Abstract: Checkpoint immunotherapy is emerging as a new therapeutic approach for metastatic breast cancer. Monotherapy of immunoagents against PD1/PD-L1 or CTLA-4 has shown little efficacy in these patients. Recently, to determine the optimal use of immunotherapy, there has been a rapid expansion in the number of clinical trials developing immunotherapy combinations. These combination therapeutic approaches can enhance various aspects of cancer immunity, such as tumor antigenicity or intratumor T cell infiltration, which provides a theoretical basis for combining them with checkpoint immunotherapy to achieve synergistic effects. Here, we review the available data and ongoing efforts to establish the safety and efficacy of immunoagents in combination with chemotherapy, radiotherapy, HER2-targeted therapy, CDK4/6 inhibitors, PARP inhibitors, and another checkpoint immunoagents.

Keywords: immunotherapy, breast, cancer, combination


Immune checkpoints are a set of inhibitory pathways that maintain a suppressive level of the immune system. Immunotherapy, which is mainly based on immune checkpoint therapeutic targets, is revolutionizing the treatment of malignancies.1,2 Breast cancer remains the most frequent malignancies and causes the second most common cause of cancer death in women. Despite advances in early diagnosis and treatment and a 38% reduction in breast cancer-related deaths, a large number of patients eventually progress to metastatic disease.3–5 There is an urgent need for innovative approaches to treat metastatic breast cancer. Recently, preclinical and clinical data support the key role of immunotherapy in breast cancer.6 However, monotherapy of immunoagents is beneficial to less than 10% of patients with metastatic disease.7 Recent research has focused on the development of immunotherapy combinations in determining the optimal use of immunotherapy. In this review, we discuss advances in combined strategies for breast cancer to maximize its clinical effectiveness.

Clinical Progress in Breast Cancer Immunotherapy

Anti-PD-1/PD-L1 in Breast Cancer

The PD1 (Programmed Cell Death Protein 1) pathway delivers inhibitory signals that function as a brake for immune response. PD1 acts as an inhibitory immune checkpoint receptor and is expressed in mature T cells, B cells, professional APCs, and natural killer cells. Through interactions with PD-L1 on tumor cells and immune cells, PD1 signaling counters T-cell activation by inhibiting kinases involved in T cell activation.8 Also, PD1 engagement inhibits TCR termination signals, and modifies the duration of T cells with APCs or target cells, thereby contributing to immune tolerance.9 Besides, PD-1 is highly expressed on Treg cells. In the presence of a ligand, PD-1 enhances Treg cell proliferation.9,10 Blocking PD-1/PD-L1 signaling can restore immune surveillance and antitumor activity. Multiple agents that inhibit the PD-1/PD-L1 axis has been approved by the US FDA in malignancies.9

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Pembrolizumab (formerly lambrolizumab, trade name Keytruda) is a humanized antibody used in cancer immunotherapy. Lambrolizumab is a humanized monoclonal IgG4-kappa isotype antibody that targets the programmed cell death 1 (PD-1) receptor expressed by T cells. The antibody is designed to block the negative immunoregulatory signaling of the receptor, thereby activating immune responses to cancer. It has been approved for the treatment in metastatic melanoma.11 TNBC (Triple-negative breast cancer, TNBC) is a heterogeneous disease with aggressive tumor pathology. By analyzing gene expression (GE) profiles from 21 breast cancer datasets, Lehmann et al identified 6 TNBC subtypes displaying unique GE and ontologies, including a basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. The IM subtype enriches gene ontologies in immune signaling processes.12,13 These processes include immune cell signaling, cytokine signaling, antigen processing and presentation, and signaling through core immune signal transduction pathways. In addition, TNBC generally has a higher expression of PD-L1 compared with other breast cancer subtypes.14 The Phase Ib KEYNOTE-012 (NCT02447003) study evaluated the safety and antitumor activity of single-agent pembrolizumab in patients with PD-L1-positive metastatic TNBC. Thirty-two patients with PD-L1-positive TNBC were enrolled and received pembrolizumab 10mg/kg intravenously every 2 weeks. Most patients are heavily pretreated. The primary endpoint was overall response rate (ORR). Among the 27 patients evaluable for efficacy, the ORR was 18.5%, including 1 complete response (CR), 4 partial response (PR), and 7 stable disease (SD). The median duration of response (DOR) was not yet reached. Treatment was tolerable. This study provides preliminary evidence of clinical benefits and acceptable safety of pembrolizumab in heavily pretreated metastatic TNBC.15 The long-lasting responses were reported with median overall survival (OS) of 10.2 months (95% CI, 5.3–17.5) and 12-month OS rate of 41.1%.16 The KEYNOTE-086 (NCT02447003) study investigated the efficacy and safety of single-agent pembrolizumab as a second or later line of treatment in a large group of patients with previously treated metastatic TNBC. 170 patients were enrolled, of which 61.8% had PD-L1 expression. The primary endpoint was ORR. The median follow-up was 10.9 months. The ORR (95%) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1-positive population. DCR was 7.6% (95% CI, 4.4–12.7) and 9.5% (95% CI, 5.1–16.8), respectively. Median duration of response was not reached in both groups. Median OS was 9 months (95% CI, 7.7–11.2). Toxicity was manageable. Overall, single-agent pembrolizumab displayed durable efficacy in patients with previously treated metastatic TNBC.17

