. Cohort B received nivolumab plus ipilimumab, with ipilimumab administered at 1 mg/kg on day 1 and nivolumab at 240 mg on day 15. Cohort C had nivolumab + ipilimumab 1 mg kg−1 on D1 and D21.
Key Endpoints and Assessments
The primary endpoint for cohorts A and B was immune activation, defined as a twofold increase in CD8+ T cells assessed via immunohistochemistry and/or an increase in IFNG gene expression. For cohort C, the primary endpoint was pCR, defined as no viable tumor remaining in the breast and lymph nodes (ypT0N0). Secondary endpoints across all cohorts included feasibility, safety, and radiological response, assessed according to RECIST v.1.1 guidelines.
Feasibility was determined based on treatment-related complications leading to delays in chemotherapy or surgery beyond 6 weeks from the start of therapy. Adverse events (AEs) were closely monitored for 100 days after the last study treatment, following the Common Terminology Criteria for Adverse Events (CTCAE) v.5.
Early Findings and Implications
The study's initial findings suggest that short courses of immunotherapy can induce early clinical responses in TNBC, particularly in tumors with high TIL levels. These early responses warrant further investigation into the potential for therapy de-escalation in select patients, contrasting with the current approach of therapy escalation for all TNBC patients.
"The observation that very early responses to ICI without chemotherapy are possible in TNBC, which warrants efforts to de-escalate therapy for a subset of patients, in contrast to the current therapy escalation for all patients with TNBC," the researchers noted.
Further analyses, including comprehensive genomic and transcriptomic profiling, are underway to identify predictive biomarkers and refine patient selection strategies for neoadjuvant immunotherapy in TNBC.
