Reduced initial dose of cabozantinib may be feasible in advanced renal cell carcinoma
FORT WORTH, Texas — Patients with advanced renal cell carcinoma may be able to receive a lower starting dose of cabozantinib without compromising efficacy, according to study results presented at HOPA Ahead 2019.
Cabozantinib (Cabometyx, Exelixis) is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with advanced renal cell carcinoma, with a recommended dose of 60 mg orally per day.
However, in the METEOR trial — which served as the foundation for FDA approval — 62% of cabozantinib-treated patients required a dose reduction and 12% discontinued therapy due to toxicity. The median daily dose in that trial was 43 mg.
Although no literature supports an initial dose reduction, some providers at Dana-Farber Cancer Institute empirically reduce the initial dose of cabozantinib for certain patients.
“We wanted to see if there was a difference in efficacy or safety between those who receive the standard dose and those who receive the reduced dose,” Erin Grannan, PharmD, PGY2 oncology pharmacy resident at Dana-Farber Cancer Institute, told HemOnc Today.
Grannan and colleagues received data from 104 patients aged 18 years or older who received cabozantinib as second-line or later therapy between January 2016 and October 2018. Researchers excluded those who received cabozantinib as first-line therapy.
Fifty patients initially received a standard 60-mg daily dose of cabozantinib. The other 54 either received an initial dose of 40 mg daily, or they began on 60 mg daily and had their dose reduced prior to their first scan.
Patients who received a reduced initial dose were older (median age, 64 years vs. 58 years; P = .0023). The groups were well-balanced for other baseline characteristics, including sex, clear cell tumor histology, prior nephrectomy, metastatic sites and ECOG performance status.
Median follow-up was 9 months (range, 0.4-36.1) among patients who were alive at data cutoff.
Patients who received the reduced initial dose appeared more likely than those who received the standard dose to require dose reductions (30% vs. 15%) or holds (34% vs. 20%). However, that was due to the inclusion of 12 patients who initially received the standard dose and then had their dose reduced prior to their initial scan.
“For the manuscript, we’re going to do a subgroup analysis and pull out those 12 patients because they are confounding our results right now,” Grannan said.
The most common toxicities that led to dose reductions or holds were fatigue (32% for reduced dose vs. 9% for standard dose), palmar-plantar erythrodysesthesia (24% vs. 14%) and diarrhea (10% vs. 6%).
Eighty patients in the study — 40 in each treatment group — discontinued therapy.
The most common reasons for discontinuation among patients who received the reduced initial dose were progression (47%), toxicity (15%), death (20%), hospice (15%) or patient decision (3%).
The most common reasons for discontinuation among patients who received the standard initial dose were progression (40%), toxicity (15%), death (32%), patient decision (8%), hospice (2%) or other (3%).
Researchers reported numerically longer median PFS (8.3 months vs. 5.9 months), a higher 1-year OS rate (54% vs. 44%) and longer time to treatment failure (6.1 months vs. 5 months) among patients who received the reduced initial dose; however, none of these differences reached statistical significance.
“We’re really excited about our survival data,” Grannan told HemOnc Today. “Based on these results, we determined you can feasibly start patients on a lower dose of cabozantinib without compromising efficacy.”
The most common grade 1 or grade 2 adverse events in both treatment groups were fatigue, diarrhea and palmar-plantar erythrodysesthesia.
The most common grade 3 or grade 4 adverse events among patients who received the standard initial dose were fatigue, non-healing wounds, palmar-plantar erythrodysesthesia and elevated transaminases. The most common grade 3 or grade 4 adverse events among patients who received the reduced initial dose were fatigue, elevated transaminases and palmar-plantar erythrodysesthesia.
“If we are feasibly able to start patients on a lower dose, we won’t have to hold it as much or do as many dose reductions, and that would be better for the patient,” Grannan said. “They wouldn’t have to experience as many toxicities with the 60-mg dose, and there also would be a cost benefit.” – by Mark Leiser
Reference: Grannan E, et al. Safety and efficacy of a lower starting dose of cabozantinib in renal cell carcinoma. Presented at: HOPA Ahead 2019; April 3-6, 2019; Fort Worth, Texas.
Disclosures : The authors report no relevant financial disclosures.