QUEST Integration - Sorafenib (Nexavar)

I. Description

Sorafenib (Nexavar) is FDA approved for the treatment of patients with advanced renal cell carcinoma (RCC) and for the treatment of unresectable hepatocellular carcinoma (HCC). Sorafenib is a small molecule that acts by inhibiting multiple receptor tyrosine kinases, some of which are implicated in tumor growth, pathologic angiogenesis and metastatic progression of cancer. It is an orally administered medication.

II. Criteria/Guidelines

1. Sorafenib is covered (subject to the Limitations/Exclusions and Administrative Guidelines) for an initial three months when recommended by an oncologist or hepatologist (for HCC) for one of the following indications:
   1. Treatment of advanced RCC
   2. Treatment of unresectable HCC in a patient who is Child Pugh class A or B (See Appendix)
   3. Treatment of thyroid carcinoma
2. For the above diagnoses and for other diagnoses, HMSA follows NCCN level 1 or 2A and/or DrugDex level I or IIa recommendations.
3. Continuation of therapy is covered (subject to Administrative Guidelines) when the initial therapy has been approved and there is no evidence of progression of disease.

III. Limitations/Exclusions

1. These criteria will continue to apply when sorafenib becomes available in generic form.

IV. Administrative Guidelines

1. Precertification is required for the initial three months of therapy.
2. To precertify, please complete HMSA's Drug Review Request and mail or fax the form as indicated. The following documentation from the medical record must be submitted:
   1. Clinical notes that include the history of previous treatments;
   2. Current oncology notes;
   3. Pathology reports;
   4. Imaging studies;
   5. Laboratory results including: bilirubin, albumin, PT/INR for HCC
   6. Documentation of absence/presence of encephalopathy and ascites for HCC.
3. Precertification is required for continuation of sorafenib for each additional three month period when the initial therapy has been approved and there is no evidence of progression of disease.  The following documentation from the medical record must be submitted:
   1. Current oncology notes documenting the patient's response to treatment, and
   2. Current laboratory results (if applicable) and current imaging studies that show no progression of disease when compared with  previous laboratory/imaging studies.

V. Scientific Background

Advanced Renal Cell Carcinoma

Renal cell carcinoma (RCC) makes up more than 80 percent of all kidney cancers. It is frequently resistant to conventional chemotherapy and patients with advanced RCC often have poor outcomes.

The safety and efficacy of sorafenib were studied for advanced RCC in two randomized controlled trials. The first study of 769 patients with advanced RCC investigated overall progression and progression-free survival (PFS) in a multi-center, randomized, double-blind, placebo-controlled phase III trial. Patients had received one prior systemic therapy. PFS was defined as the time from randomization to progression or death from any cause, whichever occurred earlier. Tumor response rate was a secondary endpoint. Subjects received 400 mg of the drug or placebo twice daily, until evidence of PFS was observed. Patients receiving 400 mg sorafenib demonstrated 167 days of PFS compared to 84 days for patients receiving placebo. . Overall survival was the clinically relevant endpoint but was not reported as the trial was unblinded before the endpoint could be calculated.

A subset analyses included patients who had not previously received interferon treatment. This resulted in PFS of 172 days versus 85 days for patients on placebo.

Another subset analysis radiologically monitored tumor response but was not statistically significant; seven patients (two percent) who received sorafenib had a confirmed partial response but placebo patients did not.

The second clinical study was a Phase II randomized discontinuation trial in patients with metastatic malignancies including advanced RCC. The study investigated PFS at 24 weeks. All patients received sorafenib for the first 12 weeks. Patients with less than a 25 percent change in tumor measurements from baseline were randomized to sorafenib or to placebo for an additional 12 weeks. If progression was observed, placebo patients were able to cross over to sorafenib. Patients with tumor shrinkage continued on sorafenib and patients with tumor growth of more than 25 percent discontinued treatment.

Two hundred two patients with advanced RCC were enrolled in this study. After the initial 12 weeks of therapy with sorafenib, 79 patients with advanced RCC continued on open label sorafenib, 65 were randomized to sorafenib or placebo. At 24 weeks, the 65 patients randomized to sorafenib had significantly longer PFS than the placebo group, 163 days versus 41 days, respectively.

There are no head to head trials that compare sorafenib to any other treatment for advanced RCC.

Hepatocellular Carcinoma

In a Phase III trial, sorafenib demonstrated improvement in patients with HCC. Patients were randomized to either sorafenib (n=299) or placebo (best supportive care) (n=303). The treatment group was given sorafenib as first-line therapy and patients were mainly Child Pugh class A. The sorafenib group demonstrated improvement in overall survival and time to progression. The median survival was 10.7 months with sorafenib and 7.9 months with placebo. Median time to progression was 5.5 months with sorafenib and 2.8 months with placebo.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend sorafenib as a treatment for unresectable (Child Pugh's class A or B) HCC or for (Child Pugh's class A or B) HCC patients who decline surgery.

