Academic Background

Breast cancer is one of the most common cancers among women worldwide, particularly triple-negative breast cancer (TNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, which are known for their aggressive nature and poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) such as the anti-PD-1 antibody Pembrolizumab have shown promise in breast cancer treatment, especially in the context of neoadjuvant chemotherapy (NAC). However, although the combination of Pembrolizumab with NAC significantly improves the pathologic complete response (pCR) rate and 3-year event-free survival (EFS), the high incidence of severe adverse events (Grade ³⁄₄ AEs) at 78% limits its widespread use.

The combination of radiation therapy (RT) with immunotherapy is believed to enhance anti-tumor immune responses. RT induces immunogenic cell death, releasing tumor-specific antigens that attract immune cells to the tumor microenvironment (TME) and upregulate PD-L1 expression. Additionally, RT can induce immune co-stimulatory molecules, further enhancing anti-tumor immunity. Therefore, researchers hypothesized that combining Pembrolizumab with preoperative RT before NAC could enhance responses to NAC without significant treatment delays.

Study Source

This study was conducted by Alice Y. Ho, Stephen Shiao, and other researchers from multiple institutions including Duke University Medical Center, Cedars Sinai Medical Center, and Massachusetts General Hospital. It was published on September 19, 2024, in the Journal of Clinical Oncology (JCO) under the title “PEARL: A Phase Ib/II Biomarker Study of Adding Radiation Therapy to Pembrolizumab Before Neoadjuvant Chemotherapy in Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer.”

Study Process

Study Subjects and Design

The PEARL study is a prospective, single-arm Phase Ib/II clinical trial designed to evaluate the safety of combining Pembrolizumab with preoperative RT in patients with operable TNBC or high-risk HR+/HER2- breast cancer. A total of 66 patients were enrolled, including 54 with TNBC and 12 with HR+/HER2- breast cancer. All patients received two cycles of Pembrolizumab (200 mg every 3 weeks) and RT (24 Gy in three fractions) within the first 3 days of the second cycle, followed by NAC. The primary endpoints were safety and changes in tumor-infiltrating lymphocytes (TILs), while secondary endpoints included pCR rate, residual cancer burden (RCB) rate, and EFS.

Experimental Methods

Peripheral blood and tumor biopsy samples were collected at three time points: baseline, after Pembrolizumab treatment (anti-PD1), and after Pembrolizumab combined with RT treatment (anti-PD1/RT). TILs were evaluated using the Salgado and International TIL Working Group criteria, and PD-L1 expression was measured using the FDA-approved 22C3 PharmDx companion diagnostic assay. Serum biomarkers were measured using multiplexed protein array kits (Mesoscale Discovery).

Data Analysis

The study employed a Bayesian sequential design to monitor the true probability (Pd) of delays in initiating NAC. If Pd exceeded 20%, the trial would be halted. The sample size for the Phase II component was estimated based on the pCR rate in TNBC, with 50 evaluable patients expected to achieve 80% statistical power to detect an effect size of 1.20. Data analysis included t-tests, Kruskal-Wallis tests, Cox proportional hazard models, and logistic regression models.

Main Results

Safety

The study met its primary safety endpoint, with only two patients (3%) experiencing delays of more than 4 weeks in initiating NAC after anti-PD1/RT. The incidence of Grade ≥3 toxicities was 41%, with nine patients (13.6%) experiencing toxicities likely related to Pembrolizumab and/or preoperative RT.

Efficacy

The overall pCR rate in the entire cohort was 54.5%, with pCR rates of 59.2% in TNBC patients and 33.3% in HR+/HER2- patients. Near pCR (RCB 0-1) was achieved in 77.8% of TNBC patients and 41.6% of HR+/HER2- patients. The 3-year EFS for the entire cohort was 80%.

Biomarker Changes

In the entire cohort, PD-L1 expression significantly increased after anti-PD1 treatment (median CPS increased from 7.49 to 23.20) and further increased after anti-PD1/RT treatment (median CPS increased to 23.41). In TNBC patients, the addition of RT significantly reduced TILs (from 28.9% to 17.1%). Baseline TILs were correlated with PD-L1 expression and TNF-α.

Conclusion

The combination of preoperative Pembrolizumab with RT is safe and results in high pCR rates and 3-year EFS in breast cancer patients, even without the use of Pembrolizumab during NAC. PD-L1 and TILs may serve as predictive biomarkers for preoperative anti-PD1/RT response. The reduction in TILs after adding RT highlights the importance of treatment sequencing.

Study Highlights

1. Safety: The study confirmed the safety of combining Pembrolizumab with RT, with a low incidence of toxicities.
2. High pCR Rates: The pCR rate in TNBC patients approached that of current standard treatments, without the need for Pembrolizumab throughout NAC.
3. Biomarkers: Changes in PD-L1 and TILs provide potential predictive indicators for future immunotherapy.
4. Treatment Sequencing: The timing of RT addition significantly impacts immune responses, offering important insights for optimizing future treatment strategies.

Study Significance

The PEARL study introduces a novel preoperative treatment strategy for breast cancer patients, combining Pembrolizumab with RT before NAC. This approach not only improves pCR rates but also reduces the incidence of severe adverse events, paving the way for future research in breast cancer immunotherapy. Additionally, the study highlights the potential of PD-L1 and TILs as predictive biomarkers, offering a basis for personalized treatment.