TEC Assessment Index

Off-Label Uses of Sorafenib and Sunitinib

Assessment Program
Volume 22, No. 11
November 2007

Executive Summary

Background

Sorafenib (Nexavar®) and sunitinib (Sutent®) are orally administered inhibitors of protein tyrosine kinases associated with the intracellular portions of certain transmembrane receptor molecules. Each targets the tyrosine kinase activity of more than one receptor, with effects that depend on each cell type’s receptor repertoire. Inhibiting these intracellular tyrosine kinases blocks signal transduction after a growth factor, cytokine, or other ligand binds to the receptor’s extracellular domain. In different cell types, this can inhibit tumor growth, metastasis, or angiogenesis (growth of new blood vessels). Both sorafenib and sunitinib are approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma. Sunitinib also is indicated to treat gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib.

Objective

The Assessment summarizes and evaluates evidence on health outcomes of sorafenib and sunitinib for off-label indications reported in published studies or currently undergoing phase III trials. Since these medications overlap only partially with respect to the receptor tyrosine kinases each inhibits, sorafenib and sunitinib were assessed separately.

Search Strategy

MEDLINE® was searched through October 2007 using the terms “Nexavar” or “sorafenib” and “Sutent” or “sunitinib,” limited to English-language articles on human subjects. Online searches of abstracts presented at the 2007 meeting of the American Society of Clinical Oncology (ASCO) supplemented the search.

Selection Criteria

The Assessment includes full-length, peer-reviewed articles reporting on 10 or more patients. Also included are meeting presentations with slides available online, showing results of phase III randomized controlled trials (RCTs) versus placebo or active comparator.

Main Results

For sorafenib, indications that met the first-level screen (i.e., either fully published results are available or a phase III trial is in progress) included: hepatocellular carcinoma (HCC), malignant melanoma, squamous cell cancer of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), GIST, and adjuvant therapy for resected RCC. For sunitinib, indications that met this first-level screen included: breast cancer, colorectal cancer (CRC), NSCLC, and adjuvant therapy for resected RCC. However, the literature search found studies meeting selection criteria (i.e., a published full study with 10 or more patients or phase III results presented at a meeting with slide available online) for only 3 sorafenib off-label indications: HCC, melanoma, and SCCHN. No studies met these selection criteria for any sunitinib off-label indication.*

Two studies evaluated sorafenib as first-line therapy for advanced HCC, a malignancy for which no drug or combination regimen has been shown to increase survival. A placebo-controlled RCT (n=602), presented at ASCO but as-yet unpublished, reported statistically significant improvement in median time to progression (TTP; 5.5 versus 2.8 months; HR: 0.58, 95% CI: 0.44–0.74) and median overall survival (OS; 10.7 versus 7.9 months; HR: 0.69, 95% CI: 0.55–0.88). Adverse effects included absolute increases of 6% in grade 3 or 4 diarrhea and 7-8% in grade 3 or 4 hand/foot skin reactions. A published, single-arm, uncontrolled study (n=137) reported OS was 9.2 months and TTP was 5.5 months.

An as-yet unpublished ASCO presentation was the only study identified on treatment of unresectable or metastatic melanoma. This RCT (n=270) compared carboplatin plus paclitaxel with versus without sorafenib as second-line therapy after progression while on dacarbazine or temozolomide. Results showed no significant difference between arms for objective response rate (ORR), progression-free survival (PFS), or OS, and absolute increases in grades 3 or 4 hand/foot skin reactions, fatigue, and diarrhea of 7%, 6%, and 5%, respectively.

One uncontrolled published study (n=28) reported outcomes of sorafenib as first- or second-line therapy for recurrent or metastatic SCCHN or nasopharyngeal carcinoma. The trial reported OS was 4.2 months.

Author's Conclusions and Comments

Lacking evidence from studies that met selection criteria, no conclusions were possible on outcomes of sorafenib to treat NSCLC or GIST, or as adjuvant therapy for resected RCC. For the same reason, no conclusions were possible on outcomes of sunitinib to treat breast cancer, colorectal cancer, or NSCLC, or as adjuvant therapy for resected RCC. Note also that drug compendia accepted as authoritative sources on off-label uses of oncology drugs by the Centers for Medicare and Medicaid Services (CMS) do not include any of these indications.

While the only available RCT on sorafenib as first-line therapy for advanced HCC has not been published as of this writing, an independent data monitoring committee (DMC) authorized release of the interim analysis showing statistically significant improvement in OS and TTP. No other systemic therapy tested to date has improved survival of patients with advanced HCC. An uncontrolled phase II trial supports conclusions of the RCT. A second RCT recently was also closed early by its DMC (http://www.onyx-pharm.com/wt/page/pr_1188237032), after interim analysis reportedly showed statistically significant improvement in TTP, PFS, and OS. Results of both manufacturer-sponsored RCTs were submitted to FDA to support a supplementary new drug application (sNDA) for adding advanced HCC as approved indication for sorafenib (see TEC criterion 1). Finally, the current guideline on hepatobiliary cancers from the National Comprehensive Cancer Network (available at http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf) includes sorafenib among recommended treatment options for HCC patients with Child-Pugh class A or B disease who are not candidates for liver transplant.

The only available study on sorafenib for second-line therapy of advanced melanoma showed no improvement in response rates, OS, or PFS. An ongoing trial compares paclitaxel plus carboplatin with versus without sorafenib as first-line treatment for patients with advanced melanoma. The only evidence on outcomes of sorafenib for first- or second-line therapy of advanced SCCHN lacks controls and thus does not permit conclusions. Additionally, CMS-accepted drug compendia do not list these indications for sorafenib.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether off-label uses of sorafenib or sunitinib meet the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

The U.S. Food and Drug Administration (FDA) approved sorafenib (Nexavar®) in December 2005 to treat advanced renal cell carcinoma (RCC). In January 2006, the FDA approved sunitinib (Sutent®) to treat advanced RCC, and to treat gastrointestinal stromal tumors (GIST) when there is disease progression on or intolerance to imatinib (Gleevec®). Use of sorafenib to treat patients with hepatocellular carcinoma, melanoma, non-small cell lung cancer, squamous cell head and neck carcinoma or GIST; use of sunitinib to treat patients with colorectal, non-small-cell lung or breast cancers; and use of either drug for adjuvant therapy of resected RCC, all are off-label indications.**

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

This Assessment reviews evidence on health outcomes of sorafenib and sunitinib for off-label indications that either have been reported in published studies or currently are undergoing phase III trials. For off-label indications of sunitinib, no studies were found that met selection criteria for this Assessment (please refer to the first footnote).

Available evidence on outcomes of sorafenib for advanced hepatocellular carcinoma (HCC) included one published, single-arm study (n=137) and one unpublished presentation of a randomized, double-blind, placebo-controlled phase III trial (n=602) from the June 2007 ASCO meeting. The comparative trial reports a statistically significant survival advantage for sorafenib over placebo from an interim analysis reviewed by an independent data monitoring committee (DMC) that authorized early release of results and terminated the study with controls crossed over to active therapy. The single-arm trial supports these results based on similar improvements in TTP and OS. No other systemic therapy for advanced HCC has demonstrated a survival benefit for this rapidly fatal malignancy. In light of this unmet medical need and DMC involvement in analysis of the RCT results, this evidence is judged sufficient to permit conclusions on outcomes of sorafenib for advanced HCC.

One unpublished presentation of a randomized, double-blind, placebo-controlled phase III trial (n=270) from the June 2007 ASCO meeting provides the only available evidence on outcomes of sorafenib for second-line therapy of advanced melanoma. This evidence was judged insufficient to permit conclusions. One published, single-arm trial (n=28) provides the only available evidence on outcomes of sorafenib as first- or second-line therapy for recurrent or metastatic squamous cell head and neck cancer. This evidence was judged insufficient to permit conclusions. No studies that met this Assessment’s selection criteria were found for any other off-label indications for sorafenib.