Thyroid Carcinoma

In a Phase II trial, sorafenib demonstrated improvement in patients with advanced thyroid carcinoma for which curative measures were no longer effective. Thirty patients with metastatic, iodine-refractory thyroid carcinoma received 400 mg of sorafenib twice daily for 16 weeks. Seven patients had a partial response and sixteen patients had stable disease. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although one patient died of liver failure that was likely treatment related.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend sorafenib as a treatment for disseminated, symptomatic, metastatic medullary thyroid carcinoma and as a treatment of papillary, Hurthle cell and follicular thyroid carcinoma, for clinically progressive or symptomatic disease in patients with nonradioiodine-avid tumors at sites other than CNS.

VI. Important Reminder

The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is intended to discourage or prohibit providing other medical advice or treatment deemed appropriate by the treating physician.

Benefit determinations are subject to applicable member contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

This Medical Policy has been developed through consideration of the medical necessity criteria under Hawaii’s Patients’ Bill of Rights and Responsibilities Act (Hawaii Revised Statutes §432E-1.4), generally accepted standards of medical practice and review of medical literature and government approval status. HMSA has determined that services not covered under this Medical Policy will not be medically necessary under Hawaii law in most cases. If a treating physician disagrees with HMSA’s determination as to medical necessity in a given case, the physician may request that HMSA reconsider the application of the medical necessity criteria to the case at issue in light of any supporting documentation.

VII. References

1. Motzer RJ, Bacik J, Schwartz L H, Reuter V, Russo P, Marion S, Mazumdar M. Prognostic Factors for Survival in Previously Treated Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol. 2004; 22 (3):454-463.
2. Sorafenib prescribing information. Bayer Pharmaceuticals Corp.; West Haven, CT.  Revised 10/2010.
3. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Gore M, Desai A, Patnaik A, Xiong HQ, Schwartz B, O’Dwyer P. Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol. 2005 ASCO Annual Meeting Proceedings. 2005;23(16S) June 1 Supplement. 4544.
4. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Gore M, Desai A, Patnaik A, Xiong HQ, Schwartz B, O’Dwyer P. Phase II, placebo-controlled, randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006; 24(16) 2505-2512.
5. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006; 24:4293-4300.
6. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers - v.2.2010.
7. Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, et al. Sorafenib in advanced melanoma: a phase II randomized discontinuation trial analysis. Br J Cancer. 2006; 95: 581-6.
8. The Regence Group. Medication Policy Manual. Nexavar, sorafenib. Policy No. dru134. Revised April 1, 2010
9. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). 2007 ASCO Annual Meeting Proceedings Part I. J Clin Onc 2007, Vol 25, No. 18S (June 20 Supplement), 2007:LBA1.
10. Family Practice Notebook.com. Child-Pugh Score.  http://www.fpnotebook.com/GI/Exam/ChldPhgScr.htm  Accessed 11/10/09.
11. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 2008; 26: 4714-4719.
12. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Thyroid Carcinoma – v.1.2010.

VIII. Appendices 

Child-Pugh Score

1. Indications
   1. Evaluating prognosis in cirrhosis
2. Criteria
   1. Total Serum Bilirubin
      1. Bilirubin <2 mg/dl: 1 point
      2. Bilirubin 2-3 mg/dl: 2 points
      3. Bilirubin >3 mg/dl: 3 points
   2. Serum Albumin
      1. Albumin >3.5 g/dl: 1 point
      2. Albumin 2.8 to 3.5 g/dl: 2 points
      3. Albumin <2.8 g/dl: 3 points
   3. PT/INR
      1. PT (seconds prolonged) <4 seconds /INR <1.70: 1 point
      2. PT (seconds prolonged) 4-6 seconds/INR 1.71 to 2.20: 2 points
      3. PT (seconds prolonged) >6 seconds/INR >2.20: 3 points
   4. Ascites
      1. No Ascites: 1 point
      2. Ascites controlled medically: 2 points
      3. Ascites poorly controlled: 3 points
   5. Encephalopathy
      1. No Encephalopathy: 1 point
      2. Encephalopathy controlled medically: 2 points
      3. Encephalopathy poorly controlled: 3 points
3. Interpretation
   1. Child Class A: 5 to 6 points
   2. Child Class B: 7 to 9 points
   3. Child Class C: 10 to 15 points

Revision History