This Article Abstract Full Text (PDF) All Versions of this Article: theoncologist.2008-0185v1 14/1/95    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kane, R. C. Articles by Pazdur, R. Search for Related Content PubMed PubMed Citation Articles by Kane, R. C. Articles by Pazdur, R.

Regulatory Issues: FDA

Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma

Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Sorafenib • Hepatocellular carcinoma • Regular approval

Correspondence: Robert C. Kane, M.D., Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2109, Silver Spring, Maryland 20993-0004, USA. Telephone: 301-796-2330; Fax: 301-796-9845; e-mail: robert.kane{at}fda.hhs.gov

Received August 21, 2008; accepted for publication December 9, 2008; first published online in THE ONCOLOGIST Express on January 14, 2009.

Disclosures

Robert C. Kane: None; Ann T. Farrell: None; Rajanikanth Madabushi: None; Brian Booth: None; Somesh Chattopadhyay: None; Rajeshwari Sridhara: None; Robert Jsutice: None; Richard Pazdur: None

Section editors René Adam and Kenneth K. Tanabe have disclosed no financial relationships relevant to the content of this article. Andrew X. Zhu discloses a consultant/advisory role with Bayer (sorafenib).

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Target audience: Physicians who wish to advance their current knowledge of clinical cancer medicine in hepatobiliary cancer.

	Learning Objectives

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 

1. Evaluate the evidence of improved overall survival with the use of sorafenib for the treatment of unresectable hepatocellular carcinoma.
   
2. Recognize the potential for drug interactions for sorafenib with concurrent use of drugs that can induce or inhibit CYP3A4.
   
3. Recognize side effects of sorafenib therapy including elevated blood pressure, diarrhea, fatigue, skin rash/ desquamation, hand–foot skin reaction, alopecia, and nausea, and counsel your patients about side effect management.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
Purpose. To describe the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar®; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Experimental Design. The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy.

Results. Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55% (grade 3, 10%), hand–foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%).

Conclusions. Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
On November 16, 2007, the U.S. Food and Drug Administration (FDA) approved sorafenib tosylate (Nexavar®, 200-mg tablets, BAY43–9006; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC). This indication is based on the demonstration of improved overall survival (OS) in a large, randomized, double-blind, placebo-controlled multinational study and a supportive phase II study. The supplemental new drug application was submitted in June 2007 and received a priority review because of the observed effect on survival.

In 2005, sorafenib was first approved for the treatment of renal cell carcinoma (RCC) based on a large, multinational, placebo-controlled trial showing a longer progression-free survival with an acceptable safety profile. A regulatory review of this approval is available [1].

	CLINICAL STUDY

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
The FDA and the sponsors agreed under a special protocol assessment on the design and analysis of this randomized, double-blind, international, multicenter trial comparing the effects of best supportive care plus sorafenib (400 mg twice daily) with those of best supportive care plus a matching placebo in patients with unresectable HCC and no prior systemic therapy. Additional principal eligibility criteria included: pathologic confirmation of HCC; an Eastern Cooperative Oncology Group performance status score of 0, 1, or 2; measurable disease using the Response Evaluation Criteria in Solid Tumors (RECIST); and a Child-Pugh A score. The central randomization and subsequent analyses were stratified by geographic region, performance status, and presence or absence of extrahepatic tumor. All analyses were based on the as-randomized, intention-to-treat (ITT) population. The primary study endpoint was OS. The sample size was planned to demonstrate a 39% longer OS versus a control median survival estimate of 7 months with approximately 90% power, and interim analyses were prespecified with O'Brien-Fleming spending.

Secondary endpoints included the time-to-tumor progression (TTP), with a single analysis planned after 227 progression events, and objective response rate. Both of these tumor measurement assessments were performed by independent blinded radiologic review using the RECIST. Pharmacokinetic (PK) and safety evaluations were also performed. Patients gave written informed consent to be randomized to either sorafenib, taken orally, 400 mg two times daily (800 mg total daily dose) in an uninterrupted schedule, or a matching placebo. The study was conducted in accordance with the precepts established by the Helsinki Declaration and with the approval of a local human investigations committee at each site. Upon disease progression, no subsequent crossover from placebo to sorafenib was provided in the protocol, but this was an option for the data monitoring committee (DMC) to advise based on study results. Clinic visits were scheduled every 3 weeks and radiographic assessments were scheduled every 6 weeks. All patients who received any treatment were included in the safety population.

