The Open Issues Regarding Cyclin-Dependent Kinase 4/6 Inhibitors in the Management of Advanced Breast Cancer

http://ejbc.kr | pISSN 1738-6756 eISSN 2092-9900 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. To the Editor, Since the new cyclin-dependent kinase 4/6 (CDK4/6) inhibitor drug class has steadily entered into the clinical practice following the PALOMA, MONALEESA, and MONARCH seminal trials [1], the therapeutic panorama of metastatic breast cancer (mBC) has been further enriched and complicated. While these trials have provided solid and reliable data that support the entry of these drugs into clinical practice, some issues remain. Many of the current international guidelines, such as those from the National Comprehensive Cancer Network (NCCN) [2] and European Society for Medical Oncology (ESMO) [3], suggest the use of CDK4/6 inhibitors for first-line treatment in postmenopausal patients with luminal mBC, except in case of visceral crisis. However, when CDK4/6 inhibitors are introduced after progression on endocrine therapy (ET) as monotherapy, it is not yet well established whether it is possible to maintain the same ET in conjunction with CDK4/6 inhibitors. Preliminary evidence suggests that CDK4/6 inhibition therapy may have the potential to reverse endocrine resistance [4], and this combination regimen would take advantage of this feature. Some preclinical evidence suggests that there is no cross-resistance among CDK4/6 inhibitors [5]. Therefore, maintaining CDK4/6 inhibition beyond progression by modifying the ET backbone may represent a future approach, but to date there are no clinical data. This issue may be addressed once results are known from the MAINTAIN (NCT02632045) [6] and TRINITI-1 (NCT02732119) [7] trials, which involve patients whose disease progressed on CDK4/6 therapy. MAINTAIN trial mandates a switch to a new ET (fulvestrant) for all patients and either additional ribociclib or placebo. The primary endpoint is progression-free survival (PFS) at 24 weeks from study entry, with a secondary endpoint of overall response rate in patients who continue CDK4/6 therapy. TRINITI-1 is a phase I/II, single-arm study of ribociclib in combination with everolimus and exemestane in patients after previous progression on a CDK4/6 inhibitor therapy. The phase II portion of this study will evaluate the clinical benefit rate at 24 weeks as a primary endpoint, and PFS as a secondary endpoint. Notably, TRINITI-1 has included men as a part of its eligible study population, thus contributing invaluable data for this particular group in whom CDK4/6 inhibitor efficacy is not well understood. One feature related to long-term exposure to CDK4/6 inhibitor treatment is activation of the Akt/mammalian target of rapamycin (mTOR) pathway [8]. As such, the combination of mTOR inhibitors, such as everolimus, and CDK4/6 inhibitors is of some interest in order to overcome potential resistance. However, this approach may be limited by toxicity caused by such combinations. Should the results of the TRINITI-1 trial [7] indicate efficacy of this combination in the context of patients at high risk of rapid progression, this treatment could be adopted as first-line treatment and potentially be trialled against upfront induction chemotherapy. International guidelines issued by the NCCN [2] and ESMO [3] currently recommend ET plus a CDK4/6 inhibitor as the preferred first-line treatment option in postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2–) mBC, excluding those patients in whom it is necessary to induce rapid disease control. However, a direct comparison between ET plus CDK4/6 inhibitors and chemotherapy has never been performed. This comparison is of considerable importance, particularly in patients with poor prognostic factors (such as an The Open Issues Regarding Cyclin-Dependent Kinase 4/6 Inhibitors in the Management of Advanced Breast Cancer