Related Experiment Video
Updated: Sep 11, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Comparative efficacy of first- versus second-line CDK4/6 inhibition in hormone receptor-positive, HER2-negative
Lis Victoria Ravani1, Zahra Bagheri2, Adam M Brufsky3
1Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
Purpose:
The greater progression-free survival (PFS) improvements observed in first-line (1L) versus second-line (2L) CDK4/6 inhibitor (CDK4/6i) trials underpin current guideline recommendations establishing these agents as standard 1L therapy in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). While earlier CDK4/6i use is associated with increased cumulative toxicity and costs, comparative survival data of earlier versus deferred use remain scarce.
Methods:
We performed a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for observational studies and randomized clinical trials (RCTs) including patients treated with first- and/or 2L CDK4/6i. Patients who received CDK4/6 inhibition as part of 1L therapy were included in the 1 L group, while those who did not receive CDK4/6i in the 1L setting and deferred it until the 2L setting were assigned to the 2 L group. Pooled analysis of Kaplan-Meier-derived individual patient data was conducted for PFS2, defined as time from randomization to progression on 2L therapy, and overall survival (OS). Both outcomes were measured from the start of 1L treatment to progression on 2L treatment for both 1L and 2L groups. Sensitivity analysis by study design was also conducted.
Results:
Nine studies (5 RCTs and 4 observational studies) comprising 7,602 patients with mBC were included. Of these, 6,475 (85.1%) received CDK4/6i in 1L, and 1,127 (14.8%) in the 2 L setting. Overall, 1L CDK4/6i therapy was associated with significantly longer PFS2 compared to 2L treatment (HR 2.08; 95%CI 1.90-2.27), a trend not observed in sensitivity analysis of RCTs alone (HR 1.10; 95%CI 0.94-1.30). No significant differences in OS were observed between 1L and 2L CDK4/6i regimens (HR 1.09; 95%CI 1.00-1.18), or in sensitivity analysis of only RCTs (HR 1.03; 95%CI 0.84-1.26).
Conclusion:
This extensive data pool suggests that deferring CDK4/6is to 2L may be associated with worse PFS2 but comparable OS when compared to early use in 1L, challenging the assumption that shifting therapies from 2L to 1L universally improves outcomes despite increased toxicity and costs.
Insights
Using CDK4/6 inhibitors earlier in first-line (1L) metastatic breast cancer treatment may lead to worse progression-free survival (PFS2) compared to second-line (2L) use, despite similar overall survival (OS). This challenges the assumption that earlier use always improves outcomes.
Area of Science:
- Oncology
- Clinical Trials
- Pharmacoeconomics
Background:
- Current guidelines recommend CDK4/6 inhibitors (CDK4/6i) as standard first-line (1L) therapy for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) based on observed progression-free survival (PFS) benefits.
- Earlier use of CDK4/6i is associated with increased cumulative toxicity and healthcare costs.
- Comparative survival data for earlier versus deferred CDK4/6i use are limited.
Purpose of the Study:
- To compare the survival outcomes of CDK4/6 inhibitors when used in the first-line (1L) versus second-line (2L) setting for HR+/HER2- mBC.
- To evaluate the impact of treatment sequencing on PFS2 and overall survival (OS).
Main Methods:
- A systematic review and meta-analysis of observational studies and randomized clinical trials (RCTs) were conducted.
- Studies included patients treated with 1L and/or 2L CDK4/6i.
- Pooled analysis of individual patient data focused on PFS2 (time to progression on 2L therapy) and OS, measured from the start of 1L treatment.
Main Results:
- The analysis included 7,602 patients from 9 studies (5 RCTs, 4 observational).
- Overall, 1L CDK4/6i use was associated with significantly longer PFS2 compared to 2L use (HR 2.08).
- No significant differences in OS were observed between 1L and 2L CDK4/6i use (HR 1.09).
Conclusions:
- Deferring CDK4/6 inhibitors to the 2L setting may be linked to worse PFS2 but comparable OS versus 1L use.
- These findings challenge the universal assumption that shifting CDK4/6i therapy to 1L improves outcomes, considering potential increases in toxicity and costs.
More Related Videos
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
08:59Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
Published on: December 11, 2017
Related Concept Videos
02:34Inhibition of Cdk Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle