Biomarker analysis of phase II pembrolizumab maintenance treatment after chemotherapy response in patients with HER2-negative inflammatory breast cancer and triple-negative breast cancer.
Authors: Iwase Toshiaki , Alexander Angela , Cohen Evan N. , Gao Hui , Chiv Vivian Y , Kai Megumi , Kida Kumiko , Krishnamurthy Savitri , Liu Dianne , Shen Yu , Ramirez David Luis , Reuben Alexandre , Tripathy Debu , Booser Daniel J. , Moulder Stacy L. , Yam Clinton , Valero Vicente , Lim Bora , Reuben James M. , Ueno Naoto T. 
Published: June 2023

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Background: Accumulating toxicities make indefinite chemotherapy unfeasible for many patients with metastatic/recurrent HER2-negative inflammatory breast cancer (IBC) or triple-negative breast cancer (TNBC). We conducted a single-arm phase II trial of pembrolizumab monotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative aggressive breast cancer and to identify biomarkers correlated with disease control. Methods: The study enrolled patients who had a complete response, partial response, or stable disease after a minimum of 3 cycles of chemotherapy for metastatic TNBC/IBC regardless of PD-L1 expression between 2015 and 2022. Pembrolizumab was administered at 200 mg every 3 weeks until disease progression, intolerable toxicity, or 2 years of exposure to the drug. The primary endpoint was the 4-month disease control rate (DCR), and the secondary endpoint was progression-free survival (PFS). Correlative studies were performed to determine associations between clinical response, and immune profiling consisting of T-cell clonality, immunophenotyping, and dendritic cell (DC) function with blood collected at baseline and after 2 cycles of pembrolizumab treatment. Results: Of 43 treated patients, 11 had metastatic IBC and 32 had TNBC. The median number of prior lines of chemotherapy for metastatic disease was 1. During a median follow-up of 11.4 months, 33 patients had progressive disease and 25 were deceased. The 4-month DCR was 58.1% (95% CI: 43.4%-72.9%) and the median PFS was 4.8 months (95% CI: 3.0-7.1 months). The median PFS of the metastatic IBC group (2.2 months) and TNBC group (4.8 months) did not differ significantly ( p = .12). Thirty-one patients discontinued treatment due to progressive disease rather than toxicity. Observed toxicities were consistent with the known profile of pembrolizumab. Correlative blood studies showed availability of PD-1 on CD8 T cells decreased on therapy. T-cell exhaustion markers 2B4, CTLA4, and TIM3 decreased in patients who had therapeutic benefit, while LAG3 increased in patients without benefit. During therapy, ex vivo cytokine synthesis (IL-6/IL-12/TNFα) by DCs was superior in patients who benefited from therapy and increased from pretreatment samples. High T-cell clonality at baseline predicted response to immunotherapy (10.4 vs 3.6 months, p = .04). Additionally, patients exhibiting the greatest clinical benefit also had a significant increase in T-cell clonality over the course of therapy (20% vs 5.9% mean increase, p = .04). Conclusions: Increased T-cell clonality and DC activity, along with reductions in T-cell exhaustion, were associated with prolonged disease control following pembrolizumab maintenance therapy, achieving acceptable disease control with manageable toxicity. Clinical trial information: NCT02411656 .