Package Insert Warnings and Liver Function Tests for CDK4/6 Inhibitors for Breast Cancer

Abstract

This cohort study examines the utilization and timing of liver function tests among patients with breast cancer treated with cyclin-dependent kinase 4/6 inhibitors as recommended by the Food and Drug Administration insert warnings for these drugs.

Introduction

There are 3 therapies in the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapies indicated for hormone receptor (HR)-positive and ERBB2 (formerly HER2)-negative breast cancer, the most common molecular subtype of breast cancer. Two of the three CDK4/6 inhibitors (ribociclib and abemaciclib) have warnings for hepatotoxicity in their package inserts,^1,2 and recommend liver function tests (LFTs) at the time of initiation and during treatment.^1,2 Palbociclib’s label currently does not include those recommendations.³ The objective of this study was to evaluate the association of the Food and Drug Administration (FDA) package inserts for CDK4/6 inhibitors with use of LFTs.

Methods

This cohort study was conducted in the Healthcare Integrated Research Database (HIRD), a US nationwide claims database covering commercial and Medicare Advantage–insured individuals. We estimated utilization of LFTs for individuals using each of the 3 CDK4/6 inhibitors during 3 time periods: (1) 2 weeks prior to treatment initiation including the day of treatment, (2) 1 day before or on the day of treatment initiation, (3) and 60 days following treatment initiation. Initiation was defined as treatment following at least 6 months with no CDK4/6 inhibitor therapy. Acute liver injury (ALI) was defined by a previously developed validated algorithm that sought to identify clinically significant ALI requiring inpatient diagnosis or procedure codes (eg, liver transplantation, necrosis of liver, hepatic failure).⁴ The algorithm did not include transaminase elevations. This study was exempt from institutional review board review because the HIPAA Privacy Rule permits protected health information in a limited dataset to be used or disclosed for research without individual authorization. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. All analyses were performed using the Instant Health Data (IHD) software (Panalgo) and R version 4.2.2 (R Project for Statistical Computing).

Results

The analysis included 15 958 initiators of CDK4/6 inhibitors: 8192 palbociclib, 5000 abemaciclib, and 2766 ribociclib between February 2015 and August 2025 (mean [SD] age, 58.5 [12.2] years; 14 720 female [99%]; 10 234 non-Hispanic White [69%]). Among initiators, 7333 (46.0%) received an LFT in the 2 weeks prior to initiating treatment and 1891 (11.8%) had LFTs at initiation of treatment, with little difference among the therapies (Table). During the first 2 months of CDK4/6 inhibitor treatment, 12 914 patients (80.9%) received LFTs. Among those receiving LFTs after treatment initiation, the mean (SD) time to the first LFT was 11.7 (110.1) days. There were 49 incidents (0.3%) of clinically significant ALI events in the 2 months following treatment, 37 (75.5%) of which occurred among patients who received LFTs in the 2 weeks prior to treatment initiation.

Table. Liver Function Test Utilization at and After CDK4/6 Inhibitor Initiation.

CDK4/6 inhibitor	Patients, No.	Patients, No. (%)
		≤2 wk prior to treatment initiationa	At treatment initiationb	After treatment initiationc
Palbociclib	8192	3844 (46.9)	996 (12.2)	6585 (80.4)
Abemaciclib	5000	2221 (44.4)	570 (11.4)	4061 (81.2)
Ribociclib	2766	1268 (45.8)	325 (11.8)	2268 (82.0)

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6.

^a Time period defined as 14 days prior to CDK4/6 inhibitor initiation through the day of treatment initiation.

^b Treatment initiation defined as 1 day prior or on the day of initiation of a CDK4/6 inhibitor.

^c After treatment initiation defined as within 60 days of CDK4/6 inhibitor initiation.

Discussion

Although LFTs are commonly performed during treatment, this study found that a majority of patients initiating CDK4/6 therapies in the US did not receive LFTs prior to treatment initiation as recommended in FDA-approved package inserts. Results were similar among palbociclib new users (which lacks a warning) compared with ribociclib and abemaciclib new users (which has a hepatotoxicity warning and LFT recommendations), suggesting the package insert warnings have limited impact in clinical practice regarding LFTs. Thus, additional strategies to encourage testing for LFTs at treatment initiation should be considered for CDK4/6 inhibitors. Previous studies have suggested improvements after interventions such electronic health record prompts and modification of National Comprehensive Cancer Network (NCCN) guidelines can improve uptake of evidence-based care. For example, after a hospital system initiated electronic health record order-set tools and other reminders, hepatitis B virus screening rose from 6% to 44%.⁵ Another study found that after NCCN guidelines were updated, the testing rates for germline BRCA increased from 15% in 2008 to 46% in 2018.⁶ This study is limited in that is restricted to commercially insured individuals. We suggest increasing LFT uptake during CDK4/6 inhibitor initiation to reduce risk of hepatotoxicity, by including electronic health record prompts, pharmacy-driven test reminders, and modification of the NCCN guidelines.

Supplement.

Data Sharing Statement