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Palbociclib for Male Patients with Metastatic Breast Cancer

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Palbociclib for Male Patients with Metastatic Breast Cancer Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. CCR-19-2580 Title: FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast Cancer Authors: Suparna Wedam1*, Lola Fashoyin-Aje1*, Erik Bloomquist1, Shenghui Tang1, Rajeshwari Sridhara1, Kirsten B. Goldberg2, Marc R. Theoret1, Laleh Amiri-Kordestani1, Richard Pazdur1,2, Julia A. Beaver1 Authors’ Affiliation: 1Center for Drug Evaluation and Research, U.S. Food and Drug Administration; 2Oncology Center of Excellence, U.S. Food and Drug Administration Running Title: FDA Approval of Palbociclib for Male Breast Cancer Corresponding Author: Suparna Wedam, Office of Hematology and Oncology Products, CDER, U.S. Food and Drug Administration, WO22 Room 2112, 10903 New Hampshire Avenue, Silver Spring, MD 20993. Phone: 301-796-1776 Fax: 301-796-9909. Email: [email protected] *: SW and LF-A contributed equally to this publication. Note: This is a U.S. Government work. There are no restrictions on its use. Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report. Word count: Abstract, 187. Text: 2836. Tables: 1. Figures: 1. References: 17 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract On April 4, 2019, the Food and Drug Administration (FDA) approved a supplemental new drug application for palbociclib (IBRANCE®), to expand the approved indications in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women and subsequently in 2016 in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. The current approval was primarily based on the results of the PALOMA-2 and PALOMA-3 trials and, supported by real-world data (RWD) from electronic health records and insurance claims. To support the safety evaluation in male patients, data from two phase 1 studies with palbociclib and safety information from the global safety database, were also reviewed. This article summarizes FDA decision-making and data supporting the approval of palbociclib for the treatment of male patients with HR-positive, HER2-negative advanced or metastatic breast cancer. Introduction There will be an estimated 2,670 new cases of breast cancer in men in 2019 which represents less than 1 percent of all newly diagnosed breast cancer cases (1-4). Most breast cancers in men express estrogen and/or progesterone receptor., but very rarely overexpress HER2 or are triple negative (5). While data on molecular subtyping and genomic profiling of breast cancer tumors in men are scarce, the available data suggests some potential biologic differences between breast 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. cancer in men and women. Luminal B and HER2 phenotypes are much less common in men than women (5-7). One study has shown that there may be a lower frequency of certain somatic mutations (PIK3CA and TP53) that are commonly seen in ER-positive/Her2-negative female breast cancers (8). Stage for stage, prognosis for men is comparable to that of women, but men are more likely to be diagnosed at an older age and with more advanced disease (2, 9, 10). Men have historically been excluded from breast cancer clinical trials. In the absence of safety and efficacy data from adequate and well-controlled studies in male patients with breast cancer, current clinical practice standards support treatment of men according to a similar treatment paradigm as women. Palbociclib is an inhibitor of the cyclin-dependent kinases (CDK) 4 and 6. Palbociclib initially received accelerated approval on February 3, 2015, for use in combination with letrozole for the treatment of ER-positive, HER2-negative metastatic breast cancer (MBC) as initial endocrine- based therapy in postmenopausal women (11). On February 19, 2016, the U.S. Food and Drug Administration (FDA) granted regular approval for palbociclib in combination with fulvestrant, for the treatment of women with HR-positive, HER2-negative MBC with disease progression following endocrine therapy based on PALOMA-3, a multicenter trial in which men were not eligible (12). On March 31, 2017, FDA granted regular approval for palbociclib as initial endocrine-based therapy for postmenopausal women in combination with any aromatase inhibitor based on PALOMA-2, a multicenter trial in which men were not eligible (13). In this article, we present the FDA rationale for the approval of palbociclib for the use in the treatment of men with breast cancer. 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Methods: Data Sources The following data were reviewed to support the expansion of the palbociclib indications to include men: the results of the PALOMA-2 and PALOMA-3 trials, real-world data (RWD) from electronic health records (EHRs) of male patients with breast cancer treated with palbociclib, insurance claims data for male patients with breast cancer treated with palbociclib, information from the global safety database for palbociclib and from two studies of palbociclib in male patients with other solid tumors, postmarketing reports for palbociclib from the FDA Adverse Event Reporting System (FAERS), and a literature search. PALOMA-2 This is a randomized, double-blind trial in 666 postmenopausal women with ER-positive, HER2- negative MBC naïve to systemic treatment for advanced disease. Patients received palbociclib or placebo, in combination with letrozole. The primary endpoint was investigator-assessed progression free survival (PFS) with key secondary endpoints including overall survival (OS) and objective response rate (ORR). PALOMA-3 PALOMA-3 is a multicenter, double-blind trial which randomized (2:1) 521 women with HR- positive, HER2-negative MBC and disease that progressed on or after prior endocrine therapy to receive palbociclib or placebo, in combination with fulvestrant. The primary endpoint was investigator-assessed PFS with key secondary endpoints including OS and ORR. Flatiron Health Analytic Database 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A retrospective outcomes analysis based upon data from EHRs in the Flatiron Health Analytic Database (FHAD) was submitted. The FHAD contains clinical data and outcomes collected through EHRs used by participating providers of cancer care across the U. S. who primarily provide such care in community oncology clinics. The EHR data processing methods used in the FHAD have been described (14, 15). This analysis identified male patients from the Flatiron database with an International Classification of Diseases (ICD) coding for MBC. Patient-level data were collected between January 1, 2011, and July 31, 2017. The data described the clinical characteristics and outcomes in a cohort of male patients with HR-positive, HER2- negative MBC who had either received a palbociclib-based regimen in any line of therapy (palbociclib cohort), or who had received an endocrine therapy-based regimen in any line of therapy but were never treated with a palbociclib-containing regimen (endocrine cohort). No formal hypothesis testing was performed. Patients were selected for the analysis and were included in one of the two cohorts based upon whether they had a structured medication order for palbociclib, or a structured medication order for endocrine therapy such as tamoxifen or fulvestrant, and without an order for palbociclib. Additional inclusion rules and data processing steps were applied to identify a subgroup of patients who would be included in the current indication for palbociclib (see Figure 1 for the data processing steps). Random sampling was used in the endocrine cohort to reduce the unstructured processing. An activity gap was employed to eliminate individuals who had an initial consult but who received 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript
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