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Immunotherapy for HER2-Positive Breast Cancer?
The use of immune checkpoint inhibitors (IO) in breast cancer has largely been restricted to patients with triple-negative breast cancer (TNBC). Currently, pembrolizumab is used in combination with chemotherapy in the preoperative setting (PD-L1 agnostic) and in the metastatic setting for those with PD-L1–positive disease. To date there has been little evidence to support the use of IO in patients with ER-positive tumors as these are generally viewed as immunologically “cold.” Two recent studies evaluated the addition of IO to preoperative HER2-directed therapy in patients with operable, HER-positive breast cancer.
In the industry-sponsored, phase 3, multinational IMpassion050 study, 454 patients with tumors >2 cm and positive axillary nodes were randomized to atezolizumab or placebo plus dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and pertuzumab and trastuzumab (PH). At the completion of preoperative therapy patients went on to surgery and completed a full year of atezolizumab or placebo with PH. Patients with residual disease at surgery were allowed to receive trastuzumab emtansine rather than PH. The coprimary endpoints were pathologic complete response (pCR; absence of residual invasive disease in the primary and lymph nodes at surgery) in the overall population and in those with PD-L1–positive disease.
The pCR rate in the entire population was 62.7% with placebo and 62.4% with atezolizumab (P=0.9551). In the PD-L1–positive population, the pCR rate was 72.5% with placebo and 64.2% with atezolizumab (P=0.1846). Rates were similar whether tumors were ER-positive or ER-negative.
In the nonrandomized phase 2 Neo-PATH trial, 67 patients in Korea with HER2-positive tumors >2 cm and involved axillary lymph nodes were eligible to receive 6 cycles of pertuzumab, trastuzumab, docetaxel, and atezolizumab every 3 weeks followed by surgery and 12 cycles of adjuvant pertuzumab, trastuzumab, and atezolizumab for those with pCR or 14 cycles of atezolizumab plus trastuzumab emtansine for those without pCR. The primary endpoint was pCR rate.
Nearly 50% of patients had tumors that were also ER-positive and nearly 20% had PD-L1–positive disease. The pCR rate was 61% overall. The rate was higher in patients with ER-negative versus ER-positive tumors (77% vs. 44%) and in those with PD-L1–positive versus PD-L1–negative disease (100% vs. 53%).
In both trials, there were no unexpected toxicities and the safety profile conformed to that in prior trials with atezolizumab.
Increasing the pCR rate in patients with HER2-positive breast cancer has translated into improved event-free survival (Ann Oncol 2013; 24:2278). Dual HER-2 targeted therapy, particularly trastuzumab and pertuzumab, combined with chemotherapy has been shown to increase the pCR rate to as high as 60% and several studies have confirmed that the pCR rate is consistently higher in tumors that are ER-negative rather than ER-positive. Although the feasibility of adding a checkpoint inhibitor has been demonstrated by an acceptable safety profile in both trials, additional clinical benefit derived from adding a checkpoint inhibitor to HER2-directed therapy has not been established by these trials. The Neo-PATH trial is small and long-term follow-up is not available to evaluate the impact, if any, on event-free survival. For now, IO treatment in breast cancer remains an option only for patients with TNBC or select other characteristics (e.g., high tumor mutational burden).
Ahn HK et al.
Title: Response rate and safety of a neoadjuvant pertuzumab, atezolizumab, docetaxel, and trastuzumab regimen for patients with ERBB2-positive stage II/III breast cancer: The Neo-PATH phase 2 nonrandomized clinical trial.
Source: JAMA Oncol 2022 Jul 7; [e-pub]. (Abstract/FREE Full Text)
Huober J et al.
Title: Atezolizumab with neoadjuvant anti-human epidermal growth factor receptor 2 therapy and chemotherapy in human epidermal growth factor receptor 2-positive early breast cancer: Primary results of the randomized phase III IMpassion050 trial.
Source: J Clin Oncol 2022 Jun 28; [e-pub]. (Abstract/FREE Full Text)