Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

Abstract

Background: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC.Patients and methods: Eligible patients had centrally confirmed mTNBC, !1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for !24 weeks), progression-free survival, and overall survival.Results: All enrolled patients (N ¼ 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received !3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ-21.5þ) and in the PD-L1-positive (range, 6.3-21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs.Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…Pembrolizumab monotherapy has also been tested in the context of the KEYNOTE‐086 phase II trial, which included two cohorts of patients: cohort A enrolled previously treated patients with TNMBC irrespective of PD‐L1 status, whereas cohort B included previously untreated PD‐L1‐positive (IHC assay using clone 22C3) TNMBC. In cohort A, overall response rate (ORR) appeared to be modest and independent from PD‐L1 status; however, a trend toward a greater clinical benefit from pembrolizumab in terms of both disease control rate (DCR) and duration of response was observed in PD‐L1‐positive versus PD‐L1‐negative patients . In cohort B, higher ORR (21.4%) and longer duration of responses (median 10.4 months) were observed as compared with cohort A, thus strengthening the hypothesis that patients with BC harboring PD‐L1 positivity may show good responses to pembrolizumab monotherapy, especially in the earliest lines of treatment for metastatic disease .…”

Inter‐ and intraobserver agreement of programmed death ligand 1 scoring in head and neck squamous cell carcinoma, urothelial carcinoma and breast carcinoma

“…PD‐L1 immunoexpression in TCs and/or ICs is a useful clinical biomarker to select patients who may benefit the most from immune check‐point inhibitors. Evaluation of PD‐L1 IHC has been included as either companion or supplementary tests in multiple anti‐PD1/anti‐PD‐L1 clinical trials of various cancers . Therefore, it becomes increasingly important for practising pathologists to provide reliable and consistent interpretation of PD‐L1 IHC across different tumour types, as it is of paramount importance in determining the eligibility for anti‐PD‐L1/anti‐PD1 therapy and to predict treatment benefits.…”

“…To determine PD‐L1 immunopositivity, the recommended cut‐off values are summarised in Table . These thresholds were established according to clinical response to the associated immune check‐point inhibitor in various clinical trials for UC,, HSCC and BC …”

“…In recent years, PD‐L1 and PD‐1 have emerged as a key check‐point that can be manipulated with inhibitory monoclonal antibodies in various cancer types. Multiple prospective randomised clinical trials have shown promising results of PD‐1/PD‐L1 immune check‐point inhibitors in a variety of cancer types, including a subset of patients with urothelial carcinoma (UC), breast carcinoma (BC) and head and neck squamous cell carcinoma (HSCC), leading to the Food and Drug Administration (FDA) approval of several anti‐PD‐1/PD‐L1 agents …”

“…To date, at least five PD‐L1 antibody clones, 22C3, SP263, SP142, 28‐8 and 73‐10, are commercially available, each marketed as a companion or complementary diagnostic test for a different anti‐PD‐1/PD‐L1 agent . Each antibody is associated with a different criterion for positivity in different cancer types . Therefore, given the complexity of PD‐L1 interpretation, it is important to determine whether pathologists can provide comparable and consistent PD‐L1 scoring in various clinical settings.…”