Addressing physician barriers to administering cyclin-dependent kinases 4 and 6 inhibitors in first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer

Cancer Management and Research Dovepress open access to scientific and medical research Review Cancer Management and Research downloaded from https://www.dovepress.com/ by 88.198.20.149 on 29-Aug-2019 For personal use only. Open Access Full Text Article Addressing physician barriers to administering cyclin-dependent kinases 4 and 6 inhibitors in first-line treatment of hormone receptor– positive, human epidermal growth factor receptor 2–negative advanced breast cancer This article was published in the following Dove Press journal: Cancer Management and Research Reshma L Mahtani Charles L Vogel Sylvester Comprehensive Cancer Center, University of Miami Health System, Deerfield Beach, FL, USA Abstract: Combination therapy with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and an aromatase inhibitor (AI) for first-line treatment of postmenopausal women with advanced breast cancer (ABC) has demonstrated improvement in progression-free survival (PFS) over AI monotherapy without adding substantial toxicity. However, CDK4/6 inhibitor plus AI therapy is not uniformly used as first-line therapy for ABC, indicating that barriers to CDK4/6 inhibitor use exist. Such barriers may include the following perceptions: patients with bone-only metastases, with a long disease-free interval, or who are older may respond to AI monotherapy and may not benefit from a CDK4/6 inhibitor; tumor response rates may be lower and delayed with CDK4/6 inhibitor plus AI therapy than chemotherapy; the increased incidence of adverse events with CDK4/6 inhibitor plus AI therapy outweighs benefits; and the cost of CDK4/6 inhibitors may be prohibitive. Some of these barriers are addressed with data from follow-up analyses of CDK4/6 inhibitor trials, which have shown a PFS benefit of combination therapy in all subgroups assessed, including older patients, those with bone-only metastatic disease, and those with a long disease-free interval. Tumor response rates with CDK4/6 inhibitor plus AI therapy are comparable to those with first-line cytotoxic chemotherapy. Finally, adverse events associated with CDK4/6 inhibitor plus AI therapy are manageable and occur with decreasing severity during treatment, with similar reports of quality of life to those with AI monotherapy. These data support CDK4/6 inhibitor plus AI therapy as the standard of care in first-line treatment of ABC. Keywords: aromatase inhibitor, ribociclib, palbociclib, abemaciclib Introduction Correspondence: Reshma L Mahtani Sylvester Comprehensive Cancer Center, University of Miami Health System, 1192 East Newport Center Drive, Deerfield Beach, FL 33442, USA Tel +1 954 698 3639 Fax +1 954 571 0118 Email 513 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 513–524 Dovepress © 2019 Mahtani and Vogel. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/CMAR.S186658 Powered by TCPDF (www.tcpdf.org) Breast cancer is the most frequently diagnosed cancer and a leading cause of cancer deaths in women in the United States, with an estimated 266,120 new cases and 40,920 deaths in 2018.1 Approximately 71% of breast cancer cases are hormone receptor– positive (HR+; estrogen receptor–positive [ER+] or progesterone receptor–positive) and human epidermal growth factor receptor 2–negative (HER2−).2 In HR+, HER2− advanced postmenopausal breast cancer, aromatase inhibitor (AI) monotherapy is the standard-of-care treatment.3 However, progression is inevitable in the advanced setting, with most patients progressing on AI monotherapy within 13–16 months of treatment, as demonstrated in published studies.4,5 Thus, providing a first-line therapy that extends Dovepress Cancer Management and Research downloaded from https://www.dovepress.com/ by 88.198.20.149 on 29-Aug-2019 For personal use only. Mahtani and Vogel the duration of response to treatment while maintaining quality of life (QoL) is critical for this population of patients with advanced breast cancer (ABC). Five randomized Phase II or III trials of the cyclindependent kinases 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib in combination with an AI have provided evidence of prolonged progression-free survival (PFS) with combination therapy compared with AI monotherapy.6–10 CDK4/6 inhibitors have been approved for use since palbociclib was approved in 2015 on the basis of PALOMA-1 trial results.11–13 However, many physicians continue to prescribe AI monotherapy or chemotherapy to patients with HR+, HER2− metastatic breast cancer in the first-line setting.14,15 Here, we briefly review the overall findings from clinical trials of CDK4/6 inhibitors in the first-line setting, present physician barriers to use of CDK4/6 inhibitor combination therapy in the first-line setting, and review current data that address these barriers. Addressing barriers to use of CDK4/6 inhibitor combination therapy in the first-line setting Five clinical trials, including four Phase III trials, have investigated the use of CDK4/6 inhibitors in combination with an AI in first-line treatment of HR+, HER2− ABC.6–10,16 Although these trials enrolled similar patient populations overall, with some notable exceptions (the MONALEESA-7 trial [ribociclib] included only premenopausal women), there are certain patient characteristics that were represented to a greater extent in some trials than others. For example, there were more Asian patients in the MONARCH 3 trial (abemaciclib) and MONALEESA-7 trial (ribociclib) than other trials (Table 1).7,8,10,16 Thus, caution is advised when comparing individual trial efficacy and safety because conclusions from such comparisons are limited by differences in trial design and patient population. The overall efficacy and safety of CDK4/6 inhibitors in combination with AIs in the first-line setting are summarized in Tables 2 and 3. As of the latest interim data cutoff dates for the Phase III trials, the median PFS in patients receiving a CDK4/6 inhibitor in combination with an AI ranged from 25.3 to 27.6 months (the median PFS was not reached at a median follow-up of 17.8 months in the MONARCH 3 trial).8–10,17 Median PFS for the AI control group ranged from 13.0 to 16.0 months.8–10,17 Combination therapy with CDK4/6 inhibitors was associated with an increased rate of asymptomatic neutropenia vs AI monotherapy, as well as other hematolog (...truncated)