Abstract PD14-06: Dynamic changes of PD-L1 and T-cell activation in ECLIPSE: A phase II study investigating preoperative immune combination strategies in untreated, operable ER+ primary breast cancer
Authors: Schmid Peter , Kockx Mark , Kim Sung-Bae , Wheatley Duncan , Phillips Melissa Mary , Hoffmann Oliver , Blohmer Jens U. , Im Seock-Ah , Schneeweiss Andreas , Zamora Esther , Waumans Yannick , Van Dam Pieter-Jan , Peeters Dieter , Wimalasingham Akhila , Marosics Patricia , Prendergast Aaron , Mousa Kelly , Cortes Javier , Kuemmel Sherko 
Published: February 2021

Background: Whilst Atezolizumab + nab-paclitaxel is the new standard of care in patients with PD-L1+ metastatic triple negative breast cancer (BC), the role of immunotherapy in ER+ BC has yet to be defined. ECLIPSE, an open label, phase II trial, aims to evaluate the effect of short-term pre-operative immune-modulatory agent combinations on ER+ tumour immune-phenotypes (NCT03395899). Here, we examined the first results of the dynamic changes of PD-L1 expression (≥1% positive immune cell by VENTANA PD-L1 SP142 IHC) and T-cell expansion and activation after 1 cycle of atezolizumab alone or in combination with AKT, MEK or VEGF inhibitors.

Methods: Patients with histologically confirmed, untreated, operable ER+/HER2- primary BC received 1 cycle of atezolizumab alone or atezolizumab + ipatasertib, atezolizumab + cobimetinib, or atezolizumab + cobimetinib + bevacizumab 3 weeks prior to surgery or neoadjuvant therapy. Biopsies were obtained pre and on completion of study treatment. Dynamic changes in biomarkers were compared in 48 evaluable patients, including 41 paired samples.

Results: PD-L1 IC expression significantly increased after 1 cycle of treatment (p &lt; 0.0001). At a 1% IC cutoff, 21/45 patients (47%) were PD-L1 IC-positive (+) at baseline while 34/44 (77%) were PD-L1 IC + post-treatment. Increased tumour cell expression was also found in post-treatment samples (p &lt; 0.01). All post-treatment PD-L1 negative patients (n = 9) were also negative at baseline. Overall, there was a small but significant increase in CD8 + T-cells post-treatment compared to baseline (p = 0.03). In parallel, the number of T-cells that were positive for both CD8 and granzyme B (GZMB) - a T-cell activation marker - increased substantially (p &lt; 0.01). Single GZMB+ cells and single FOXP3+ cells did not change with treatment. In 2 cases, no tumour was detected post-treatment, suggesting a major pathological response. Baseline biopsies of both patients stood out as having the largest amount of CD8+GZMB+ T-cells. Post-treatment tumour bed profiling of these patients showed major infiltration of CD8+ and CD8+GZMB+ T-cells. Dynamic gene expression analysis showed upregulation of genes related to innate immunity and a cytotoxic T-cell transcriptional signature (tGE8), (p &lt; 0.001). Patients were grouped as immune-responsive or non-responsive based on a dynamic increase of CD8+GZMB+ cells. The immune-response group was characterized by increased IFN response signatures and decreased luminal gene signatures at baseline.

Conclusions: Our data indicate that short-term induction treatment with atezolizumab ± targeted treatments induce dynamic changes toward inflamed immune phenotypes both at the morphological and transcriptional level, in patients with operable ER+/HER2- primary BC. These findings might help identify novel immunotherapy combination strategies in this setting, alongside the most appropriate biomarkers that can aid in identifying patients most likely to benefit from these treatments.

Citation Format: Peter Schmid, Mark Kockx, Sung-Bae Kim, Duncan Wheatley, Melissa Mary Phillips, Oliver Hoffmann, Jens U. Blohmer, Seock-Ah Im, Andreas Schneeweiss, Esther Zamora, Yannick Waumans, Pieter-Jan Van Dam, Dieter Peeters, Akhila Wimalasingham, Patricia Marosics, Aaron Prendergast, Kelly Mousa, Javier Cortes, Sherko Kuemmel. Dynamic changes of PD-L1 and T-cell activation in ECLIPSE: A phase II study investigating preoperative immune combination strategies in untreated, operable ER+ primary breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-06.