3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.

In the only reported RCT on HCC, sorafenib improved median TTP (5.5 versus 2.8 months; HR=0.58, 95% CI: 0.44–0.74) and median OS (10.7 versus 7.9 months; HR: 0.69, 95% CI: 0.55–0.88) compared with placebo. Adverse effects included absolute increases of 6% in grade 3 or 4 diarrhea and 7–8% in grade 3 or 4 hand/foot skin reactions. Median OS was 9.2 months and median TTP was 5.5 months in the published single-arm uncontrolled study. Advanced hepatocellular carcinoma has been unresponsive to chemotherapy; no agent has shown a survival benefit in treating this tumor. The available evidence suggests that sorafenib is the first agent to improve overall survival in this disease, relative to best supportive care.

Since evidence is lacking, it cannot be determined whether sorafenib improves outcomes, and is at least as good as alternatives, for patients with advanced melanoma, advanced squamous cell head and neck cancer, or any other off-label indication. For the same reason, it cannot be determined whether sunitinib improves outcomes, and is at least as good as alternatives, for patients with any off-label indication.

5. The improvement must be attainable outside the investigational settings.

The outcomes of sorafenib for advanced HCC reported from the multicenter RCT should be achievable outside the clinical trial setting by clinicians experienced with management of HCC patients. Whether sorafenib improves outcomes for patients with any other off-label indication, and whether sunitinib improves outcomes for patients with any off-label indication, has not yet been determined in the investigational setting.

For the reasons outlined above, sorafenib meets the TEC criteria as a treatment for advanced hepatocellular carcinoma. Sorafenib does not meet the TEC criteria for any other off-label uses, including but not limited to advanced melanoma, unresectable or metastatic squamous cell carcinoma of the head and neck, non-small cell lung cancer (NSCLC), gastrointestinal stromal tumor (GIST), or as adjuvant therapy for renal cell carcinoma. Sunitinib does not meet the TEC criteria for any off-label use, including but not limited to treatment for advanced or metastatic breast cancer, metastatic colorectal cancer, advanced or metastatic NSCLC, or as adjuvant therapy for renal cell carcinoma.

*As this Assessment went to press, a report was published from a Phase II trial of sunitinib for metastatic colorectal cancer that failed standard therapy (Saltz et al. 2007). The study stratified patients by whether they had (group 1; n=43) or had not (group 2; n=41) previously received bevacizumab. Only one patient (from group 1) achieved a partial response, and 13 patients (2 from group 1, 11 from group 2) achieved stable disease for ≥22 weeks. Median time to progression was 2.2 and 2.5 months, respectively, in groups 1 and 2. The authors concluded that “sunitinib did not demonstrate a meaningful single-agent objective response rate in colorectal cancer refractory to standard chemotherapy.” Data are presently unavailable from studies on sunitinib in combination with standard regimens for metastatic colorectal cancer.

**On November 19, 2007, as this Assessment went to press, FDA approved a supplemental new drug application to add advanced hepatocellular carcinoma as a labeled indication for sorafenib.

TEC Assessment Index

KEYWORDS: adjuvant; advanced; angiogenesis; antiangiogenic; BAY43-9006; bladder; breast; carcinoma; c-Kit; clear cell; colorectal; cytokine; extracellular domain; foot; gastrointestinal stromal tumor; GIST; glycoprotein; hand; hand/foot; HCC: cancer; head; hematologic; hepatic; hepatocellular; imatinib; intracellular; kidney; liver; lung; malignancies; malignant; melanoma; metastatic; microvasculature; nasopharyngeal; neck; neovascularization; neuroblastoma; Nexavar; non-small; nonsmall cell; objective response rate; off-label; oncology; ovarian; ovary; overall survival; PDGF; progression free survival; receptor; renal cell; RTK; RTKs; small cell; small molecular; soft tissue; squamous; SU11248; supergene; Sutent; tyrosine kinase; unresectable; VEGF;