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David B. Page, MD:
To date, treatment with anti–PD-1/PD-L1 immune checkpoint inhibitor monotherapy has achieved modest response rates in patients with metastatic TNBC, ranging from as low as approximately 5% to as high as approximately 20%.[18,19] Although selection for PD-L1 positivity or using these therapies as early as possible in the course of metastatic disease may enrich for improved responses, there is more promise to be had in the pursuit of combination immunotherapy strategies.
What Is the Rationale for Combination Therapy With Immune Checkpoint Inhibitors in Metastatic TNBC?
First, anti–PD-1 and anti–PD-L1 antibodies are safe and well tolerated. Across all different types of cancer, there is evidence that we can combine immune checkpoint inhibitor therapy with standard-of-cancer treatments, such as chemotherapy and radiation therapy, with limited increases in toxicity. That said, we must be diligent to monitor for immune‑related toxicities that can arise with the use of these agents, which is discussed in a companion commentary here.
Second, and to me the most exciting rationale, is the possibility that 2 drugs with different mechanisms of action can synergize with one another to improve response. One way this can be achieved is by using chemotherapy or radiation therapy to increase tumor immunogenicity and thereby enhance the response to immunotherapy, an effect that is seen across multiple tumor types, and was recently demonstrated for metastatic TNBC in the phase III IMpassion130 trial that evaluated the addition of the anti–PD-L1 antibody atezolizumab to nab-paclitaxel in patients with previously untreated disease.[4,5] In this trial, the addition of an anti–PD-L1 antibody to chemotherapy improved response, PFS, and potentially OS. However, it must be noted that the trial did not contain a control arm for anti–PD-L1 monotherapy. Therefore, it remains unanswered whether combination therapy would be superior to a sequential monotherapy approach.
Rational Clinical Drug Development
Because patients with metastatic TNBC may be in acute need of effective therapy upon diagnosis (eg, for organ dysfunction), it is important to give them the best care that is available at the time. Thus, from a practical perspective, many of the emerging clinical trials of combination therapy are adding immunotherapy to standard-of-care chemotherapy, which we know is effective. For example, the IMpassion130 trial comparing the combination of atezolizumab plus nab-paclitaxel vs nab-paclitaxel was designed such that we could evaluate the combination without sacrificing the benefits of chemotherapy.[4,5]
Purely novel combinations are being examined in first-in-human trials in later lines of therapy due to uncertainty about their efficacy. However, prolonged chemotherapy has been shown to have profound effects on the immune system as evidenced by depletion of lymphocyte reserves. Thus, the low response rates seen in trials of patients with very refractory disease may be due to impaired immune system function after chronic chemotherapy. In addition, responses may be lower in this setting due to impaired functional status of patients with advanced disease, acquired immune resistance (termed “immuno-editing”), and/or direct immunosuppressive effects related to increased tumor burden.
Immunotherapy Combination Strategies Being Evaluated for Metastatic TNBC
There is a large number of novel combination regimens with immunotherapy being evaluated in early phase trials for metastatic TNBC, but I will highlight those combinations with considerable rationale in breast cancer.
As noted above, it is practically appealing to combine standard-of-care chemotherapy with anti–PD-1 or anti–PD-L1 antibodies. This approach also is supported by preclinical data showing potential synergy between these agents. There is evidence that chemotherapy may enhance the immune response through depletion of immunosuppressive immune cells such as T‑regulatory cells and macrophages and through immunogenic cell death, which releases factors, such as interferon, that could stimulate immunity. It could also have the untoward effect of upregulating PD-L1 but which we can then block with immune checkpoint inhibition.
However, which chemotherapy has the best immune-stimulating effects is an open question. Well-designed comparative studies are needed to address this, such as the phase III KEYNOTE-355 trial examining the addition of pembrolizumab to 3 different chemotherapy backbones, including nab-paclitaxel, paclitaxel, or the taxane-free regimen of gemcitabine/carboplatin, in patients who relapsed ≥ 6 months after completion of treatment for early-stage TNBC. Furthermore, choice of optimal chemotherapy backbone may differ between patients. For example, in a recent small trial, patients who recently had received neoadjuvant/adjuvant paclitaxel did not respond to pembrolizumab/paclitaxel in the first line setting, whereas responses were observed with pembrolizumab/capecitabine in these patients.
