At this year’s virtual San Antonio Breast Cancer Symposium (SABCS)—the world’s largest scientific conference dedicated to breast cancer—investigators reported a number of key findings from trials testing immunotherapies and targeted agents for triple-negative breast cancer (TNBC), an aggressive form of the disease.
TNBC is named for what it lacks: the three major receptors (estrogen, progesterone, and HER2) found in other breast cancers. It accounts for 10 to 15 percent of breast cancers, including many driven by BRCA1/2 gene mutations, and it unfortunately lacks many targeted treatments.
Here, we highlight developments from notable TNBC trials.
Testing checkpoint inhibitors with chemotherapy for TNBC
Immunotherapy was a hot topic at this year’s SABCS meeting, as it was at other scientific conferences in 2020, with researchers presenting key findings from several immunotherapy trials in TNBC at both ASCO and ESMO’s annual meetings. Given the promising but limited results of checkpoint inhibitor (anti-PD-1/PD-L1) therapy plus chemotherapy in advanced TNBC, several trials are underway to determine whether adding immunotherapy earlier in the course of disease can improve outcomes without reducing quality of life in patients with early-stage disease.
IMpassion031 is a phase III trial in patients with early-stage TNBC testing the safety and effectiveness of the checkpoint inhibitor atezolizumab used in tandem with standard chemotherapy prior to surgery (called neoadjuvant therapy). Checkpoint inhibitors work by blocking the immune suppression action of the PD-1/PD-L1 pathway, which is shown to be activated in immune cells in the microenvironment of some breast cancers allowing tumors to avoid detection by the immune system.
IMpassion031 builds on the IMpassion130 study, which led to FDA approval of atezolizumab plus nab-paclitaxel for metastatic TNBC (mTNBC). IMpassion031 involved 333 newly diagnosed patients with TNBC who were randomly assigned to receive either atezolizumab plus chemotherapy (nab-paclitaxel, doxorubicin, or cyclophosphamide) or the same chemotherapy agents plus a placebo prior to undergoing breast cancer surgery. Their response to treatment was assessed at the time of surgery. At the 2020 ESMO meeting, researchers reported a 16 percent increase in pathological complete response (no invasive cancer at time of surgery) in patients receiving the checkpoint inhibitor therapy plus chemotherapy compared to those who received the placebo.
At SABCS, BCRF investigator Dr. Elizabeth Mittendorf presented results on patient-reported outcomes from the trial, whereby patients assessed the impact of treatment on their ability to perform their normal roles within family or work environments, their physical, emotional, social, and cognitive function, and their overall health-related quality of life. Dr. Mittendorf reported that patients receiving checkpoint inhibitor therapy did not experience additional burden on quality of life and functionality compared to those receiving chemotherapy alone. This is an important finding, since adding any kind of treatment can reduce a patient’s quality of life and functional status, in addition to the fact that many patients with early-stage breast cancer do not experience symptoms from their breast cancer.
Keynote-355 is a randomized, double-blind, phase III study testing the combination of another checkpoint inhibitor called pembrolizumab (pembro) with chemotherapy, versus a placebo plus chemotherapy, in patients with previously untreated, locally recurrent inoperable or metastatic TNBC. Earlier reported results showed a clinically meaningful improvement in progression-free survival (9.7 months vs. 5.6 months) with the addition of pembro compared to placebo in patients whose tumors had high levels of the PD-L1 protein.
At SABCS, BCRF investigator Dr. Hope Rugo presented results from a subgroup analysis looking at the benefit of pembro in each chemotherapy group (nab-paclitaxel, paclitaxel, and gemcitabine/carboplatin). While the study was not designed to make statistical comparisons between the chemotherapy groups, an added benefit of immunotherapy was seen across all chemotherapy regimens, providing additional support for the use of anti-PD-L1 immunotherapy for the treatment of mTNBC.
In discussing the results, Dr. Rugo stressed that patients who had a longer disease-free interval before a metastatic diagnosis, as well as those who had not previously been treated with chemotherapy, tended to respond better overall. Based on these findings, pembrolizumab was granted accelerated FDA approval in combination with chemotherapy in PD-L1-positive mTNBC patients with no prior treatment. This is the second FDA-approved checkpoint inhibitor for mTNBC. Data on overall survival are expected to be reported in 2021.
Looking at emerging targeted agents for TNBC
In addition to the excitement around checkpoint inhibitors, new targeted agents for treating TNBC were also a focus at SABCS.
IPATunity 130 is a double-blind, placebo-controlled, randomized phase III study testing the combination of the targeted agent ipatasertib with paclitaxel in patients with locally advanced or mTNBC that harbor mutations in PIK3CA/AKT1/PTEN pathway. AKT acts as a primary regulator of this potent growth-promoting pathway and is the target of ipatasertib, an orally administered AKT inhibitor. In contrast to the LOTUS and PAKT phase II trials—where patients receiving ipatasertib or a similar AKT inhibitor plus chemotherapy had greater overall survival than those receiving chemotherapy plus a placebo—the IPATunity trial did not show a difference in progression-free survival in patients receiving ipatasertib plus chemotherapy compared to those who received a placebo with chemotherapy.
Overall survival analysis, however, is ongoing, along with biomarker analysis to identify patients most likely to benefit from ipatasertib therapy. In discussing the results and the future of targeted inhibition of the AKT pathway, given inconsistent clinical trial results, Dr. Rebecca Dent of Singapore National Cancer Center noted that there is still much we don’t understand about the effects of targeting AKT, particularly in TNBC, a highly heterogeneous disease with a variety of molecular drivers. She stressed that ongoing and future studies will likely reveal markers that will help identify the right population of patients for AKT inhibition.
ASCENT is an open-label randomized phase III study in patients with mTNBC that has progressed on at least two chemotherapies. The trial is designed to compare the efficacy (as measured by progression-free survival) of the targeted agent sacituzumab govitecan (SG) versus chemotherapy. SG is an antibody-drug conjugate that targets Trop-2, a protein associated with poor prognosis in breast cancer and that has shown to be present at high levels on TNBC cells. The drug works by recognizing and attaching to Trop-2 on cancer cells and then releasing a toxic drug that kills the cell. Based on results from the phase II study published in The New England Journal of Medicine, SG was granted accelerated FDA approval in 2020 for advanced, refractory TNBC under the trade name Trodelvy©.
The subgroup analysis presented by Dr. Sara Hurvitz of The University of California, Los Angeles included 468 patients (265 receiving SG and 233 receiving chemotherapy) and compared the efficacy of SG to chemotherapy based on the tumor expression of Trop-2 and germline (inherited) BRCA1/BRCA2 mutation status of the patient. Confirming findings from the phase II study, patients receiving SG had better progression-free survival FS) and overall survival. While all patients benefited regardless of Trop-2 levels, those with the highest levels received the most benefit, nearly doubling their progression-free and overall survivals compared to chemotherapy. The researchers did not report any association with germline BRCA mutation status but noted a relatively small number of BRCA-positive patients in the subgroup analysis and the subgroup analysis did not include patients with brain metastases.
Read more of BCRF’s SABCS 2020 coverage here.
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