Dose escalation of tyrosine kinase inhibitors (TKIs) after disease progression in patients with metastatic renal cell carcinoma (mRCC) can lead to a decrease in tumor burden and extend duration of therapy, according to a study.
The finding is from a retrospective study of 22 mRCC patients treated with TKIs and received a dose escalation at the occurrence of progressive disease (PD). The most commonly escalated agent after PD was axitinib (17 patients), followed by sunitinib (3 patients) and pazopanib (2 patients). Of the 18 patients with evaluable tumor measurements after dose escalation, 14 (78%) had a decrease in tumor burden, Moshe C. Ornstein, MD, and colleagues at Cleveland Clinic in Ohio reported online ahead of print in Clinical Genitourinary Cancer. The median decrease in tumor burden after dose escalation was 14%. The median duration of TKI therapy was 6.8 months prior to disease progression and 10.1 months after escalated therapy.
The study population had a median age at diagnosis of 58 years. The most common histologic type was clear cell, occurring in 73% of patients.
The findings of continued TKI benefit with dose escalation at PD are especially noteworthy because the study included a heavily pretreated population, with most patients having received 2 or more previous therapies, according to the investigators.
Dr Ornstein’s team concluded that escalated therapy at PD should be considered for select patients.
The researchers stated that a practical concern of TKI dose escalation is the subsequent development of adverse events (AEs) at higher doses. In their study, they pointed out, no grade 4 AEs developed, but the rates of grade 3 AEs were greater after dose escalation after PD than at the lower dose before PD. “Vigilant AE monitoring and a strong supportive care approach to treat the AEs are critical to maintaining patients at higher doses to achieve maximal benefit,” Dr Ornstein and his colleagues stated.
The authors offered some possible explanations for the beneficial clinical effect of dose escalation. One hypothesis is that patients may initially receive a suboptimal dose that results in subtherapeutic plasma drug levels. “As such, the the tumor burden decreases after dose escalation at PD might be a product of higher or adequate drug levels.”
Another possibility is that even with adequate plasma levels of the drug at the starting dose, the plasma levels of the TKIs might decrease over time, resulting in decreased efficacy. “Increasing the dose at PD can therefore return the plasma levels to a therapeutic range.”