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08-12-2013 | Article

Dose titration improves axitinib response in RCC


Free abstract

medwireNews: Dose titration of axitinib in treatment-naïve patients with renal cell carcinoma (RCC) may help to increase the number who achieve an objective response, findings from a phase II study show.

Researchers Brian Rini (Cleveland Clinic Taussig Cancer Institute, Ohio, USA) and colleagues recruited 213 patients from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and the USA. The patients’ median age was 62 years, 67% were male, and 64% had an Eastern Cooperative Oncology Group performance status of 0.

After a 4-week lead-in period during which all patients were given axitinib 5 mg twice daily, those patients who met the criteria for eligibility (such as blood pressure 150/90 mmHg or lower, no grade 3 or 4 axitinib-related toxic effects, and no dose reduction) were randomly assigned to one of two groups: axitinib or placebo titration (n=56 for each). Patients and investigators were blinded to these groups. The 91 patients who were not eligible for randomization continued on axitinib 5 mg twice daily, if it was tolerated.

Thirty (54%) patients in the axitinib titration group had an objective response, as radiographically assessed using Response Evaluation Criteria in Solid Tumors, compared with only 19 (34%) patients in the placebo group. Fifty-nine percent of non-randomized patients achieved an objective response; and the authors suggest that these patients “presumably achieved therapeutic exposure at the 5 mg twice daily starting dose.”

The researchers selected a subset of 73 patients to undergo serial 6-hour pharmacokinetic sampling. This showed that mean axitinib drug exposure on day 15 of the lead-in period was lower in patients who were judged eligible for dose titration (up to a maximum of 10 mg axitinib/5 mg axitinib and 5 mg placebo) than those not deemed eligible.

The authors note in The Lancet Oncology that, although the overall progression-free survival curve favored axitinib, the differences were not significant, and the study was underpowered to detect a difference in progression-free survival between the randomized groups.

Some adverse events were more common in the axitinib titration group, with patients experiencing hypertension, hand–foot syndrome, and vomiting at least 10% more frequently than those in the placebo group.

In a related commentary, Sebastiano Buti (University Hospital, Parma, Italy) and Camillo Porta (IRCCS San Matteo University Hospital Foundation, Pavia, Italy) say the finding of a dose–response relationship with axitinib suggests that tyrosine-kinase inhibitors may have more in common with chemotherapy than previously thought.

“Nevertheless, dose titration to toxicity is not yet ready to become standard practice, given that it does not seem easily applicable to the majority of patients, due to the greater toxicity and subsequent possible resistance by patients and physicians themselves,” they add.

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Afsaneh Gray, medwireNews Reporter