Key Points
• In the current review, authors examined approaches to boost immunotherapeutic activity in HR+, HER2− metastatic breast cancer, including combinations of checkpoint inhibition with chemotherapy, endocrine therapy, PARP inhibitors, HDAC inhibitors, CDK4/6 inhibitors, and radiotherapy.
• To date, checkpoint inhibition alone or with standard chemotherapy has failed to demonstrate similar clinical efficacy in patients with HR+, HER2− metastatic breast cancer vs those with triple-negative breast cancer (TNBC), although combinations including CDK4/6 inhibitors and PARP inhibitors show potential. According to preclinical studies, synergy with immune checkpoint inhibition and these targeted agents may be due to alternative mechanisms of facilitating anti-tumor response.
• “There are several challenges to utilizing immunotherapy in HR+, HER2− breast cancer. It is becoming clear that immune checkpoint inhibition is most efficacious when used in early line settings, and with numerous effective agents in HR+, HER2− mBC, early investigations with immunotherapy have been limited to patients often refractory to multiple agents. Additionally, finding a biomarker predictive of response to immunotherapy remains a challenge,” the authors wrote.
• The authors stressed that data from immunotherapy-based clinical trials in HR-positive patients question the reliability of PD-L1 expression as a biomarker of response. Such results express the need to identify alternative immune signatures that can predict response, as well as identify candidates for novel treatment strategies.
• “In the early-stage setting, the innovative I-SPY2 clinical trial design offers an opportunity for the investigation of novel immunotherapy combinations in the neoadjuvant setting, with the potential to lead to further drug development in the advanced/metastatic setting,” they wrote. ”However, the risk of long-term toxicities with immunotherapy must be weighed against potential benefit in localized disease, particularly in a patient population with better outcomes when compared to their triple negative counterparts. The emerging safety concerns when combining immunotherapy with endocrine therapy reflects the potential for toxicity with immunotherapy combinations despite well described toxicity profiles as monotherapy.”