Androgen Receptor Blockers
Blocking the androgen receptor has unique promise in TNBC because it is upregulated to some degree in approximately 50% of these tumors. Androgen receptor blockade may cause immunogenic effects, such as inducing production of naive T-cells by the thymus, an immune organ that is turned off by androgens. In particular, there is interest in determining whether androgen receptor blockers such as bicalutamide or enzalutamide may help regenerate lymphocyte reserves that have been depleted due to previous treatment with chemotherapy, especially in heavily pretreated disease, and thereby pave the way for synergy with immunotherapy. Furthermore, blocking the androgen receptor may directly suppress tumor growth. Research on this combination is very preliminary, but there are a couple of promising studies ongoing, including one evaluating the androgen receptor blocker enobosarm plus pembrolizumab and another that I am participating in evaluating bicalutamide plus nivolumab and ipilimumab.[26,27]
Another immunotherapy combination partner under evaluation is the PARP inhibitor. PARP inhibitors were uniquely developed to target tumors with mutations in the BRCA gene and induce tumor cell death due to the inability of the cells to repair DNA. A subset of patients with TNBC has an inherited or acquired BRCA mutation. For these patients, 2 PARP inhibitors—olaparib and talazoparib—are approved for use in breast cancer with BRCA mutations.[29,30]
There are preclinical data demonstrating immunogenic effects of PARP inhibitors. Failure to repair DNA can activate the innate immune pathway—in particular, the STING pathway that induces immune-mediated cancer clearance—and this could provide a route for synergy with immunotherapy. One caveat is that there may be limited immunogenic effect of PARP inhibitors in BRCA-proficient cells. For example, the recent phase I/II trial TOPACIO in TNBC found that the combination of pembrolizumab plus the PARP inhibitor niraparib achieved an ORR of 47% in patients with BRCA mutations vs 11% in those without. Thus, the benefit of immune checkpoint inhibition in combination with PARP inhibition should be evaluated separately in BRCA-proficient and BRCA-deficient TNBC.
Radiation therapy is another standard-of-care cancer treatment that has shown promise in combination with immunotherapy. In addition to evidence of synergy between radiation and immune checkpoint inhibitors across tumor types, both preclinical and clinical data show that radiation can not only induce immune responses against breast cancer but also activate certain immune cell types and release factors that could induce immunogenic cell death. There are several ongoing studies looking at radiation therapy plus immune checkpoint inhibition in the treatment of metastatic TNBC.
However, several questions remain, including whether the combination is superior to immune checkpoint inhibitor therapy alone, and what is the optimal dosing and schedule of radiation for induction of an immune response without killing T-cells in the tumor itself. In my clinical practice, I often add a checkpoint inhibitor if a patient needs radiation therapy, for example, to treat pain in a palliative fashion, with the hope that the combination might facilitate a response.
A multitude of immunotherapy combination approaches are being evaluated, with corresponding trials available for patient enrollment. The multiplicity of clinical trial options is a bit overwhelming, and there is a need for a collaborative forum for comparing immunotherapy combinations in a rigorous, prospective way.
My clinical approach is to test for PD-L1, evaluate eligibility for combination trials, and weigh the pros and cons of standard therapy vs the available clinical trial options. For patients with PD-L1–positive tumors without early relapse (< 12 months), atezolizumab plus nab-paclitaxel is a good first-line option based upon the Impassion130 data.[4,5] However, should a first-line trial become available that addresses the needs of a unique patient population such as those with BRCA mutations who might fare better with a PARP inhibitor/immunotherapy combination in the first-line setting, I would consider it. For my patients in later lines, I favor clinical trials combining 2 different immune therapies, such as a cytokine plus an immune checkpoint inhibitor, because I think these unique combinations may one day be shown to transcend resistance to anti–PD-1 and anti–PD-L1 checkpoint inhibitors.
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