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

Abstract

Purpose: To assess safety and immune biomarkers after preoperative radiation therapy (RT) and anti-PD1 therapy in breast cancer.

Materials and methods: A phase I/IIb trial of pembrolizumab with RT was conducted in patients with triple-negative breast cancer (TNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. All received pembrolizumab followed by a second cycle + RT (anti-PD1/RT) of 24 Gy/three daily fractions delivered to the breast tumor and then neoadjuvant chemotherapy (NAC). Blood and tumor biopsies were obtained at baseline, after anti-PD1, and after anti-PD-RT. Coprimary end points were safety and change in tumor-infiltrating lymphocytes (TILs). Secondary end points were pathologic complete response (pCR), residual cancer burden (RCB) rates, and event-free survival (EFS).

Results: Sixty-six patients with stage I-III breast cancer (54 TNBC, 12 HR+/HER2-) were enrolled. The median follow-up was 32 months. Safety end point was met. Incidence of grade ≥3 toxicities was 41%. The pCR rate was 59.2%, 33.3%, and 54.5% for the TNBC, HR+/HER2-, and entire cohort, respectively. A total of 77.8% of TNBC and 41.6% of HR+/HER2- had a near pCR (RCB 0-1). The 3-year EFS was 80%. In the entire cohort, PD-L1 expression increased after anti-PD1 (median Combined Positive Score [CPS], 7.49-23.20; 95% CI, -41.88 to -6.30; P = .044) and anti-PD1/RT (median CPS, 7.49-23.41; 95% CI, -41.88 to -6.30; P = .009), compared with baseline. In TNBC, adding RT to anti-PD1 significantly decreased TILs (28.9%-17.1%; 95% CI, 2.46 to 21.09; P = .014). Baseline TILs correlated with PD-L1 expression and TNF-a.

Conclusion: Preoperative RT with pembrolizumab is safe and results in high pCR rates and 3-year EFS, despite the lack of pembrolizumab during NAC. PD-L1 and TILs may be predictive biomarkers for preoperative anti-PD1/RT response. Reduction in TILs after adding RT to anti-PD1 highlights the importance of treatment sequencing.

Trial registration: ClinicalTrials.gov NCT03366844.

Fig A1.

Dynamics of circulating blood biomarkers: angiogenesis markers. HR+, hormone receptor–positive; RT, radiation therapy; TNBC, triple-negative breast cancer; VEGF, vascular endothelial growth factor.

Fig A2.

Dynamics of circulating blood biomarkers: proinflammatory markers. HR+, hormone receptor–positive; RT, radiation therapy; TNBC, triple-negative breast cancer.

Fig A3.

Dynamics of circulating blood biomarkers: chemokine markers. HR+, hormone receptor–positive; RT, radiation therapy; TNBC, triple-negative breast cancer.

Fig A4.

Changes in PD-L1 across (A) three biopsy timepoints and (B) two biopsy timepoints using paired samples. CPS, Combined Positive Score; RT, radiation therapy.

Fig A5.

Changes in proportion of TILs across (A) three biopsy timepoints and (B) two biopsy timepoints using paired samples. RT, radiation therapy; TILs, tumor-infiltrating lymphocytes.

Fig 1.

Study treatment and biopsy schema. ^aAdjuvant therapy included RT to the breast/chest wall and regional nodes, capecitabine for patients with TNBC, or endocrine therapy for patients with HR+/HER2− as per the standard of care. HER2−, human epidermal growth factor receptor 2–negative; HR+, hormone receptor–positive; RT, radiation therapy; TNBC, triple-negative breast cancer.

Fig 2.

CONSORT diagram. ^aOne patient with TNBC had two separate tumors biopsied. HER2−, human epidermal growth factor receptor 2–negative; HR+, hormone receptor–positive; TNBC, triple-negative breast cancer.

Fig 3.

Kaplan-Meier curve for EFS for (A) the entire cohort (n = 66) and (B) by subtype (TNBC v HR+/HER2−). EFS, event-free survival; HER2−, human epidermal growth factor receptor 2–negative; HR+, hormone receptor–positive; TNBC, triple-negative breast cancer.

Fig 4.

Longitudinal changes in PD-L1 expression. The PD-L1 IHC 22C2 pharmDx assay was performed to assess PD-L1 CPS ranging from 0 to 100, with changes in expression across all three timepoints (baseline, anti-PD1, anti-PD1 + RT) evaluated using the t-test. The box plot depicts of PD-L1 expression across three timepoints in unpaired samples in (A) the entire cohort, (B) by subtype, and (C) by treatment response groups. Longitudinal changes in PD-L1 expression (A) in unpaired samples, (B) by subtype, and (C) by response status. CPS, Combined Positive Score; HER2−, human epidermal growth factor receptor 2–negative; HR+, hormone receptor–positive; IHC, immunohistochemistry; RT, radiation therapy; TNBC, triple-negative breast cancer.

Fig 5.

Longitudinal changes in TILs. TILs were measured and scored according to the Salgado criteria. The box plot depicts TIL score across all three timepoints (baseline, anti-PD1, anti-PD1 + RT) evaluated using the t-test. The box plot depicts PD-L1 expression across three timepoints in unpaired samples (A) in the entire cohort, (B) by subtype (B), and (C) by treatment response groups. Longitudinal changes in TILs in (A) unpaired samples, (B) by subtype, and (C) by treatment response. HER2−, human epidermal growth factor receptor 2–negative; HR+, hormone receptor–positive; RT, radiation therapy; TILs, tumor-infiltrating lymphocytes; TNBC, triple-negative breast cancer.