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First Published Online January 14, 2009
The Oncologist, Vol. 14, No. 1, 92-94, January 2009; doi:10.1634/theoncologist.2008-0294
© 2009 AlphaMed Press

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Regulatory Issues: FDA

Commentary: Sorafenib—The End of a Long Journey in Search of Systemic Therapy for Hepatocellular Carcinoma, or the Beginning?

Ghassan K. Abou-Alfa

Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Correspondence: Ghassan K. Abou-Alfa, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10022, USA. Telephone: 212-639-3112; Fax: 212-396-5561; e-mail: abou-alg{at}mskcc.org

Received December 31, 2008; accepted for publication January 5, 2009; first published online in THE ONCOLOGIST Express on January 14, 2009.

Disclosures

Ghassan K. Abou-Alfa: Consultant/advisory role: Bayer; Honoraria: Bayer; Research funding/contracted research: Bayer

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers.

In this issue of The Oncologist, Dr. Kane and his colleagues from the U.S. Food and Drug Administration (FDA) give readers an insight into the thought processes of the FDA in following a drug's development up to its approval.

The approval of sorafenib for unresectable hepatocellular carcinoma (HCC) is a major effort that the FDA should be congratulated for, in particular considering the short period of time from its initial recommendations on the design and study plan to the independent analysis of the raw data, up to granting the approval. This approval is timely considering the high prevalence of HCC worldwide [1], its rapidly increasing incidence in the U.S. [2], and the almost three decades of frustrating attempts to identify active agents in this disease.

Moving the median survival time from the historical 6–7 months [3] to 10.7 months with the use of sorafenib is like crossing the first mile of a 1,000-mile desert. Other than offering patients with HCC a new therapy, it also sets a new reference for clinical research in HCC and has generated enthusiasm in clinical researchers and pharmaceutical companies, big and small, in developing therapies in this heretofore neglected disease.

The approval of sorafenib comes after a long, frustrating 30 years of testing different chemotherapeutic agents that did not show any substantial improvement in survival despite some occasional notable responses. These frustrating efforts, other than opening the door for the evaluation of novel therapies in HCC, happened at the same time that the interest in the use of local therapies was growing rapidly. In two well-conducted clinical trials [4, 5], there was a reported survival advantage for transarterial chemoembolization (TACE) over best supportive care. However, this positive outcome was not reproduced by others [6–9]. Bland transarterial embolization (TAE) also has never been shown to have a survival advantage over symptomatic treatment [10, 11]. A meta-analysis of randomized controlled trials between 1980 and 2000 included 2,466 patients [12]. This meta-analysis concluded that TACE significantly reduced the overall 2-year mortality rate, but that TACE was not more effective than TAE. The most recent, and frequently cited, randomized controlled study comparing TACE, TAE, and supportive care [13] again demonstrated a survival advantage for TACE over supportive care. Two older meta-analyses [14, 15] reported no survival advantage for different forms of local therapies, including TACE. Despite this lack of consistent data, chemoembolization with lipiodol or with cytotoxic agents has become accepted de facto on a worldwide basis as a treatment option for patients with unresectable HCC. This historical debate supports and may well explain the decision of the FDA to approve the drug in the unresectable setting and not solely for advanced or metastatic disease. Additionally, 18% of patients in the same analyzed data of the randomized phase III study of sorafenib versus placebo had intermediate disease [16], potentially amenable to local therapy. The ultimate decision to use sorafenib in patients who otherwise are candidates for local therapies will be left to the clinical judgment and intuition of physicians, preferably those working in the collaborative context of a multidisciplinary group.

Given the limited treatment options for hepatocellular carcinoma and what Kane and colleagues explain as "variability in Child Pugh scoring," the FDA approved sorafenib for all patients with unresectable HCC, without specific reference to their level of liver dysfunction. However, the randomized phase III trial of sorafenib versus placebo was conducted only in patients with a good to excellent performance status and Child-Pugh A score [16]. Despite the presence of a very small number of patients with Child-Pugh B liver impairment in this study, the safety and efficacy of sorafenib in patients with Child-Pugh B cirrhosis have not yet been fully determined, and data on the safety and efficacy of patients with lower performance status scores are completely lacking. In a preceding phase II study evaluating sorafenib in HCC [17], 28% of patients had Child-Pugh B cirrhosis. The pharmacokinetics of sorafenib were comparable between the Child-Pugh A and Child-Pugh B patients, with similar drug-related toxicity profiles. However, it was subsequently observed that the Child-Pugh B patients had worsening of their liver function more frequently [18]; an increase in total bilirubin (all grades based on the National Cancer Institute Common Toxicity Criteria, version 3.0) was reported in 40% of Child-Pugh B patients compared with 18% of Child-Pugh A patients. Worsening ascites was noted in 18% of Child-Pugh B patients compared with 11% of Child-Pugh A patients. In addition, 11% of Child-Pugh B patients had emerging or worsening encephalopathy, compared with 2% of Child-Pugh A patients. Because of the fact that direct bilirubin measurements were not collected, it cannot be known from this study if the bilirubin elevation was a result of worsening liver function caused by a toxic effect of sorafenib, a benign inhibitory effect of uridine diphosphate-glucuronosyl-transferase 1A1 by sorafenib leading to decreased bilirubin glucuronidation, or simply a result of disease progression. The median time to progression for Child-Pugh A patients was 21 weeks (95% confidence interval [CI], 16–25 weeks) and for Child-Pugh B patients was 13 weeks (95% CI, 9–18 weeks). The overall survival time for Child-Pugh A patients was 41 weeks (95% CI, 36.6–63.6 weeks) and was 14 weeks for Child-Pugh B patients (95% CI, 11.6–25.7 weeks). It was concluded that Child-Pugh B patients, as would be expected, fared worse than Child-Pugh A patients, and had more frequent worsening of their cirrhosis. It remains unclear though if this is drug related or a result of natural disease progression. More data are needed to appropriately define the safety and efficacy of sorafenib in patients with HCC and Child-Pugh B cirrhosis. In a phase I study evaluating two different doses of sorafenib in Japanese patients with advanced HCC [19], there were no substantial differences in the incidence of adverse events between the Child-Pugh A and B groups. However, pharmacokinetic studies showed that the geometric means of the area under the concentration–time curve from 0–12 hours and maximum concentration at steady state were slightly lower in patients with Child-Pugh B cirrhosis than in patients with Child-Pugh A cirrhosis. Again, patient numbers were too small to permit a meaningful comparison. One additional study, evaluating sorafenib in patients with organ dysfunction, helps give some guidance on the use of sorafenib in such patients [20]. The most commonly reported drug-limiting toxicity among patients with elevated bilirubin at baseline was a further elevation in bilirubin. Suggested recommendations regarding the dosing of sorafenib from this study are: 400 mg orally (PO) twice per day for bilirubin up to 1.5x the upper limit of normal (ULN) and 200 mg PO twice per day (or 400 mg PO daily) for bilirubin 1.5–3x ULN. There was no safe dose of sorafenib established for bilirubin above 3x ULN. One caveat is that this trial was conducted in patients with different types of tumors and not specifically HCC; therefore, the degree of cirrhosis present may not accurately reflect the HCC population.

Dr. Kane and colleagues describe the rigorous process of drug approval and reviewing of the data on sorafenib in HCC by the FDA, and shed important light on the approach they took in granting the broad approval of sorafenib for unresectable HCC. In the next few years, there will be a wealth of data on how to integrate local therapies and systemic treatments in HCC. There will also be further experience and emerging data to help define the safety and efficacy of sorafenib in patients with more advanced cirrhosis.


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