Clinical Trials Landscape
One of the first trials with checkpoint inhibitor monotherapy in breast cancer was the phase Ib KEYNOTE-012 trial that evaluated pembrolizumab in heavily pretreated metastatic TNBC.51 In this trial, monotherapy pembrolizumab demonstrated an 18.5% overall response rate (ORR) among 27 patients who were evaluable for antitumor activity. Although preliminary evidence of clinical activity was seen from monotherapy pembrolizumab in this trial, compared to the results in melanoma and lung cancer, these results were discouraging. Other early trials with monotherapy pembrolizumab, atezolizumab, or avelumab were also unhopeful and demonstrated ORR of around 10% or less.36,39,41,52,53
The suggestion to combine chemotherapy and immunotherapy emerged from concept from the cancer-immunity cycle. It was hypothesized that immunotherapy activity can be enhanced by the addition of chemotherapy by priming the immune system to elicit an immune response by releasing antigens and danger signals that recruit antigen-presenting cells.42,54 Several chemotherapeutic agents commonly used in breast cancer such as anthracyclines, cyclophosphamide, and taxanes can promote immunogenic cell death resulting in release of antigens.54 However, it was determined that taxanes in particular may additionally activate toll-like receptor activity and promote dendritic cell activity.42 In the IMPASSION 130 trial, the first breakthrough for immunotherapy in breast cancer, atezolizumab was used in combination with nab-paclitaxel in metastatic TNBC.
Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking monoclonal antibody that binds to PD-L1 on tumor cells and tumor-infiltrating immune cells.55 It executes a complete dual blockade of PD-1 and the B7.1 receptor, which is a costimulatory cell surface protein. The blockage of both PD-1 and B7.1 receptors on T cells and antigen-presenting cells suppress cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Ultimately, blocking PD-L1 activity results in decreased tumor growth.
In the IMPASSION 130 trial, patients with previously untreated metastatic TNBC were randomized to receive either atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel.42 PFS was found to be significantly longer with those that received atezolizumab plus nab-paclitaxel compared to those that received placebo plus nab-paclitaxel (7.2 months vs 5.5 months, respectively; HR 0.80, 95% CI 0.69–0.92, p=0.0025). In those that were found to have PD-L1 positivity of at least 1% on the tumor-infiltrating immune cells, the difference in PFS between the two groups was more pronounced. Patients receiving atezolizumab and nab-paclitaxel had a 7.5-month PFS, compared to 5.0 months in those receiving placebo plus nab-paclitaxel (HR 0.62; 95% CI 0.49–0.78, p<0.001). Overall response rates were higher with those that received the checkpoint inhibitor, with 7.1% achieving a CR, compared to 1.6% in those that did not receive atezolizumab. In terms of safety, the safety profile was consistent with the toxic effects of each agent, with no new adverse events observed. The most common immune-related toxicity reported in the study was hypothyroidism, 13.7%. However, overall, the combination of atezolizumab and nab-paclitaxel appeared to be well tolerated. These results led to the FDA approval in 2019 in patients with unresectable, locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity cover > 1% of the tumor area) in combination with nab-paclitaxel. Pivotal trials are summarized in Table 1.
There are currently close to 300 clinical trials ongoing trials investigating the use of immunotherapy in breast cancer54. Most of the trials focus on evaluating checkpoint inhibitors, however some trials are exploring the possibility of vaccines as well as adoptive T-cell therapy. Most of the ongoing trials are phase 1 or 2 and about 15% are Phase 3 studies. In terms of subtypes of breast cancer being studied, most trials that are investigating immune checkpoint blockade alone or in various combinations are in TNBC, however exploration with ERBB2 positive breast cancer is being considered as well. About 80% of the studies are being conducted in the metastatic setting, however there are several ongoing trials in the neoadjuvant and adjuvant setting.
Neoadjuvant clinical trials with combination chemotherapy with or without Immunotherapy have shown promising results, as evidenced by the KEYNOTE-173 and ISPY2 trials. The KEYNOTE-173 trial is a 6-cohort, phase 1b trial of pembrolizumab in combination with platinum and taxanes as neoadjuvant treatment in patients with locally advanced TNBC.56 In this small population of 60 patients, overall pCR rate was 60%, and ORR was 100%. Overall, it appears that pembrolizumab in combination with chemotherapy has some promising antitumor activity in the neoadjuvant TNBC setting. The ISPY2 trial is a Phase II trial evaluating pembrolizumab in combination with standard therapy (paclitaxel followed by doxorubicin and cyclophosphamide) as a neoadjuvant treatment for TNBC.57 Findings revealed a signification increase in pathologic complete response rate of 60% with the addition of pembrolizumab versus 20% without.
Several other studies in the neoadjuvant and adjuvant settings, with immunotherapy in the TNBC population are currently ongoing. The ongoing neoadjuvant trials include the Impassion 031, NeoTRIPaPDL1, and Keynote522. In the adjuvant setting, the current ongoing trials include SWOG 1418; IMPASSION 030; A-BRAVE. With these emerging investigations, there is a robust potential for the role of immunotherapy in the breast cancer setting.
READ FULL ARTICLE From Dovepress