Axitinib Dose Titration Improves Outcomes in Metastatic Renal Cell Carcinoma

Brian Rini, MD

Titrating dose levels of axitinib (Inlyta) improved response rates and extended overall survival by 12.3 months in patients with metastatic renal cell carcinoma (mRCC), according to updated results from a phase II study presented earlier this year at the 2015 ASCO Annual Meeting.^1,2

These results highlight the importance of determining proper dosing for each individual patient on axitinib, said lead study author Brian Rini, MD, associate professor of Medicine, Department of Solid Tumor Oncology, at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

“If we give everyone the same dose the drug levels are going to vary widely, and not every patient that could benefit will benefit,” said Rini in an interview with OncLive. “This drug has been extensively studied and the dosing is still not precise. However, there is a clear advantage seen in the patients that were titrated, along with the patients who could not be titrated, that presumably had adequate levels from the start. The primary endpoint of this study was response rate and it did show a 20% advantage in response rate to patients who were titrated. This argues that those patients needed a higher dose for clinical effect.”

In the international, multicenter, randomized, double-blind phase II study, 213 patients with previously untreated mRCC (N = 213) received axitinib at 5 mg twice daily for a 4-week induction period. Of the 213 patients, 112 were eligible for titration. Patients were only titrated if their blood pressure was 150/90 mm Hg or lower, they had no grade 3/4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks.

The 112 eligible patients were randomly assigned in a 1:1 ratio to either the axitinib titration group (n = 56) or the placebo titration group (n = 56). Those in the axitinib titration group received an increased dose of 7 mg twice daily and were then moved to 10 mg twice daily if they continued to tolerate the drug at the higher dose.

If patients in the axitinib titration group experienced too much toxicity, their dose was reduced to the previous level. Ninety-one patients were not eligible for titration, and 10 patients withdrew during the lead-in period.

Median overall survival (OS) from first dose was 42.7 months (24.7—not estimable [NE]) in the axitinib titration arm versus 30.4 months (95% CI, 23.7-45.0) in the placebo titration arm (hazard ratio [HR], 0.785; 95% CI, 0.485-1.272; P = .1616). Median OS in the nonrandomized arm was 41.6 months (95% CI, 33.0-NE). In all patients, median OS was 39.3 months (95% CI; 32.7-45.8).

Fifty-four percent (95% CI, 40-67) of the patients in the axitinib titration group had an objective response versus 34% (22-48) of the patients in the placebo titration group (one-sided P = .019). Progression-free survival (PFS) favored axitinib titration but was not significant. Of the patients not eligible for titration, 59% (95% CI, 49-70) had an objective response.

Following treatment periods of less than 3.5 years, 16% (n = 9) of patients remained on treatment in the axitinib arm, 2% (n = 1) remained on treatment in the placebo arm, and 11% (n = 10) remained on treatment in the nonrandomized arm.

Subtle dose escalation can be done safety with axitinib, said Rini.

“This drug is unique in that it has a very short half-life—4 to 6 hours—so it allows you some flexibility to go up or down in dose and you are not going to overshoot it,” said Rini. “If you go up too much and the patient has toxicity, then you can simply stop the drug and the patient will be better later that day or early the next. You are not putting patients at risk by doing that, and there really is a clinical benefit to doing so.”

The most common treatment-emergent, all-causality adverse events in the axitinib titration, placebo titration, and nonrandomized arms, respectively, were hypertension (63% vs 43% vs 84%), diarrhea (61% vs 63% vs 63%), and fatigue (48% vs 46% vs 54%).

Forty-seven patients (84%) discontinued treatment in the axitinib titration arm, 55 (98%) of patients discontinued in the placebo arm, and 81 (89%) patients discontinued in the nonrandomized arm.

The ongoing study is unique as there are few randomized trials of dose titration, said Rini. However, the findings leave unanswered questions, and additional studies looking at whether smaller dose escalation increases are needed, he added.

“What we have learned in the whole development of this drug is there is a lot of nuance and subtly to this process in finding the right dose of drug for patients,” Rini said. “The biggest unanswered question is, ‘How do we actually do it?’ In clinical practice, the dose escalation should probably be subtler. More research is planned but, for now, oncologists need to be aware that the same dose is not right for every patient and there needs to be a lot of care in finding that perfect individualized dose for each patient.”

1. Rini B, Melichar B, Ueda T, et al. Overall survival analysis from a randomized phase II study of axitinib with or without dose titration for first-line metastatic renal cell carcinoma. J Clin Oncol. 2015;33 (suppl; abstr 4545).
2. Rini B, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. The Lancet Oncology. 2013;14(12):1233-1242.