Sorafenib Dose Escalation Not Supported in Most Untreated RCC Patients

Although the use of sorafenib in patients with treatment-naive metastatic renal cell carcinoma (RCC) demonstrated clinical benefit, a phase IIb study published in BJU International did not support the use of dose escalation in these patients.

“We conclude that escalating the sorafenib dose from the standard 400 mg BID may have benefited individual patients able to tolerate this approach. However, this study does not support this type of scheduled dose escalation for all patients with treatment-naive metastatic RCC,” concluded researchers led by Martin E. Gore, PhD, of the Royal Marsden Hospital in London.

The study was designed to test dose escalation of sorafenib as a more effective strategy to treat this incurable disease. A prior study of dose escalation of sorafenib in patients with prior treatment showed some positive results in terms of response rate and progression-free survival.

For this study, 83 patients were treated initially with a standard dose of 400 mg twice daily (BID) sorafenib. Two dose escalations were planned of 200 mg BID after 28 days at the prior dose level. Dose could be adjusted to manage adverse events. The primary endpoint was objective response rate in the modified intent-to-treat (ITT) patients with 6 months or longer of treatments, including at least 4 months at their highest tolerated dose. Forty-nine patients were excluded from the modified ITT population.

Overall, 48.2% of patients received a maximum dose of 400 mg; 15.7%, 600 mg; and 24.1%, 800 mg. In the modified ITT population, the objective response rate was 44.4% (95% CI, 21.5–69.2); it was 17.9% in the ITT population. The 400-mg dose was received for the longest duration (29.5 days).

According to the authors, a response rate of 44% compares favorably to that of other sorafenib trials in the first-line setting, and to the 47.7% response rate in a phase II dose-escalation study published in 2012. “These observations suggest that modified ITT patients may have gained additional benefit from sorafenib dose escalation,” the authors wrote.

In the modified ITT population, all 18 patients had a partial response or stable disease. Tumor shrinkage occurred in 72% of patients on 400 mg, 75% of patients on 600 mg, and 85% of patients on 800 mg.

“These results should be interpreted cautiously due to small patient numbers and the fact that, by definition, the modified ITT population had tolerated sorafenib relatively well,” the researchers wrote. “The modified ITT population may only represent a small proportion of patients with metastatic RCC.”

The modified ITT patients had at least 4 months at the maximum tolerated dose and had “slow-growing tumors” as they were able to stay in study for 6 months or more.

The median progression-free survival for the ITT population was 7.4 months, with 62.3% of patients progression-free at 6 months and 33.4% at 1 year. These rates are “within the ranges reported in phase II/III studies of first-line standard-dose sorafenib in metastatic RCC,” the researchers wrote. “Therefore, the results of this study do not support an improved benefit/risk ratio with sorafenib dose escalation up to 800 mg BID in metastatic RCC compared to historical data with sorafenib 400 mg BID.”

The median progression-free survival increased with increasing dose; it was 3.7 months for 400 mg, 7.4 months for 600 mg, and 8.5 months for 800 mg.

All patients reported at least one adverse event. The most common adverse events of any grade were hand-foot skin reaction (66.3%) and diarrhea (63.9%). Serious treatment-emergent adverse events occurred in 53% of patients. The most common were fatigue, rash/desquamation, gastrointestinal events, hyponatremia, and intra-operative injury.