Patients with triple-negative breast cancer (TNBC) who harbor more than 40% tumor-infiltrating lymphocytes in their tumor respond well to neoadjuvant immune checkpoint blockade, results from the phase 2 BELLINI trial show.


High tumor-infiltrating lymphocyte (TIL) levels correlate with good prognosis in early triple-negative breast cancer (TNBC). In patients with early TNBC, neoadjuvant chemotherapy combined with PDL1- blocking agents have demonstrated an increase in pathologic complete response (pCR) and event-free survival. However, it is not known which patients with TNBC benefit from neoadjuvant anti-PD1 treatment, for which patients neoadjuvant chemotherapy can be de-escalated, nor what the additional value is from other (new generation) immune checkpoint inhibitors. At ESMO 2022, Dr. Marleen Kok (Netherlands Cancer Institute) presented the first results of the phase 2 basket trial BELLINI, which tested the hypothesis that there is a highly immunogenic subset of patients with TNBC and that TIL levels (at baseline) can help identify them.

BELLINI was a non-randomized, window-of-opportunity study with groups for nivolumab and nivolumab plus ipilimumab. Each group (N=15) included at least five TIL “low” patients (5% to 10% TIL in the tumor biopsy), five TIL “intermediate” patients (11% to 49% TIL) and five TIL “high” patients (≥50% TIL). Patients with stage I–III TNBC (T1c–T3, N/N+, TIL ≥5%) were treated with nivolumab (2 cycles, N=16) or nivolumab/ipilimumab (2 cycles nivolumab, 1 cycle ipilimumab, N=15) before surgery or starting neoadjuvant chemotherapy. The primary endpoint was immune activation, defined as a two-fold change in CD8-positive T cells or a two-fold IFN-γ expression increase after 4 weeks. Secondary endpoints included safety and radiological responses.

At 4 weeks, 19% of patients treated with nivolumab and 27% treated with nivolumab/ipilimumab showed a partial radiological response. Of these responders, three were TIL “high” and four were TIL “intermediate.” All responders had TIL greater than 40%. No responses were observed in TIL “low” patients. Most biopsies of patients with a partial radiological response were free from tumor cells, indicating pCR, after 4 weeks. A two-fold increase of CD8-positive T cells was observed in 53.3% of nivolumab-treated patients and 60.0% of nivolumab/ipilimumab-treated patients, meaning both cohorts met the primary endpoint, allowing expansion to stage II of the trial.

Radiological responders and non-responders were clearly discriminated by a significant difference in both level of IFN-γ expression (higher in responders, P=0.014) and spatial distribution of CD8-positive T cells (closer to tumor cells in responders, P=0.0014). In all patients who showed a partial response on MRI, circulating tumor DNA at 4 weeks was either cleared or less than 50% of baseline.

“The majority of TNBC patients with TIL showed increased immune activation after only 4 weeks of immune checkpoint blockade and a substantial fraction of these patients experienced a clinical response, highlighting the potential of immune checkpoint blockade without chemotherapy for TNBC patients,” concluded Dr. Kok.

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