An analysis of time-to-symptomatic progression (TTSP) was initially prespecified as a coprimary endpoint because of the uncertainty about assessing radiologic response and progression in HCC and to study symptomatic outcomes independently of the radiographic results. Prior to the formal analyses, the FDA and the sponsors agreed that the TTSP analysis would be regarded as exploratory, in part because of concerns about the measurement of symptomatic changes. (Please see the FDA Guidance on patient-reported outcome measures available at http://www.fda.gov/cder/guidance/5460dft.htm.)

	RESULTS

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
Trial enrollment began in March 2005 and was completed in April 2006. Of the total 602 patients, 299 were randomized to sorafenib and 303 were randomized to placebo. Baseline demographic and disease-related factors were well balanced between the two study arms for age, gender, race, performance status, underlying diseases, tumor–node–metastasis stage, presence or absence of extrahepatic tumor (macroscopic vascular invasion or extrahepatic tumor spread), Barcelona Clinic Liver Cancer stage, and liver impairment as reflected by Child-Pugh score. Overall, 87% of patients were enrolled from European sites and 9% from North America. The median age was 67 years; 61% were aged 65 years, 89% were white, and 87% were male. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). By Child-Pugh score, 97% were classified as A and 3% were B. Macroscopic venous extension and/or extrahepatic metastases were present radiographically in 70% of the patients.

Patients could have received prior surgical or local interventional treatments. Prior treatments, also balanced between the arms, included surgical resections (20%), liver-directed therapies (40%, including radiofrequency ablation, percutaneous ethanol injection, and transarterial chemoembolization [TACE]), radiotherapy (5%), and systemic therapy (4%, primarily hormonal). Overall, 491 (82%) patients had received either prior surgery (including excisional biopsy) or prior locoregional treatments. In each group, 29% had received some form of TACE. Protocol violations were uncommon; no randomized patients were excluded from the efficacy analyses, and only three patients who did not receive study drug were excluded from the safety analyses.

Efficacy
The Kaplan–Meier OS curves are shown in Figure 1. At the time of the second planned interim analysis of OS in October 2006, there were 321 deaths, 143 on sorafenib and 178 on placebo. The hazard ratio for sorafenib versus placebo was 0.69 (95% confidence interval [CI], (0.55, 0.87)), and the stratified log-rank test nominal p-value was 0.00058. (For this interim analysis, the associated was 0.0073.) The median OS time for sorafenib was 10.7 months, versus 7.9 months for the placebo group (Table 1). The DMC then advised the sponsor to stop the study on the basis of the positive efficacy findings in conjunction with acceptable safety. The sponsor agreed, and all patients remaining in the placebo arm were offered the option to receive sorafenib. Because the study was stopped and all patients were offered sorafenib, this result was considered the final study analysis for OS.

View larger version (13K): [in this window] [in a new window]   Figure 1. Kaplan–Meier curves for overall survival in the phase III hepatocellular carcinoma trial. At the second interim survival analysis for the intention-to-treat population, with 44.5% of events in the sorafenib group and 55.5% of events in the placebo group, the hazard ratio for sorafenib versus placebo was 0.69 [95% confidence interval, (0.55, 0.87)], and the stratified log-rank test p-value was 0.00058.

The response rate also was based on the independent radiologic review of the ITT population. There were no complete responses; RECIST-confirmed partial responses (PRs) were reported for seven (2.3%) sorafenib patients and two (0.7%) placebo patients. Response durations are not available because of censoring at the time of analysis. By investigator assessment of the RECIST response, 18 (6.0%) sorafenib patients and eight (2.6%) placebo patients were judged as confirmed PRs.

