Triple negative breast cancers (TNBC) are defined as tumors lacking expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2 and account for approximately 15%–20% of all breast cancers. TNBC has been characterized by an aggressive natural history and poor outcomes with the majority of recurrences and deaths occurring in the first 3 to 5 years after initial diagnosis . Given the absence of traditional breast cancer targets, conventional chemotherapy remains the standard of care in the majority of clinical settings with suboptimal outcomes .
In recent years, it has been shown that treatment with checkpoint inhibitors are an effective strategy for the management of several solid tumors. It was initially developed in selected “immunogenic” cancers such as melanoma and renal cancer. Better understanding of the mechanisms of tumor immune response, led to significant advances in a wide spectrum of solid malignancies, such as lung cancer, gastrointestinal cancers and many others. Although breast cancer is not considered to be an immunogenic tumor, recent advances in TNBC research have revealed that it may represent a more promising target for immunotherapy than other breast cancer subtypes. TNBC has been classified into six distinct molecular subtypes by gene expression profiling, among them the immunomodulatory (IM) subtype. Additionally, over last few years, the prognostic and predictive roles of tumor infiltrating lymphocytes (TILs) have been extensively studied in breast cancer and different studies have demonstrated their association to better outcome in TNBC . TNBC is also characterized by genomic instability with high rates of genetic mutations, which leads to higher production of neoantigens and subsequently increases its immunogenicity. Therefore, the use of immunotherapy among patients with TNBC who express high levels of TILs could lead to higher tumor responses.
The immunomodilatory TNBC subtype is composed of genes encoding immune antigens and cytokine and core immune signal transduction pathways and likely represents signaling components contributed by both the tumor cells and infiltrating lymphocytes. This subtype is also characterized by higher expression of programmed death-1 (PD1), programmed death ligand-1 (PD-L1), and CTLA-4 than in luminal breast cancers that may be targetable by checkpoint inhibitors .
PD1 and its ligand PDL1 deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. PD1 negatively regulates T-cell activity by blocking T cells and modulating immune responses at different phases . PD-L1, a T-cell inhibitory molecule, which is expressed on cancer cells, tumor-infiltrating inflammatory cells, and immune cells, is expressed in around 20% to 30% of TNBC and was found to be associated with TILs, in addition to be correlated with worse clinico-pathologic features such as higher grade, greater tumor size, and higher proliferation rate. The binding of PD-L1 to PD-1 on T cells is a major mechanism of tumor immune evasion . Therefore, the blockade of these targets increase the anti-tumor immune response by blocking immune regulating proteins that down-regulate the immune system, and was associated with better relapse-free survival when compared to other TNBC subtypes.
These findings and the impressive results that were seen with active immunotherapy using immune checkpoint inhibitors in several other cancers lead to conducting several trials in TNBC in different settings.
Atezolizumab in combination with nab-paclitaxel became the new upfront standard of care in the subset of patients with unresectable locally advanced or metastatic PDL1 positive TNBC after it was granted accelerated approval by the Food and Drug Administration (FDA) in March 2019. Atezolizumab is a monoclonal antibody that binds selectively to PD-L1 on immune cells or tumor cells to prevent interactions with the PD-1 receptor or B7-1. The combination had shown very promising results in phase I and II trials, which lead to subsequent phase III trials. Important results were recently presented from the phase III IMpassion130 trial, last year at the European Society for Medical Oncology (ESMO 2018) conference. This included data from 902 patients with treatment-naïve metastatic TNBC who were randomly assigned to receive nab-paclitaxel alone or in combination with atezolizumab which is an anti-PD-L1. The combination regimen was associated reduced the risk of disease progression or death by 20% in all patients and by 38% in the subgroup expressing PD-L1 which accounted for 41% of all patients . After a median follow-up of slightly more than 1 year, the median progression-free survival (PFS) was 7.2 months with the combination compared with 5.5 months for placebo plus nab-paclitaxel in the intention-to-treat analysis (hazard ratio [HR] for progression or death = 0.80; P = .002). Patients with PD-L1–positive tumors who received the combination had a 2-month increase in PFS compared with nab-paclitaxel lone (7.5 vs 5.0 months; HR = 0.62; P < .001).
