BERKELEY, CA (UroToday.com) - Sorafenib is an orally active small molecule that inhibits tumor cell proliferation and tumor angiogenesis, and increases cellular rates of apoptosis in a wide range of tumor models by inhibiting the serinethreonine kinases Raf-1 and B-Raf and the receptor tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3, and platelet-derived growth factor receptor 1-3.
It was approved by the U.S. Food and Drug Administration at a dose level of 400 mg twice a day (b.i.d.) for the treatment of advanced renal cell carcinoma (RCC).
Phase I studies have evaluated the maximum tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, pharmacodynamics, and recommended phase II dose of sorafenib on the following schedules: sorafenib administered by mouth twice daily, continuous dosing, 4 weeks on, then 1 week off; 3 weeks on, then 1 week off; and 1 week on, then 1 week off.[1, 2] Toxicities have been mild to moderate and included reversible skin rash, hand-foot syndrome, diarrhea, and fatigue. Dose-limiting toxicities were diarrhea (800 mg b.i.d.) and skin toxicity (800 mg b.i.d., 7 days on, then 7 days off). The MTD was established to be 400 mg b.i.d.
Results of a phase II double-blind, placebo-controlled study in patients with advanced metastatic RCC have demonstrated a clinically and statistically significant progression-free survival (PFS) advantage in patients randomized to sorafenib 400 mg b.i.d. compared with those randomized to placebo.[3, 4] In a large, multicenter, randomized phase III trial, sorafenib doubled PFS of patients with advanced RCC compared with placebo.4 In summary, both the preclinical and clinical data support further evaluation of sorafenib in patients with RCC.
Enrolled patients had pathologically confirmed clear cell RCC with progressive metastatic disease, and they had previously received no more than 1 prior cytokine therapy. Additional eligibility criteria included the following: Karnofsky Performance Status (KPS) 70% and adequate hematologic, hepatic, renal, pancreatic, and cardiac function. An initial dose of 400 mg b.i.d. was given from days 1-28. This dose was escalated to 600 mg b.i.d. from days 29-56, and the final escalation to 800 mg b.i.d. was on day 57 onward, unless grade 3 or 4 toxicities were experienced. Treatment delays and dose modifications were permitted for grade 3 or 4 drug-related toxicities.
The primary endpoint of the study was to establish whether the intrapatient dose-escalated strategy can occur in the majority of patients. The secondary endpoints included establishing PFS and OS. Also included was the disease control rate, which is defined as the percentage of patients who had a best response rating of complete response (CR), partial response (PR), or stable disease (SD) according to Response Evaluation Criteria in Solid Tumors version 1.0 that was maintained for at least 28 days from the first demonstration of that rating. Safety was assessed by using version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events.
Forty-six patients were enrolled. Of these, 44 patients were evaluable for toxicity and response. Twenty-three (52%) patients had undergone prior systemic immunotherapy. Eight (18%) patients achieved CR, and 13 patients (30%) achieved PR. In addition, 21 (48%) of the patients had SD, and 8 (18%) had progressive disease < 4 months. Median OS was 35.70 months (range, 0.33-73.33 months), and median PFS was 8.43 months (range, 2.07-66.20 months).
The most common treatment-related adverse events during the intrapatient dose escalation phase were gastrointestinal, constitutional, or dermatologic in nature. Frequent nonhematologic adverse events included diarrhea, weight loss, hand-foot syndrome, alopecia, anorexia, abdominal pain, and hypertension. Grade 3 or 4 laboratory abnormalities consisted of hypophosphatemia. The rate of intrapatient dose escalation for 400 mg b.i.d. (800 mg total dose) was 93% (39 of 42 patients) and from 600 mg b.i.d. (1200 mg total dose) to 800 mg b.i.d. (1600 mg total dose) was 79% (31 of 39 patients). The most frequent reasons for the lack of patient dose escalation are hand-foot syndrome or gastrointestinal adverse events. The rate of dose interruptions was 50%, and the median interval for dose interruption was 11.16 days.
Daily treatment with oral sorafenib at escalating doses produced an encouraging number of objective responses and prolonged disease control in a small population of patients. Furthermore, sorafenib exhibited a CR rate of 18%, a PFS of 35.48 months, and an OS of 35.70. Ninety-two percent of the patients had the ability to dose escalate to 600 mg b.i.d. or 800 mg b.i.d. Although there were some interruptions, these interruptions were infrequent. What is intriguing is that, the longer the patients were receiving sorafenib, the more manageable the adverse events became, and, in fact, with the exception of the loose stool, less frequent. This is the first demonstration of intrapatient dose-escalated sorafenib that showed a significant objective response rate (48%, 21 patients) of which 38% (8 patients) had a durable CR. This efficacy of increased doses of sorafenib and favorable safety data represent an important opportunity in the treatment of advanced RCC. Additional phase III trials should be considered.
References:
- Strumberg D, Voliotis D, Moeller JG, et al. Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors. International Journal of Clinical Pharmacology and Therapeutics 2002; 40(12): 580-1.
- Wong YN, Rossignol D, Rose JR, Kao R, Carter A, Lynn M. Safety, pharmacokinetics, and pharmacodynamics of E5564, a lipid A antagonist, during an ascending single-dose clinical study. Journal of Clinical Pharmacology 2003; 43(7): 735-42.
- Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology: Official journal of the American Society of Clinical Oncology 2006; 24(16): 2505-12.
- Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356(2): 125-34.
Written by:
Robert J. Amato, DO as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Oncology
Department of Internal Medicine
University of Texas
Health Science Center at Houston (Medical School)/Memorial Hermann Cancer Center
Houston, TX USA