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Part 1. Gefitinib and Erlotinib for Non-Small Cell Lung Cancer (continued)
Policy Context of the Current Technology Assessment
Section 641 of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) calls for a demonstration that would pay for drugs and biologicals that are prescribed as replacements for drugs currently covered under Medicare Part B. The demonstration project will be national in scope and will be limited to 50,000 beneficiaries or $500,000,000 in funding, whichever comes first. Forty percent of the funding for this demonstration will be reserved for oral anti-neoplastic drugs.
CMS has requested an assessment of the efficacy of selected oral cancer therapies included in the demonstration relative to drugs currently covered under Medicare Part B. This assessment will provide information that will be used to evaluate the likely effects of the demonstration on patient outcomes and may also provide underlying information to be used for cost-effectiveness analyses that will be
completed by CMS.
The scope of the assessment will be limited to the following demonstration drugs and conditions:
- Imatinib for treatment of chronic myeloid leukemia.
- Imatinib for treatment of gastrointestinal stromal cancer.
- Gefitinib for treatment of non-small cell lung cancer.
- Thalidomide for treatment of multiple myeloma.
This report is responsive to the third item: an assessment of gefitinib for the treatment of non-small cell lung cancer. After work on this report was begun, the parameters were modified to include the closely related orally administered epidermal growth factor tyrosine kinase inhibitor, erlotinib. This was done for three reasons:
- Pivotal trial data suggested that gefitinib had little clinical efficacy.
- A large number of studies were forthcoming on erlotinib suggesting that this drug may have greater clinical efficacy than gefitinib.
- Erlotinib was added to the demonstration project in January 2005.
Clinical Context of the Current Technology Assessment
An estimated 172,570 people will be diagnosed with lung cancer in the United States in 2005.1 Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death in both men and women in this country.1 An estimated 163,510 deaths from lung cancer will occur in 2005 in the United States, accounting for about 29 percent of all cancer-related deaths in the nation.1 Moreover, unlike other cancers there has been no significant improvement in survival rates in the past 30 years.
There are two major types of lung cancer tumor, usually classified as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 84 percent of cases,a has clinical characteristics and treatment approaches that are distinct from SCLC, and accounts for the majority of lung cancer patients who are long-term survivors.
There is a range of treatment options (including non-curative interventions) for patients with lung cancer, and choice of treatment depends on a variety of factors including tumor type, size, and location, and the general health status of the patient. Treatments and combinations of treatments include surgery, chemotherapy, radiotherapy, and best supportive care (BSC). BSC is essentially palliative, but may include radiotherapy and occasionally chemotherapy used with non-curative intent.
Lung cancers at the time of diagnosis have already spread to regional or distant sites in more than 80 percent of cases.1 Five-year survival is approximately 16 percent for patients with regional metastasis and approximately 2 percent for patients with distant metastases. In fact, median survival for advanced non-small cell lung cancer without treatment is only 4 months from time of diagnosis, and fewer than 20 percent of patients survive longer than the first year.
Chemotherapy, in patients with stage IV NSCLC, has been shown to improve survival and palliate symptoms. Cytotoxic agents used in treating NSCLC include platinum-based combination regimens, which are currently recommended as first-line treatment for patients with good performance status.2,3 Furthermore, in the United States, both docetaxel and pemetrexed are approved for use as single agents in second-line chemotherapy.
A new class of drugs has been developed that selectively inhibit the epidermal growth factor receptor tyrosine kinase (EGFR-TK). These drugs block the signal pathways involved in cell proliferation. There are two types of EGFR-TK inhibitors, the small molecules and monoclonal antibodies. Small molecules are orally active and include two drugs currently licensed in the U.S. (Table 1): gefitinib (ZD1839, trade name Iressa™) and erlotinib (OSI-774, trade name Tarceva™). Other drugs are in development. Several monoclonal antibodies directed against EGFR-TK are under investigation, and one is currently licensed in the US: cetuximab (trade name Erbitux™). Monoclonal antibodies directed against EGFR-TK must be administered intravenously.
Gefitinib is a once daily oral medication (250-mg tablet) that was FDA-approved for use as "monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies"( Iressa™ labeling, 2004, AstraZeneca). Gefitinib received accelerated approval by the FDA conditional on the manufacturer agreeing to undertake further clinical studies in order to fully ascertain the drug's clinical benefit. Gefitinib was voluntarily withdrawn in September 2005. Erlotinib is a once daily oral medication (150-mg tablet) that is FDA-approved "for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen"(Tarceva™ labeling, 2004, OSI Pharmaceuticals). Licensure of erlotinib by the FDA included post-marketing obligations on the manufacturer to undertake further clinical studies.90
This report reviews all post-FDA-approval data including recently released data on the efficacy, adverse effects, and potential predictors of response related to the orally active small-molecule EGFR-TK inhibitors gefitinib and erlotinib.
EGFR-TK inhibitors have been undergoing testing for clinical uses beyond the FDA-approved indications. These include: (1) use as monotherapy for first-line treatment for advanced or metastatic NSCLC; and (2) use in combination with chemotherapy for first-line treatment for advanced or metastatic NSCLC. These agents are also under clinical investigation for use in a wide range of cancers.
Scope and Key Questions
The key questions for this review were developed with experts in the field of oncology, health economics, and health policy. The final key questions are as follows:
- In patients with locally advanced or metastatic non-small cell lung cancer, what are the effects of gefitinib and erlotinib compared to platinum-based chemotherapy regimens on survival, disease-free survival, and quality of life?
- In patients with locally advanced or metastatic non-small cell lung cancer who have failed to respond to platinum-based chemotherapy, what are the effects of gefitinib and erlotinib compared to docetaxel plus supportive care or best supportive care alone on survival, disease-free survival, and quality of life?
- In patients with locally advanced or metastatic non-small cell lung cancer, what are the effects of gefitinib and erlotinib compared to platinum-based chemotherapy regimens on adverse effects, tolerability and compliance?
- In patients with locally advanced or metastatic non-small cell lung cancer who have failed to respond to platinum-based chemotherapy, what are the effects of gefitinib and erlotinib compared to docetaxel plus supportive care or best supportive care alone on adverse effects, tolerability, and compliance?
- What patient or tumor characteristics distinguish treatment responders from non-responders and have potential to be used to target therapy?
a Based on crude incidence rates of 52 per 100,000 for NSCLC and 60.3 per 100,000 for all lung and bronchus cancers for the years 1997-2001 (http://seer.cancer.gov/). Thus, NSCLC represents 50/60.3 x 100 = 84% of all incident lung cancer cases.
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