At first interim analysis, in the intent-to-treat group, median OS was 21.3 months with the combination compared with 17.6 months for placebo plus nab-paclitaxel (HR = 0.84; P = .08). Among those with PD-L1–positive tumors, the median overall survival was 25.0 months compared with 15.5 months, respectively. The safety of atezolizumab plus nab-paclitaxel was consistent with the known toxic effects of each agent .
Another phase III trial is evaluating atezolizumab in combination with paclitaxel compared with placebo with paclitaxel for patients with previously untreated inoperable locally advanced or metastatic TNBC (NCT03125902). In the neoadjuvant setting, a phase III randomized study is investigating the efficacy and safety of atezolizumab in combination with neo-adjuvant anthracycline/nab-paclitaxel-based chemotherapy compared with placebo and chemotherapy (NCT03197935). Another phase III neo-adjuvant trial is studying the efficacy of atezolizumab in locally advanced TNBC patients undergoing treatment with nab-paclitaxel and carboplatin (NCT02620280).
Avelumab is another PD-L1 inhibitor undergoing clinical development. In a phase Ib solid tumor basket trial (JAVELIN; NCT01772004), avelumab was used to treat an expansion cohort consisting of 168metastatic breast cancer patients, with tumors that were unselected for PD-L1 status and breast cancer subtype(12). The TNBC subtype represented 34.5% of patients. Approximately 50% of the TNBC patients had ≤1 prior regimen for metastatic disease. The ORR in the TNBC cohort was 8.6% (95% CI, 2.9-19); 5 of 58 patients had a PR, and 13 had stable disease (22.4%) . Avelumab is also under assessment in adjuvant setting in the A-BRAVE-Trial (NCT02926196). It is a phase III randomized trial evaluating adjuvant treatment with avelumab in 335 patients with TNBC who completed definitive curative therapy.
In metastatic TNBC, durvalumab is being evaluated in combination with Vigil (autologous tumor cell immunotherapy; NCT02725489), and in combination with paclitaxel (NCT02628132), olaparib (NCT02484404), tremelimumab (NCT02527434), and epacadostat, an inhibitor of indoleamine 2,3-dioxygenase (NCT02318277). It was also tested in combination with other agents for early-stage TNBC.
The addition of durvalumab to anthracycline/taxane-based chemotherapy showed encouraging results as neoadjuvant therapy for early TNBC in the randomized phase II GeparNuevo study . The primary endpoint, was the pCR rate that was 53.4% in the durvalumab arm vs 44.2% for chemotherapy alone (control arm), and the best response rates were observed when durvalumab was given for a window of 2 weeks before chemotherapy, priming the immune system first.
Another phase I/II neoadjuvant study (NCT02489448) of weekly nab-paclitaxel followed by dose-dense doxorubicin and cyclophosphamide with concurrent durvalumab in stage I-III TNBC showed that addition of durvalumab is safe and the pCR rates appear to be higher than what is expected with chemotherapy alone . A phase Ib study is evaluating the role of durvalumab and the PVX-410 vaccine as adjuvant therapy for stage II/III TNBC (NCT02826434).
Pembrolizumab, a PD1 inhibitor, has been evaluated as monotherapy in a phase Ib trial, which included 32 patients with PD-L1-positive metastatic TNBC (KEYNOTE-012 trial) (5). All patients expressed PDL1 and 47% of them had received more than 3 lines of treatment and 21.9% had received 5 or more treatments. The objective response rate (ORR) reached 18.5%, and among the 27 patients with measurable disease one participant (3.7%) had a complete response (CR), four participants (14.8%) had partial response (PR), and 25.9% had stable disease (SD). Overall survival stood at 22% after 2 years . However, rapid disease progression was observed in patients with more than two fold elevations in baseline lactate dehydrogenase (LDH) levels.
Pembrolizumab as monotherapy was assessed in previously treated metastatic TNBC in a single-arm multi-cohort phase II study (KEYNOTE-086) . Cohort A assessed the efficacy and the safety of pembrolizumab regardless of PD-L1 expression and primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival. Sixty percent of the patients had PD-L1 positive tumors. After a median follow-up of 11.9 months among 170 patients, the overall response rate was 5% and the disease control rate was 8%. The response rate was not impacted by PD-L1. The median PFS and the OS were 2.0 month (95% CI 1.9-2.0) and 8.9 months (95% CI 7.2-11.2) respectively. Six months of PFS and OS were seen in 12% and 69% patients respectively . Cohort B of the study evaluated the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1 positive metastatic TNBC.
