High TIL levels correlate with good prognosis in early TNBC1,2. In patients with early TNBC, neoadjuvant chemotherapy combined with PDL1- blocking agents has demonstrated an increase in pathologic complete response (pCR) and event-free survival3,4. However, it is not known which TNBC patients 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. Dr Marleen Kok (Netherlands Cancer Institute, the Netherlands) presented the first results of the phase 2 basket trial BELLINI (EudraCT 2018-004188-30), which tests the hypothesis that there is a highly immunogenic subset of TNBC patients and that TIL levels (at baseline) can help to identify this subset of patients4.
BELLINI is a non-randomised window-of-opportunity study with baskets for nivolumab and nivolumab plus ipilimumab. Each basket (n=15) included at least 5 TIL “low” patients (5–10% TIL in the tumour biopsy), 5 TIL “intermediate” patients (11–49% TIL) and 5 TIL “high” patients (≥50% TIL). Stage I–III TNBC patients (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 start of neoadjuvant chemotherapy or surgery. The primary endpoint is immune activation, defined as a 2-fold change in CD8-positive T cells or a 2-fold IFN-γ expression increase after 4 weeks. Secondary endpoints include safety and radiological responses.
At 4 weeks, 3/19 (19%) patients treated with nivolumab and 4/15 (27%) patients treated with nivolumab/ipilimumab showed a partial radiological response. Of these 7 responders, 3 were TIL “high” and 4 were TIL “intermediate”. All responders had TIL >40%. No responses were observed in TIL “low” patients. Most biopsies of patients with a partial radiological response were free from tumour cells, so pCR, after 4 weeks. A 2-fold increase of CD8-positive T cells was observed in 53.3% of nivolumab-treated patients and 60% of nivolumab/ipilimumab-treated patients, so both cohorts met the primary endpoint, which allows 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 tumour cells in responders, P=0.0014). In addition, in all patients who showed a partial response on MRI, circulating tumour DNA (ctDNA) at 4 weeks was either cleared or <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.