Post-CDK 4/6 Inhibitor Therapy: Current Agents and Novel Targets

Abstract

Front-line therapy for advanced and metastatic hormone receptor positive (HR+), HER2 negative (HER-) advanced or metastatic breast cancer (mBC) is endocrine therapy with a CDK4/6 inhibitor (CDK4/6i). The introduction of CDK4/6i has dramatically improved progression-free survival and, in some cases, overall survival. The optimal sequencing of post-front-line therapy must be personalized to patients' overall health and tumor biology. This paper reviews approved next lines of therapy for mBC and available data on efficacy post-progression on CDK4/6i. Given the success of endocrine front-line therapy, there has been an expansion in therapies under clinical investigation targeting the estrogen receptor in novel ways. There are also clinical trials ongoing attempting to overcome CDK4/6i resistance. This paper will review these drugs under investigation, review efficacy data when possible, and provide descriptions of the adverse events reported.

Keywords: CDK4/6 inhibitor; HER2 low; SERD; hormone receptor positive; metastatic breast cancer; second line.

Figure 1

Suggested post-first-line CDK4/6i sequencing of therapy. T-DXd = trastuzumab deruxtecan, gBRCA = germline BRCA mutation, PARPi = PARP inhibitor. Please note that there are no data on the use of fulvestrant post-elacestrant.