The median treatment duration was 18.6 weeks for placebo and 23 weeks for sorafenib. Based on pill counts at visits, the sponsor estimated that, overall, 284 (94%) patients in the placebo group and 227 (76%) patients in the sorafenib group received an average daily dose of at least 80% of the planned daily dose. The dose of study drug was reduced in 39 (13%) patients in the placebo group and in 96 (32%) patients in the sorafenib group.

Safety
Comparing the placebo-treated group with the sorafenib-treated group (placebo versus sorafenib), there were more serious adverse events (AEs) (54% versus 51%), more AEs leading to permanent drug discontinuation (35% versus 32%), and more deaths within 30 days of receiving the study drug (32% versus 23%) in the placebo group. For sorafenib-treated patients, cardiac ischemia or infarction was reported in 2.7%, versus 1.3% of placebo-treated patients. Among the AEs reported more frequently overall in patients in the sorafenib arm (Table 2), diarrhea occurred in 55% (grade 3, 10%), hand–foot skin reaction occurred in 21% (grade 3, 8%), and hypertension occurred in 9% (grade 3, 4%). Considering the severe AEs (grade 3) that occurred more frequently among the sorafenib-treated patients, hypertension, diarrhea, and hand–foot skin reaction were notable (Table 3). Hemorrhage was not more frequent in the sorafenib group. Hemorrhage/bleeding was reported in 18% of sorafenib patients and 20% of placebo patients. The rates of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 and 4 bleeding were also higher in the placebo group (CTCAE grade 3/4, 3%/2% on sorafenib and 5%/4% on placebo). Bleeding from esophageal varices was reported in 2.4% of sorafenib-treated patients and 4% of placebo-treated patients. Serious AEs were reported more frequently among the placebo-treated patients than among those in the sorafenib arm; vascular thrombosis/embolism was reported in three patients in each group.

Because this HCC study and the earlier RCC study both used the same sorafenib dose and schedule against a placebo control arm, the FDA performed an exploratory cross-study evaluation of severe (grade 3) AEs reported for sorafenib. The frequencies of severe adverse events were similar in the two studies (Table 4).

View this table: [in this window] [in a new window]   Table 4. Exploratory cross-study evaluation of selected severe adverse reactions (grade 3) reported for sorafenib in the RCC and HCC phase III studies

Sorafenib is eliminated primarily by metabolism in the liver mediated by cytochrome P-450 (CYP)3A4 and UDP-glucuronosyltransferase (UGT)1A9. However, in a cross-study evaluation with healthy subjects, sorafenib AUCs were 23%–65% lower in HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with HCC, the PK of sorafenib was similar between groups with Child-Pugh A and B impairment, and no dose adjustment appears necessary between these two groups. The PK of sorafenib in patients with Child-Pugh C hepatic impairment has not been studied. Renal impairment did not alter the PK of sorafenib.

As sorafenib is metabolized by CYP3A4, its PK may be affected by drugs that influence the function of this enzyme. The CYP3A4 inducer rifampin, given 600 mg daily for 8 days, decreased the AUC of sorafenib by 37%. Other drug interactions resulting from coadministration were also assessed. Among various infusional fluorouracil regimens, both increases (21%–47%) and decreases (10%) in the AUC of fluorouracil occurred with concomitant sorafenib treatment. In a study with either 200-mg or 400-mg sorafenib given twice daily prior to docetaxel, increases in the docetaxel AUC averaged 36%–80%, although the sorafenib dosing was stopped 2 days before and resumed 1 day after the docetaxel.

	DISCUSSION

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
No systemic therapy has previously been demonstrated to show a survival improvement in a randomized controlled trial for the treatment of unresectable HCC [2]. In this large, multinational, blinded, placebo-controlled trial, sorafenib therapy resulted in statistically significant and clinically meaningful improvements in OS and in TTP for the population studied. These improvements occurred in the absence of substantial tumor reduction as assessed similarly by both the investigators and the blinded independent radiologic reviewers using the RECIST. Benefits of disease stabilization can be discerned in a parallel-group, blinded, controlled trial. Based on the spectrum of underlying liver conditions, the population studied reasonably represents the HCC condition as encountered in the U.S., except that enrollment was predominately white and Child Pugh A score. In exploratory analyses, the clinical benefit did not appear to depend on the type of underlying liver disease or Child Pugh score A or B. Child Pugh C patients were not enrolled. Given the paucity of treatment options and variability in Child Pugh scoring, the FDA approved the broad indication for therapy of unresectable HCC to facilitate clinical judgment for individual patients.

