Disparities in dosing, drug reduction, and drug discontinuation among US FDA approved tyrosine kinase inhibitors

Introduction

The United States Food and Drug Administration (FDA) uses the recommended phase 2 dose (RP2D) in clinical trials to approve the starting dose for tyrosine kinase inhibitors (TKIs). While kinase inhibitors pose a lower risk for toxic effects than traditional chemotherapy, adequate dosing needs to be studied in greater detail with post-marketing surveillance and more clinical guidance for starting doses and titration. Understanding the mechanisms leading to specific side effects and also including pharmacokinetic studies testing minimal effective dosing may help decrease dose-related adverse events.¹ Since most TKI’s are dosed continuously, undesired toxic side effects may lead to discontinuation. Development of more selective TKIs and dissemination of more specific dosage guidance for oncologists are warranted.² The trailblazer that initiated this cascade of discovery was imatinib which was so effective that now 76 more protein kinase inhibitors have been approved for clinical use.³ Until these more selective TKIs are developed, as they are currently available, they still remain an attractive treatment option. Understanding the nuances that lead to discontinuation will remain important in translating these dosing regimens to clinical practice. Additionally, the populations studied in the drug labels need to be representative of the clinicians’ population.

Nonadherence is not uncommon when people are on TKIs long-term. While data is still evolving and clinical guidance on safe discontinuation is being developed, the negative side effects of the medications that patients face is reason enough for self-discontinuation. The findings from this paper were previously presented at the 2021 ASCO and the 2022 IJCCD conferences.^4,5

Methods

We established a database of all FDA approved TKIs up until 2021 from the FDA online label repository (https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases). 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 years and 75 years. We looked at drug labels from 2001 to 2021.

Continuous variables were summarized as means, medians, and standard deviations, while discrete variables were summarized as frequency with percentage. These statistical summaries were performed using R statistical software (version 4.1.2, 2021, The R Foundation for Statistical Computing).

Results

The TKIs we examined were approved for 143 different indications (Table 1). The greatest number of indications was 11 in the drug imatinib. This data was collected from 2,816 patients for a specific indication. Among the TKIs we studied, the median dose was 200 mg and average dose was 307.7 mg. 36 (24%) TKIs were approved to be dosed bid vs 107 (72%) approved to be dosed qd. In oncology, 52 (35%) indications were biomarker based (e.g., estimated glomerular filtration rate (EGFR) and mutant non-small cell lung cancer (NSCLC)) and 98 (65%) were non-biomarker based for specific diseases (e.g., metastatic renal cell carcinoma (RCC)). Among the approved indications, median rates, dose reduction rate (DRR), drug interruption rate (DIR), and drug discontinuations rate (DDR) were 31%, 52%, and 10% respectively. The most common reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. 111 indications listed geriatric use (>65 years, median 39%; >75 years, median 11%). African American and Hispanic races are consistently underrepresented among the TKI studies (Table 2). Patient reported outcomes (PROs) as reported directly by the patient without interpretation by clinicians prescribing these therapies were not available.^4,5 FDA drug label data does not currently incorporate PROs in their data collection methods.

Conclusions

The introduction of tyrosine kinase inhibitors (TKIs) has altered the treatment patterns of multiple solid malignancies, but studies are still needed in more diverse populations in order to generalize studies to reflect real-world clinical populations. The progress made in tyrosine kinase inhibitor drug development has impacted the way we treat many cancers and has improved prognosis for our patients. Since imatinib’s approval in 2001, there have been a slew of new considerations in the development of new therapeutic agents. While resistance to these agents is mediated through primary mutations as well through metastatic tumor cells evading the inhibitor, there is limited information available regarding dosing of these agents to avoid toxicities.³

The dose reduction and discontinuation rates of TKIs remain variable.^6,7 Further clinical trials should be conducted to evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve quality of life (QOL) in patients. It is also prudent to broaden the study population so that the studies will be generalizable to patients in clinical practice. Future studies are needed to: a. increase representation in the studies to address the disparities; b.to investigate flat dosing vs alternative dosing, such as weight-based dosing for TKIs; and c. report patient reported outcomes as reported directly by the patient without interpretation by clinicians prescribing these therapies, as part of the label.