TILs identify patients with immunogenic triple-negative breast cancer

Patients with TNBC with over 40% Tumour Infiltrating Lymphocytes in their tumour, respond well on neoadjuvant immune checkpoint blockade.

The BELLINI trial tested if TIL levels could spot a highly immunogenic subset of TNBC patients

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. 

A majority of patients with TIL showed increased immune activation after only 4 weeks

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.

  1. Loi S, et al. J Clin Oncol. 2019;37:559–569.
  2. De Jong VMT, et al. J Clin Oncol. 2022;40:2361–2374.
  3. Mittendorf EA, et al. Lancet 2020;396:1090–1100.
  4. Schmid P, et al. N Engl J Med 2022;386:556–567.
  5. Nederlof I, et al. Nivolumab and ipilimumab in early-stage triple negative breast cancer (TNBC) with tumor-infiltrating lymphocytes (TILs): First results from the BELLINI trial. Abstract LBA13, ESMO Congress 2022, Paris, France, 09–13 September.