Abstract P1-19-23: Impact of early dose reduction of palbociclib on clinical outcomes in patients with hormone-receptor positive metastatic breast cancer
Authors: Moftakhar Bahar , Lekkala Manidhar Reddy , Strawderman Myla , Smith Tae C , Meacham Philip , Fitzgerald Bryan , Dhakal Ajay 
Published: March 2020

Abstract
Background: Palbociclib (palbo), a CDK4/6 inhibitor, is commonly added to an aromatase inhibitor (AI) as the first line therapy in managing estrogen receptor positive, HER2 non amplified (ER+ HER2-) metastatic breast cancer (MBC). Though more tolerable than chemotherapy, palbo may need dose interruption, delay or reduction due to toxicities like neutropenia. Currently, there are no clinical data on the effect of relative dose intensity (RDI) of palbo in the first line setting on clinical outcomes. The primary objective of this study is to explore the correlation of RDI and dose reduction of palbo in the first line setting with median progression free survival (PFS). Methods: This is a retrospective chart review of ER+ HER2- MBC patients (pts) at Wilmot Cancer Center from Jan 1st 2015 to Feb 1st 2019 who had received palbo plus an AI in the first line setting. Men/women more than 18 years old with biopsy proven MBC, who were started on 125 mg of palbo daily, had completed at least 1 cycle of palbo, and did not have disease progression within the first 12 weeks were eligible. Pts receiving fulvestrant with palbo or those switched to other CDK4/6 inhibitors in the first 12 weeks were excluded. Statistical analyses were performed at 12 and 36 weeks landmarks (LM) to compare clinical outcomes. RDI was defined as the total amount of palbo actually taken per total amount of palbo planned within respective LM. RDI-high-12 and RDI-low-12 cohorts were defined as pts receiving palbo with RDI &gt;/= 80% and RDI &lt;80% during the first 12 weeks, respectively. Reduction-12 and No-reduction-12 cohorts were defined as pts who had any reduction and no reduction of the dose of palbo during the first 12 weeks, respectively. Cohorts for 36 weeks LM analysis were defined in a similar fashion. PFS was assessed from the LM rather than from the start of palbo. Objective response rate (ORR) was defined as the rate of complete or partial responses (CR or PR). Response to therapy and clinical benefit (CR, PR or stable disease for at least 6 months) were assessed after LM. Results: 172 charts were screened yielding 56 eligible pts for final analysis. 54% of eligible patients were &gt; 60 years old, 71% had ECOG performance status (PS) 0-1, 88% were post-menopausal, 21% had de novo MBC, and 57% had visceral metastases. By 12 weeks, 24 (43%) pts had a dose reduction and 8 (14%) had RDI &lt;80%. Causes of dose reduction were neutropenia (83%), thrombocytopenia (21%), anemia (8%) and fatigue (8%). Kaplan Meier analysis at 12-week LM showed a median PFS of 17.1 months in RDI-high-12 vs. 6.8 months in RDI-low-12 cohort (p = 0.0014). After adjusting for PS, menopausal status, cancer stage at diagnosis, visceral metastases, and disease-free interval between initial diagnosis and metastatic disease using multivariable Cox proportional hazard model, RDI-low-12 was associated with almost 5 times higher risk for progression compared to RDI high-12 cohort (hazard ratio 4.98. 95% CI 1.87 - 13.28, p=0.001). There was a 7.0 month improvement in median PFS in No-reduction-12 cohort vs. Reduction-12 cohort (17.1 versus 9.8 months, p = 0.1229). At the 36-week LM, median PFS was not reached in RDI-high-36 cohort vs. 8.6 months in RDI-low-36 cohort (p=0.0714). 82.14% of No-reduction-12 achieved clinical benefit compared to 71.43% of Reduction-12 (p=0.49). No-reduction-12 had ORR of 85.7% while Reduction-12 had ORR of 65.0% (p=0.1622). Conclusions: Reduced RDI of palbo (&lt;80%) during the first 12 weeks, when used in combination with an AI in the first line setting in ER+ HER2- MBC, is associated with significantly shorter PFS compared to palbo dose intensity &gt;/= 80%. Similarly, there is a trend towards shorter PFS among pts with RDI of palbo &lt;80% in the first 36 weeks compared to those with RDI &gt;/= 80%. A larger study is needed to validate these findings.
Citation Format: Bahar Moftakhar, Manidhar Reddy Lekkala, Myla Strawderman, Tae C Smith, Philip Meacham, Bryan Fitzgerald, Ajay Dhakal. Impact of early dose reduction of palbociclib on clinical outcomes in patients with hormone-receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-23.