Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study

Abstract

Background: Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker.Patients and methods: This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months and cohort B received four to six prior lines with a PFI/TFI of !3 months. Pembrolizumab 200 mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.Results: Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2 months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS <1, 5.7% CPS !1, and 10.0% for CPS !10. PFS was 2.1 months for both cohorts. Median OS was not reached for cohort A and was 17.6 months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials.Conclusions: Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response.

Current state and perspectives of checkpoint inhibitors in ovarian cancer treatment

“…Moreover, as suggested by Wieser et al in 2018, PD-L1 expression may be controlled by interferon-gamma, which in return is affected by both TP53 and BRCA mutation status. These findings, however, are to be considered highly experimental and clinical studies will be necessary to confirm these preliminary results [9,[21][22][23].…”

“…ORR differed according to the combined positive score (CPS) <1: ORR 5.0% (95% CI 2.0-10.0%); CPS >1: ORR 10.2% (95% CI 6.3-15.2%); CPS >10: 17.1% (95% CI 9.7-27.0%). Stratification of response according to CPS cut-offs may be of future interest both for patient selection and for prediction of therapy response, even though larger trials will be necessary to validate these results [9].…”

“…Other recent phase 1 and 2 monotherapy studies of three PD1/PD-L1 inhibitors (nivolumab, pembrolizumab, avelumab) reported modest ORRs ranging from 8.0 to 22.0% and a median PFS of 1.9 to 8.2 months, further questioning the efficacy of CPI monotherapy in EOC patients [9,15,16]. However, results of only few clinical trials combining CPIs with antiangiogenic agents and/or PARP inhibitors have been published to date [11,12].…”

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

“…17 Cancer December 15, 2019 This study included 376 patients with recurrent, nonmucinous ovarian cancer who were treated with pembrolizumab at a dose of 200 mg intravenously every 3 weeks in 2 different cohorts.…”

“…The median progression-free survival (PFS) was 2.1 months in both cohorts. 17 Cancer December 15, 2019 The second coprimary endpoint was ORR according to PD-L1 expression measured as the combined positive score (CPS). The CPS is the rate of the total number of PD-L1-positive cells (tumor, lymphocytes, or macrophages) per the total number of cells.…”