Dosing, drug reduction, drug interruption, and drug discontinuation rates among U.S. FDA approved tyrosine kinase inhibitors.

Abstract

3112 Background: The advent of tyrosine kinase inhibitors (TKIs) has altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. Since many of these drugs are continuously dosed, ongoing toxicities may lead to drug reductions and drug discontinuations. Hence in practice, many patients are started on lower doses due to tolerability concerns or are dose-reduced subsequently for toxicity. Herein, we assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: TKIs were approved for 143 different indications, ranging from 1 indication to 11 indications (eg. Imatinib) from data arising from 7 patients to 2816 patients for a specific indication. Among all TKIs, median dose was 150 mg and average dose was 237 mg; 34 (23.8%) were approved bid vs 71 (49.7%) qd. Specifically for oncology, 54 indications were biomarker based (eg. EGFR mutant NSCLC) and 52 were non-biomarker based for specific diseases (eg. metastatic RCC). Among approved indications range of dose reduction rate (DRR), drug interruption rates (DIR), drug discontinuations rates (DDR) were 0.80-89%, 3%-89%, and 1-39% respectively. Most common reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Geriatric use was listed in 99 indications ( > 65 yrs, 6-68%; > 75 yrs, 0.50-24%). Patient reported outcomes were not available. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients. Future studies are warranted to look into flat dosing vs alternative dosing, like weight-based dosing for TKIs, and to report patient reported outcomes.