The KEYNOTE-119 (NVT02555657) study is a Phase 3 randomized trial evaluating pembrolizumab monotherapy compared to single-agent chemotherapy of the physician’s choice in the second- or third-line treatment of patients with metastatic TNBC.18 Outcomes were stratified by PD-L1 tumor status as measured by combined positive score (CPS). The primary endpoint was OS. Overall, 309 patients participated in the pembrolizumab treatment group. 292 patients were enrolled in chemotherapy group. The OS did not reach significant difference between two groups among those with a CPS ≥1 (Hazard ratio 0.86, 95% CI 0.69–1.06, p=0.073) or a CPS ≥10 (Hazard ratio 0.78, 95% CI 0.57–1.06, p=0.057). The one hope was an exploratory analysis in patients with a CPS ≥20. Among these patients, the hazard ratio for 12-months OS was 0.58 (95% CI 0.38–0.88).18 Conclusively, the Phase III KEYNOTE-119 study detected a failure in outcomes with the use of pembrolizumab versus chemotherapy for recurrent metastatic TNBC. Nevertheless, these patients with the highest tumor and immune cell level of PD-L1 may benefit from pembrolizumab.

Additionally, the efficacy of single-agent therapy with pembrolizumab was evaluated in ER+/HER2 advanced breast cancer (NCT02054806).19 This research included 25 cases of ER+/HER2 and PD-L1-positive advanced breast cancer. After a median follow-up of 9.7 months, patients treated with pembrolizumab had an ORR of 12.0% (95% CI, 2.5–31.2%). Three patients experienced PR and none experienced CR. Besides, 16% of patients experienced stable disease (SD). The median duration of response was 12 months (range, 7.4–15.9 months). In conclusion, for heavily pretreated, PD-L1-positive, ER+/HER2 advanced breast cancer, pembrolizumab may bring a durable response. A large cohort of studies should be performed in patients to support its utility in ER+/HER2- advanced breast cancer.19

Avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, was evaluated in patients with metastatic breast cancer (MBC) form a Phase 1b JAVELIN study.20 A total of 168 heavily pretreated MBC patients (including 58 TNBC patients) were treated with avelumab monotherapy. For the total population, the confirmed ORR was 3%, including 1 CR and 4 PRs. For TNBC patients, the ORR was 5.2%. Besides, a higher ORR was observed in patients with PD-L1 positive versus PD-L1 negative tumor-associated immune cells, both in the overall population (16.7% vs 1.6%) and in the TNBC group (22.2% vs 2.6%). In conclusion, Avelumab showed tolerability and clinical activity in patients with MBC. High expression of PD-L1 on tumor-associated immune cells may predict response to the treatment of Avelumab.20

Atezolizumab is a humanized Ig1 isotype monoclonal antibody that selectively inhibits the binding of PD-L1 to its receptors PD-1 or B71, thereby reinvigorating anti-tumor immunity of T cells.21 Emens et al investigated the safety and clinical efficacy of single-agent atezolizumab in a metastatic TNBC (mTNBC) cohort.22 This phase 1 trial enrolled 116 mTNBC patients regardless of lines of prior therapy. The median follow-up time was 25.3 months (range, 0.4–45.6 months). In first-line patients, the ORR was 24% (5 of 21) and median OS was 17.6 months (95% CI, 10.2 months to not estimable). However, in patients receiving atezolizumab as second-line and beyond therapy, ORR was only 6% (6 of 94) and median OS was 7.3 (95% CI, 6.1–10.8) months by RECIST. Median DOR of all patients was 21 (range, 3 to ≥38) months. Median PFS was 1.4 (95% CI, 1.3–1.6) months by RECIST. Besides, patients with PD-L1 expression of ≥1% tumor-infiltrating immune cells (ICs) had higher ORR (12% [11 of 91]) and longer OS (10.1 [95% CI, 7.0–13.8] months) compared with those with less than 1% ICs (ORR: 0% [0 of 21]; OS: 6.0 [95% CI, 2.6–12.6] months). Atezolizumab was well-tolerated in mTNBC patients. Conclusively, encouraging clinical benefit, especially in first-line individuals or those with higher tumor immune cell infiltration, suggest a promising therapeutic efficacy of atezolizumab in mTNBC.22

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