After a median follow-up of 7 months in 52 enrolled patients, the ORR was 23%, the median PFS was 2.1 months (95% CI, 2.0-3.9); the estimated 6-month PFS rate was 29% and the median duration of response was 8.4 months .
The combination of pembrolizumab with eribulin mesylate was eassessed in a phase Ib/II study enrolling 89 patients with metastatic TNBC patients treated with less than 3 prior lines of CT for their metastatic disease . The interim analysis revealed a 33.3% ORR in the first 39 patients evaluated. SD was observed in 28.2% patients and the durable SD rate (SD lasting ≥24 weeks) was 7.7%. There were no differences in RRs based on PD-L1 expression (29.4% and 33.3% in the PD-L1-positive and PD-L1-negative cohorts, respectively) .
The phase III KEYNOTE-119 study (NCT02555657) has randomized 662 patients to receive either pembrolizumab as a monotherapy in second- and third-line or chemotherapy per investigator’s choice in patients diagnosed with metastatic or locally advanced TNBC. Pembrolizumab failed to extend overall survival in patients.Another phase III trial is evaluating the addition of pembrolizumab to chemotherapy in first-line treatment of PD-L1-positive metastatic TNBC (KEYNOTE-355, NCT02819518).
Based on the clinical benefit and the safety shown in the metastatic setting, pembrolizumab has moved for evaluation in early stage of TNBC. I-SPY 2 phase II multi-center trial investigated the role of pembrolizumab plus standard neo-adjuvant therapy for high-risk breast cancer showed that in TNBC, there was nearly threefold increase in patients who achieved pCR (60% vs 20%) .
A phase III clinical trial (KEYNOTE-522; NCT03036488) is assessing pembrolizumab in combination with chemotherapy for stages IIa to IIIb TNBC. Another phase III trial (SWOG-S1418, BR006; NCT02954874) is evaluating the efficacy and safety of pembrolizumab as adjuvant therapy for TNBC with ≥ 1 cm residual invasive cancer or positive lymph nodes (ypn+) after neo-adjuvant chemotherapy.
Nivolumab, another PD1 inhibitor, is being evaluated in several phase I and II trials of TNBC patients. TONIC-trial is an adaptive phase II randomised non-comparative trial that evaluated nivolumab in patients with metastatic TNBC after induction treatment including radiation, low-dose doxorubicin, metronomic cyclophosphamide, and cisplatin in metastatic . The objective response rate (ORR) per RECIST v1.1 with nivolumab for the whole cohort was 22% and 24% for iRECIST, which included 1 (2%) CR, and 11 (22%) PR. Additionally, stable disease (SD) lasting more than 24 weeks was achieved in 1 (2%) patient, which resulted in a 26% clinical benefit rate (CBR = CR+PR+SD>24 weeks). The median duration of response was 9 months (95% confidence interval [CI] 5.5-NA). Preliminary analyses showed that response rate might be higher after induction therapy with doxorubicin or cisplatin and that patients with higher leukocyte infiltration and CD8 T cell counts were better responders to treatment . Another phase II is evaluating Carboplatin +/- Nivolumab in Metastatic TNBC (NCT03414684).
Immunotherapy appears very promising in TNBC especially after recent resluts from IMpassion 130 trial that may change the standard of care in at least a subset of patients with metastatic PDL1 positive TNBC. New strategies by combination of immune checkpoint blockade with conventional therapies including chemotherapy, radiotherapy, targeted therapies or in association with other immunotherapeutic agents are promising and further research is needed to identify better responders to these treatments.
Conflict of interest statementNone to report.
CITE THIS ARTICLE:
Karima Oualla, MD. Immunotherapy with Checkpoint Inhibitors in Triple Negative Breast Cancer (TNBC). Doctors Lounge. Available at: https://www.doctorslounge.com/index.php/articles/page/89207. Accessed June 20 2019.
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