Abstract PS5-07-08: CDK4/6 inhibitor (CDK4/6i) dosing knowledge (CDK) study: A pragmatic randomized trial of indicated vs. titrated CDK4/6i dosing in older adults with HR+/HER2- metastatic breast cancer (MBC)

Abstract Background Many cancer drugs have been FDA approved based on a drug development paradigm using a maximum tolerated dose (MTD) approach. For targeted anticancer agents, including CDK4/6is, the MTD approach is less relevant, as the optimal biological dose may be lower than the MTD. CDK4/6is are commonly combined with endocrine therapy (ET) for treatment (tx) of HR+/HER2- MBC. Clinical trials and real-world data show that CDK4/6is are commonly dose-reduced to manage side effects and improve tolerability, without loss of efficacy. Benefits of CDK4/6i therapy are similar in younger and older patients (pts); however, toxicity can be worse in older pts leading to more dose reductions, tx interruptions, and discontinuations. We hypothesize that titrated dosing (i.e., initiating tx at lower doses and escalating as tolerated) may enable older pts to remain on tx longer with fewer adverse events (AEs). The CDK Study (NCT06377852), a multicenter, pragmatic, randomized trial, was developed to determine if titrated dosing of palbociclib (P) or ribociclib (R) in pts aged ≥65 years with HR+/HER2- MBC would allow pts to stay on tx longer than the standard FDA-approved indicated dosing approach. This study is funded through a Patient-Centered Outcomes Research Institute (PCORI) Award (BPS-2022C3-26451). Trial Design For CDK4/6i dosing, pts are randomized 1:1 to: Arm 1 (Indicated): FDA-approved dose (P 125 mg or R 600 mg), or Arm 2 (Titrated): provider-choice lower starting dose (P 75 or 100 mg, or R 200 or 400 mg) with escalation to full dose as tolerated. All pts receive CDK4/6i (P or R) for 21 days in a 28-day cycle plus ET (aromatase inhibitor (AI) or fulvestrant (F)), agent selection is by physician choice. Subsequent dose reduction and discontinuation in both arms is per standard-of-care management. Main Eligibility Criteria Eligible pts are ≥65 years old with HR+/HER2- MBC, adequate organ function, and planned ET initiation in combination with first use of P or R in the metastatic setting. Specific Aims The primary aim is to compare time to discontinuation (TTD), on the indicated dosing arm vs. the titrated dosing arm. Secondary aims include evaluation of progression-free survival, overall survival, toxicity, dose intensity, quality of life (PROMIS-29 and FACT-G, AEs, health care utilization), and associations of baseline factors with outcomes. Statistical Methods Randomization is stratified by CDK4/6i (P vs. R), age (65-74 vs. >75 yrs), and ET (AI vs. F). The primary analysis will estimate the hazard ratio (HR) comparing TTD in the two arms using a stratified Cox proportional hazards model. The null hypothesis will be rejected if the 2-sided p-value for the HR is