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Keytruda, Hormone Therapy Combination Benefits Advanced Breast Cancer Subgroup in AACR Study

NEW YORK – The combination of pembrolizumab (Merck's Keytruda), the aromatase inhibitor exemestane (Pfizer's Aromasin), and hormone therapy leuprolide may offer a survival benefit to certain metastatic breast cancer patients who previously haven't responded to hormone treatment, according to interim results researchers presented from the Phase I/II PEER study at the American Association for Cancer Research's virtual annual meeting.

The data, presented by I-Chun Chen, an attending physician at the National Taiwan University Cancer Center, were derived from a small cohort of 14 patients. Although the pilot analysis was based on a few patients, Chen emphasized that there is an unmet need for new treatment approaches for advanced breast cancer patients who are refractory to hormone therapy and tend not to fare well on immunotherapy.  

The low response rates historically seen with single-agent pembrolizumab in this patient population may be due to the presence of estrogen, which Chen said can create an immunosuppressive microenvironment in breast cancers. In designing the PEER study, Chen and colleagues hypothesized that the combination of two drugs that reduce estrogen — exemestane and leuprolide — and an anti-PD-1 immunotherapy, may overcome this barrier. "We hypothesized that estrogen suppression, such as hormone therapy and an LHRH agonist, will augment immunotherapy effect," Chen said.

All patients enrolled in the PEER trial were pre- or peri-menopausal and had hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer; had not responded to prior hormone therapy; and were chemotherapy-naive. After eight months, nine out of 13 efficacy-evaluable patients, or just more than 69 percent, were alive and had not experienced disease progression.

The efficacy results were encouraging to Chen and colleagues. Five of the 13 patients had confirmed partial responses to the pembrolizumab-containing regimen and six had confirmed stable disease, contributing to an overall response rate of 38.4 percent and a disease control rate of 84.6 percent. The median progression-free survival time was 10.1 months and the median overall survival was 27.4 months.

Although cross-trial comparisons are imperfect, Chen referenced data from several studies to highlight the relatively low responses seen among breast cancer patients to just immunotherapy. In Keynote-028, the overall response rate for patients with advanced PD-L1 positive, HR-positive, HER2-negative breast cancer was 12 percent on single-agent pembrolizumab. In the Javelin-1b trial of single-agent avelumab (Pfizer/EMD Serono's Bavencio), the overall response rate among metastatic breast cancer patients not selected according to HR or HER2 status was just 3 percent.

Meanwhile, in the Bolero-2 trial, when HR-positive, hormone treatment refractory breast cancer patients received just exemestane, the overall response rate was 0.4 percent; adding the mTOR inhibitor everolimus (Novartis' Afinitor) to exemestane pushed the overall response rate to 9.5 percent.

"Therefore, the overall response rate we observed in this (PEER) study was clinically higher than the historical control for this hormone therapy-resistant group," Chen said, adding that most of the treatment-related adverse events noted in the group were tolerable. Four subjects had grade 3 elevated AST or ALT, which could indicate liver problems.

Chen acknowledged that going into the study the research team was concerned about the potential for liver toxicities given the safety issues seen in prior breast cancer treatment combination studies. "We tried to adapt our safety monitoring protocol," she said, "and in our subsequent enrollment, we will keep an eye on it."

The PEER investigators will continue to follow patients for the primary endpoint of progression-free survival at eight months, which according to Chen, will allow for better comparisons with historical controls. Researchers will also assess biomarkers predictive of treatment response beyond HR and HER2 status.

In her presentation at AACR, Chen shared outcomes according to patients' luminal subtype, as determined by Veracyte's PAM50 prognostic signature, and by immune score, as assessed by the NanoString BC360 assay. Patients with a higher clinical benefit to the pembrolizumab-exemestane-leuprolide regimen, defined as responding for more than eight months, tended to have tumors classified as luminal subtype B. In turn, patients with luminal subtype B tumors tended to have a higher immune score, Chen said.

This finding is consistent with prior research, Chen noted, showing that this breast cancer subtype tends to have higher neoantigen expression, higher interferon gamma signatures, and higher immunogenicity than luminal subtype A tumors, making them potentially more responsive to immunotherapy.

An analysis of outcomes according to patients' PD-L1 expression status — a key biomarker of immunotherapy response — is ongoing, though according to Chen that exploratory assessment was not complete prior to the AACR presentation. "PD-L1 is the only biomarker that probably correlates with the immunotherapy results or efficacy for breast cancer, so we do plan to do that," she said.