Dosing Oncology Therapeutics in Combination Therapy for Renal Dysfunction: The University of California San Diego Study of Personalized Cancer Therapy to Determine Response and Toxicity (UCSD-PREDICT) Experience

Abstract

IntroductionDose reductions are often required to avoid toxicity in combination therapy for advanced cancers, but information on appropriate dose reductions in renal dysfunction is lacking. This study assessed dose reductions of renally cleared oncology agents given in combination therapy in the setting of renal dysfunction.MethodsA database of 1,072 patients was screened to identify patients with renal dysfunction (glomerular filtration rate < 60 mL/min) receiving oncology combination therapy with at least one agent requiring dose reduction for renal insufficiency. The dose of the renal agent was compared to the single-agent renal dosing recommendations to calculate a dose percentage. Tolerability was determined from electronic medical records review.ResultsThirty-three regimens (n = 25 patients) were identified: 11 included at least one targeted agent (n = 8 patients) and 22 had only cytotoxic chemotherapy (n = 18 patients). The renal agent was given at the recommended single-agent renal dose in ~50% of combinations; ~50% of all regimens were tolerated, and only six combinations had dose reductions for toxicity. The median final dose percentage was 100% of the recommended renal dose (range: 25% - 333%); no significant differences were seen between groups (cytotoxic - tolerated, cytotoxic - not tolerated, targeted - tolerated, targeted - not tolerated; p = 0.38). No significant differences were observed between tolerated vs. non-tolerated (p = 0.97) or targeted vs. cytotoxic (p = 0.80) regimens.ConclusionsDose reductions of renally cleared agents are highly variable in oncology patients with renal dysfunction. Additional studies are needed to determine appropriate dosing adjustments in this population.

From Tissue-Agnostic to N-of-One Therapies: (R)Evolution of the Precision Paradigm

“…However, the genomic heterogeneity of advanced malignancies indicates that unique combinations of drugs are needed for each patient [128]. In the I-PREDICT trial [43], this challenge was safely addressed by performing intrapatient dose escalation to tolerance, with baseline doses determined from the analysis of thousands of patients in the literature who received combination anticancer drugs on clinical trials [129][130][131][132][133].…”