PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial

Abstract

Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.

Neoadjuvant immune checkpoint blockade triggers persistent and systemic T reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors

“…Strikingly, T reg frequency in the circulation increased from baseline to the on-nivolumab timepoint ( Figure 1L ). To assess whether intratumoral T reg infiltration may also be affected by immunotherapy in breast cancer patients, we examined FOXP3 gene expression in sequential tumor biopsies obtained in the GELATO trial 44 . Sequential tumor biopsies were taken from metastatic lesions before start of treatment (baseline), after two cycles of low-dose carboplatin as induction treatment (post-induction), and after two cycles of atezolizumab/anti-PD-L1 and continued carboplatin (on-atezolizumab) in patients with metastatic ILC (mILC).…”

“…The clinical data used in the study were kindly provided by the investigators of the GELATO and TONIC trials in the Netherlands Cancer Institute. Clinical trial procedures were performed as described in their respective publications 2 , 44 . Briefly, the TONIC trial evaluated the efficacy of nivolumab (anti-PD-1) after a two-week induction therapy with low-dose chemotherapy or irradiation in patients with metastatic triple-negative breast cancer.…”

“…Sequential tumor biopsies from a metastatic lesion were taken before start treatment (baseline), after two weeks of carboplatin treatment (post-induction), and after two cycles of anti-PD-L1 (on-atezolizumab). Flow cytometry analysis of fresh blood samples was performed as previously described 2 , 44 . The clinical studies were approved by the medical-ethical committee of the NKI and conducted in accordance with ICH Harmonized Tripartite Guideline for Good Clinical Practice and the principles of the Declaration of Helsinki.…”

Reporting on invasive lobular breast cancer in clinical trials: a systematic review

“…A higher clinical benefit rate (61.5% vs 18.2%) of neratinib was described for patients with ILC in comparison to patients with IBC-NST. The use of atezolizumab for patients with ILC was investigated in the GELATO trial 50 , which was terminated prematurely due to short-lived treatment responses. The responses they observed were mostly in patients with triple-negative ILC.…”

Tumor Mutational Burden in Breast Cancer: Current Evidence, Challenges, and Opportunities

“…In terms of histology, it has been consistently shown that the prevalence of hypermutated tumors is significantly higher among metastatic invasive lobular carcinomas compared to metastatic invasive ductal carcinomas (17.0% versus 7.8%) [19,20], which raises the question of whether a subgroup of those tumors could be treated with immunotherapybased regimens. Recently, the GELATO trial investigated the role of weekly carboplatin as immune induction plus atezolizumab exclusively in patients with metastatic invasive lobular carcinoma [21]. Although the trial met its primary endpoint, with four partial responses out of 23 patients, only one out of 23 patients had a TMB ≥ 9 mut/Mb; therefore, further studies are needed to address this question specifically in patient populations with high TMB.…”