The sorafenib dose studied (400 mg twice daily) was the same in both the HCC and the RCC populations, and severe AEs (grade 3) occurred with similar frequencies in both studies. Higher sorafenib doses (600 mg twice daily) in early studies produced dose-limiting diarrhea and hand–foot syndrome. The most common adverse reactions (20%), which were considered related to sorafenib, were fatigue, weight loss, skin rash/desquamation, hand–foot skin reaction, alopecia, diarrhea, anorexia, nausea, and abdominal pain. Blood pressure monitoring for hypertension during initiation of sorafenib therapy is important. Temporary interruption of sorafenib therapy is appropriate for patients having major surgical procedures. Laboratory findings of elevated lipase or amylase were observed with or without sorafenib, and such elevations in isolation should not be assumed to be diagnostic of pancreatitis.

Unexpectedly, while sorafenib is eliminated primarily by metabolism in the liver, the sorafenib AUC was lower in HCC patients with hepatic impairment in a cross-study comparison with normal subjects; however, the PK of sorafenib appears similar in HCC patients with Child-Pugh A or B score. The sponsor will evaluate further the effects of hepatic impairment on sorafenib PK in non-HCC patients. In vitro data indicate that sorafenib is metabolized by the CYP3A4 and UGT1A9 pathways. Inducers of CYP3A4 activity (e.g., Hypericum perforatum, also known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may increase the metabolism of sorafenib and thus decrease sorafenib concentrations. Additional cautions are described in the revised label regarding potential drug interactions for coadministration of sorafenib with docetaxel, doxorubicin, or fluorouracil.

Editor's Note: The investigators' study report has been published: Llovet JM, Ricci S, Mazzaferron V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390.

	AUTHOR CONTRIBUTIONS

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
Conception/design: Robert Kane, Ann T. Farrell, Brian Booth

Collection/assembly of data: Robert Kane, Rajanikanth Madabushi, Somesh Chattopadhyay

Data analysis: Robert Kane, Ann T. Farrell, Rajanikanth Madabushi, Brian Booth, Somesh Chattopadhyay, Rajeshwari Sridhara, Robert Justice, Richard Pazdur

Manuscript writing: Robert Kane, Ann T. Farrell, Rajanikanth Madabushi, Brian Booth, Somesh Chattopadhyay, Rajeshwari Sridhara, Robert Justice, Richard Pazdur

Final approval of manuscript: Robert Kane, Ann T. Farrell, Rajanikanth Madabushi, Brian Booth, Somesh Chattopadhyay, Rajeshwari Sridhara, Robert Justice, Richard Pazdur

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 
The views expressed herein are independent work and do not necessarily represent the views of the U.S. Food and Drug Administration.

	REFERENCES

Top Learning Objectives Abstract Introduction Clinical Study Results Discussion Author Contributions References

 

1. Kane RC, Farrell AT, Saber H et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 2006;12:7271–7278.[Abstract/Free Full Text]
2. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519–524.[CrossRef][Medline]

This article has been cited by other articles:

				D. S. Hong, S. M. Sebti, R. A. Newman, M. A. Blaskovich, L. Ye, R. F. Gagel, S. Moulder, J. J. Wheler, A. Naing, N. M. Tannir, et al. Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies Clin. Cancer Res., November 15, 2009; 15(22): 7061 - 7068. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: theoncologist.2008-0185v1 14/1/95    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kane, R. C. Articles by Pazdur, R. Search for Related Content PubMed PubMed Citation Articles by Kane, R. C. Articles by Pazdur, R.