Abstract PS10-15: Analysis of systemic therapies following progression on frontline CDK4/6-inhibitor therapy
Authors: Martin James M , Handorf Elizabeth A , Montero Alberto J , Goldstein Lori J 
Published: February 2021

Background: Hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (Her2-) breast cancers represent the majority of metastatic breast cancers (mBC) among women and are often treated with sequential courses of endocrine therapy (ET) prior to the eventual need for chemotherapy (CT). Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) block cell cycle progression and decrease proliferation of breast cancer cells. Currently, there are three available CDK4/6i: palbociclib, ribociclib and abemaciclib. Each has been shown to improve progression-free survival (PFS) when given with ET in the frontline setting, compared to ET alone. After progression on CDK4/6i, no standard of care exists for the next line of systemic therapy, and there are no prospective data to help guide clinical practice. Analysis of real-world data may provide insight into optimal second-line treatment for women who have progressed on CDK4/6i therapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was utilized for this analysis. We evaluated patient data collected from 2015-2020 for women with HR+/Her2- mBC who received CDK4/6i as frontline therapy and received a documented second-line systemic therapy. The objectives of this study were to describe what therapies were given as second-line treatment and estimate the real-world PFS (rwPFS) of those therapies. rwPFS was defined as time between initiation of second-line therapy until clinician-recorded progression (or death). Patients (pts) who did not progress or die were considered censored at the end of follow-up or end of second-line therapy. Results: A total of 1,210 pts with HR+/Her2- mBC received CDK4/6i with ET in the frontline setting, including 29.1% with de novo metastatic disease. Average age at diagnosis of metastatic disease was 64.4 years (range 28-84). A majority of pts received palbociclib in the frontline setting (88.2%), and 68.8% received an aromatase inhibitor (AI) as the frontline ET partner. 839 pts subsequently received second-line therapy (Table 1). CDK4/6i was continued as part of second-line treatment in 308 (36.7%) pts. 249 (29.7%) pts received CT as second-line treatment. The proportion of pts who continued CDK4/6i increased from years 2015-2020 (p=0.035), and the proportion who received CT decreased over time (p&lt;0.001). Of the 308 pts who received a CKD4/6i in the second-line setting, most received the same CDK4/6i in both lines; however, pts treated with abemaciclib or ribociclib in the first-line setting were more likely to receive a different CDK4/6i than those who started with palbociclib (54.2% and 39.1%, respectively, vs. 22.3%). Among 160 pts who received CDK4/6i with fulvestrant in the second-line setting, 81.2% had previously received an AI in the frontline setting. Unadjusted rwPFS appears to favor those pts who continued the CDK4/6i (rwPFS 11.27 months, 95% CI [8.87, 13.31]), compared to CT (rwPFS 4.73 months, 95% CI [3.88, 5.59]), fulvestrant (rwPFS 3.68 months, 95% CI [2.99, 5.22]), or mammalian target of rapamycin (mTOR) inhibitor-based therapy (rwPFS 4.27 months, 95% CI [3.23, 6.14]) (p&lt;0.001). Conclusion: The use of CDK4/6i continuation after frontline progression has increased over time, while the use of CT has decreased. Continuation of CDK4/6i in the second-line setting appears to be the strategy with the greatest rwPFS benefit on unadjusted analysis. Adjusted rwPFS and overall survival will be reported in the future.

TABLE 1. Second-Line Therapy Used. F, fulvestrant; T, tamoxifenSECOND-LINE THERAPYOverall (N=839)AI23 (2.7%)CDK4/6i4 (0.5%)CDK4/6i + AI97 (11.6%)CDK4/6i + F160 (19.1%)CDK4/6i + F + AI35 (4.2%)CDK4/6i + F + T3 (0.4%)CDK4/6i + T3 (0.4%)CT249 (29.7%)F70 (8.3%)F + AI14 (1.7%)mTOR99 (11.7%)PARP4 (0.5%)PI3K16 (1.9%)T11 (1.3%)Clinical Trial51 (6.1%)

Citation Format: James M Martin, Elizabeth A Handorf, Alberto J Montero, Lori J Goldstein. Analysis of systemic therapies following progression on frontline CDK4/6-inhibitor therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-15.