Elsevier

Gynecologic Oncology

Volume 152, Issue 2, February 2019, Pages 243-250
Gynecologic Oncology

Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: Analysis of KEYNOTE-028

https://doi.org/10.1016/j.ygyno.2018.11.017Get rights and content

Highlights

  • Most patients with ovarian cancer eventually relapse and ultimately die of chemoresistant disease

  • Sustained responses are less likely after second-line and subsequent therapies, suggesting a need for new treatment options

  • Responses to pembrolizumab were modest but durable in patients with advanced ovarian cancer expressing PD-L1

  • The safety profile of pembrolizumab was acceptable, with no deaths or treatment-related discontinuations

  • Further evaluation of pembrolizumab is warranted to identify the tumors most likely to respond in this patient population

Abstract

Objective

To evaluate safety, tolerability, and antitumor activity of pembrolizumab monotherapy in patients with programmed death ligand 1 (PD-L1)–expressing advanced ovarian cancer enrolled in the multicohort, phase Ib KEYNOTE-028 trial.

Methods

Key inclusion criteria were age ≥18 years; advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of previous therapy; and tumor PD-L1 positivity. Patients received pembrolizumab (10 mg/kg every 2 weeks) for ≤24 months or until disease progression/intolerable toxicity. Tumor response was assessed per RECIST v1.1 (investigator review). Adverse events (AEs) were graded using CTCAE version 4.0. Primary end point was confirmed objective response rate (ORR) per RECIST v1.1 (investigator review); data cutoff date was February 20, 2017.

Results

Twenty-six patients (median age, 57.5 years) with PD-L1–positive advanced metastatic ovarian cancer received pembrolizumab; 38.5% had metastatic disease, and 73.1% previously received ≥3 lines of therapy. Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients, most commonly arthralgia (19.2%), nausea (15.4%), and pruritus (15.4%). One grade 3 TRAE (increased plasma transaminase level) occurred. No deaths and no treatment discontinuations due to TRAEs occurred. After a median follow-up duration of 15.4 months, ORR was 11.5% (1 complete response, 2 partial responses); 7 patients (26.9%) achieved stable disease. Median progression-free and overall survival were 1.9 (95% CI, 1.8–3.5) and 13.8 (95% CI, 6.7–18.8) months, respectively.

Conclusion

Pembrolizumab conferred durable antitumor activity with manageable safety and toxicity in patients with advanced PD-L1–positive ovarian cancer and is under further investigation in an ongoing phase II trial, KEYNOTE-100.

Section snippets

Background

Ovarian cancer is the seventh most common cancer in women worldwide (sixth in the United States [1]) and ranks 18th overall. Of 239,000 patients who received diagnoses in 2012, almost two thirds (64%) died of the disease [2], largely because symptoms are vague and nonspecific and appear only when the disease is advanced and because effective screening strategies are lacking [3].

First-line treatment options include cytoreductive surgery followed by carboplatin plus paclitaxel or docetaxel [3].

Study design and patient population

KEYNOTE-028 is a nonrandomized (open-label), multicohort, phase Ib trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for the present cohort were age ≥18 years; advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of previous therapy (or disease for which no standard therapy exists or therapy is not considered appropriate by the patient and treating physician), measurable disease based on Response Evaluation

Baseline patient characteristics

Of 90 screened patients with ovarian cancer, 26 had PD-L1–positive disease and were enrolled (Supplemental Fig. 1). The median age of this cohort was 57.5 years (range, 44 to 75 years). More than one third (38.5%) presented initially with metastatic disease, and more than half (n = 15; 58%) previously received more than three lines of therapy for recurrent/metastatic disease; ten patients (38.5%) previously received at least five lines (Table 1). Consistent with NCCN guidelines [3], all

Discussion

The high rate of relapse or chemotherapy resistance after first-line treatment of ovarian cancer and the diminishing responses to currently recommended second-line or subsequent therapies [[3], [4], [5]] highlight an urgent need for an effective therapeutic strategy in this patient population. The role of PD-L1 selection for pembrolizumab in ovarian cancer has not been explored; however, the established success of pembrolizumab for the treatment of certain PD-L1–positive malignancies [[28], [29]

Acknowledgments

We thank the patients, investigators, and trial site personnel for their contributions to the study. We also thank Roger Danscy and Reshma Rangwala (employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc., Kenilworth, NJ, USA, at the time of this analysis) for contributions to the development of the analysis. Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, Jacqueline Kolston, PhD, and the ApotheCom pembrolizumab team (Yardley, PA, USA). This

Role of the funding source

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc., Kenilworth, NJ, USA. This trial was designed by Merck representatives and academic advisors. Data were analyzed and interpreted by authors and representatives of the sponsor. Data were collected by investigators and site personnel and analyzed and interpreted by authors and Merck representatives. All authors had access to the data. Medical writing and editorial assistance was provided by

Data availability

Merck & Co., Inc.'s data sharing policy, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to [email protected].

Authors' disclosures of potential conflicts of interest

Andrea Varga: Principal/sub-Investigator of Clinical Trials - Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis,

Author contributions

Conception and design: Patrick A. Ott, Janice M. Mehnert.

Collection and assembly of data: Dominique Berton-Rigaud, Patrick A. Ott, Janice M. Mehnert, Anne Morosky.

Data analysis and interpretation: Andrea Varga, Patrick A. Ott, Janice M. Mehnert, Dominique Berton-Rigaud, Daniela Matei, Anne Morosky, Ping Yang, Jane Ruman.

Manuscript writing: All authors.

Final approval of manuscript: All authors.

Accountable for all aspects of the work: All authors.

Provision of study materials: Daniela Matei,

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