Tumour infiltrating lymphocytes identify patients with immunogenic triple-negative breast cancer

Patients with triple-negative breast cancer (TNBC) and more than 40% tumour-infiltrating lymphocytes (TIL) responded well to neoadjuvant immune checkpoint blockade, results from the phase 2 BELLINI trial showed.

High TIL levels correlate with a good prognosis in early TNBC [1,2]. In patients with early TNBC, the combination of neoadjuvant chemotherapy with PD immune checkpoint-blocking agents increased the pathological complete response (pCR) and event-free survival [3,4]. However, it is not known which TNBC patients specifically benefit from neoadjuvant PD1 inhibition, for which patients’ neoadjuvant chemotherapy can be de-escalated, or whether there is an additional value of other (new generation) immune checkpoint inhibitors. Prof. Marleen Kok (Netherlands Cancer Institute, the Netherlands) presented the first stage I findings of the phase 2 basket trial BELLINI (EudraCT 2018-004188-30) testing the hypothesis that there is a subset of TNBC patients with highly immunogenic tumours and that TIL levels (at baseline) can help identify this subset [4].

BELLINI is a non-randomised window-of-opportunity study with baskets for nivolumab and nivolumab plus ipilimumab. Each basket included at least 15 participants with stage I–III TNBC (T1c–T3, N^–/N⁺, TIL ≥5%), divided into 3 TIL categories (at least 5 participants per category): TIL-low (5–10% TIL), TIL- intermediate (11–49% TIL) and TIL-high (≥50% TIL). Participants were treated with nivolumab (2 cycles, n=16) or nivolumab/ipilimumab (2 cycles nivolumab, 1 cycle ipilimumab, n=15) before the start of neoadjuvant chemotherapy or surgery. The primary endpoint was immune activation, defined as a 2-fold change in CD8-positive T cells or a 2-fold increase in IFN-γ expression after 4 weeks. The secondary endpoints included safety and radiological responses.

At 4 weeks, 3/19 (19%) participants treated with nivolumab and 4/15 (27%) participants 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 >40% TIL. No responses were observed in TIL-low participants. Most biopsies of patients with a partial radiological response were free from tumour cells, illustrating pCR, after 4 weeks. A 2-fold increase of CD8-positive T cells was observed in 53.3% of nivolumab-treated participants and 60% of nivolumab/ipilimumab-receiving participants. Both cohorts met the primary endpoint, encouraging the progression to stage II of the trial.

Radiological responders and non-responders were discriminated by a significant difference in both the levels 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). For all patients showing a partial response on MRI, circulating tumour DNA at 4 weeks was either cleared or <50% of baseline measurements.

“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 Prof. Kok.

1. Loi S, et al. J Clin Oncol. 2019;37(7):559–569.
2. De Jong VMT, et al. J Clin Oncol. 2022;40(21):2361–2374.
3. Mittendorf EA, et al. Lancet. 2020;396(10257):1090–1100.
4. Schmid P, et al. N Engl J Med. 2022;386(6):556–567.
5. Nederlof I, et al. Nivolumab and ipilimumab in early-stage triple-negative breast cancer (TNBC) with tumour-infiltrating lymphocytes (TILs): First results from the BELLINI trial. Abstract LBA13, ESMO Congress 2022, 09–13 September, Paris, France.

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Posted on 16 November 202225 March 2024