Abstract S5-07: Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028

Abstract

Background: The programmed cell death 1 (PD-1) pathway is used by tumors to evade immune surveillance. Pembrolizumab is a humanized anti–PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab has shown robust antitumor activity against several advanced malignancies, including triple-negative breast cancer. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive, ER+/HER2-negative advanced breast cancer. Methods: KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is an ongoing multicohort, open-label phase 1b study evaluating the safety and efficacy of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for this cohort include ER+ and HER2-negative tumor status defined by institutional standards, locally advanced or metastatic disease, ECOG performance status of 0 or 1, failure of or inability to receive standard therapy, and PD-L1 expression in stroma or in ≥1% of tumor cells as assessed at a central laboratory using a prototype immunohistochemistry assay with the 22C3 antibody (Merck). Pembrolizumab was administered at a dose of 10 mg/kg every 2 weeks for up to 24 months or until confirmed progression or intolerable toxicity. Response is based on RECIST v1.1 as assessed by investigator review every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary efficacy end point is overall response rate (ORR). Results: Of the 248 patients with ER+/HER2-negative breast cancer who had evaluable tumor samples screened for PD-L1 expression, 48 (19%) had PD-L1–positive tumors. Of these, 25 patients were enrolled. Median age was 53 years (range, 36-79), and 44% of patients had an ECOG performance status of 1. Patients were heavily pretreated, with 76% having received ≥3 prior lines of therapy for advanced disease, including 48.0% who received ≥5 prior lines. Analyses of ORR, duration of response, and adverse events are ongoing and will be completed by September 4, 2015. Conclusion: Data from this KEYNOTE-028 cohort will provide information on the antitumor activity and safety of pembrolizumab in patients with heavily pretreated, PD-L1–positive, ER+/HER2-negative advanced breast cancer. Citation Format: Rugo HS, Delord J-P, Im S-A, Ott PA, Piha-Paul SA, Bedard PL, Sachdev J, Le Tourneau C, van Brummelen E, Varga A, Saraf S, Pietrangelo D, Karantza V, Tan A. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-07.

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…Mirroring findings in the clinic, 4,10 some subjects (mice) did not respond to immunotherapy at all, while others experienced slower tumor growth or eradication of the tumor altogether. RON inhibition alone (RON i single agent) did not result in appreciable clinical benefit, and it did not significantly reduce tumor growth rate compared to the vehicle group (Figure 3a-c).…”

“…Preliminary results in trials involving inhibitors of PD-1 or its ligand PD-L1 suggest that some breast cancer patients can benefit from checkpoint immunotherapy, although response rates were only 10–20%. 10–13 …”

Pembrolizumab (Keytruda)

“…In 25 patients with estrogen receptor positive / HER2 negative breast cancer, who had received prior chemotherapy and hormonal therapy, the ORR was only 12%. 71 One patient had grade 3 hepatitis requiring dose interruption. In 23 patients with advanced CRC, the ORR was merely 4.3%.…”

Recent advances in breast cancer treatment

“…An improved clinical activity has been observed in treating triplenegative breast cancer and those expressing PD-L1. 16 We await further results of clinical trials using immunotherapy.…”