Thursday, February 19, 2009

NICE and SMC tighten purse strings

The UK's National Institute for Health and Clinical Excellence (NICE) has issued its final appraisal document recommending the use of Pfizer's Sutent (sunitinib) as a first-line treatment for patients with metastatic renal cell carcinoma (RCC). However, sunitinib is the only one of four drugs being appraised that has been preliminarily cleared for use on the NHS, once again raising the question of drug access in the UK compared to the rest of Europe.

NICE is also currently appraising the use of Roche/Genentech's Avastin (bevacizumab), Bayer/Onyx Pharmaceuticals' Nexavar (sorafenib) and Wyeth's Torisel (temsirolimus) for the treatment of advanced and/or metastatic RCC. Following the independent advisory Committee meeting on 14th January, NICE has decided to split this appraisal in two in order to get guidance out to the NHS as quickly as possible. In the first appraisal, sunitinib is recommended as a first-line treatment option in advanced and/or metastatic RCC for patients who are suitable for immunotherapy with an ECOG performance status of 0 or 1. Sunitinib demonstrated a significant improvement in progression-free survival versus interferon alpha. The median survival of patients treated with sunitinib exceeded two years. In September 2008, NICE had issued an appraisal consultation document that advised against the use of all four medicines for the treatment of advanced and/or metastatic RCC. The latest announcement reverses NICE's previous recommendation regarding the coverage of sunitinib, making it the only one of the four medicines under review, that is so far recommended for coverage.

Sunitinib, an oral multi-kinase inhibitor, was first approved in January 2006 for advanced RCC. The drug works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer. Pfizer has agreed a patient access scheme with the Department of Health, in which the first treatment cycle of sunitinib is free to the NHS.

In the second appraisal, bevacizumab, sorafenib and temsirolimus are not recommended as first-line treatment options for advanced and/or metastatic RCC. In addition, the two drugs also licensed for second-line treatment of advanced or metastatic RCC, sorafenib and sunitinib, are not recommended for this indication. Guidance on bevacizumab, sorafenib and temsirolimus for first-line treatment and sorafenib and sunitinib for the second-line treatment of RCC is available for public consultation via NICE until 4th March.

In a statement from Wyeth, the company commented that it believes that denying patients access to the benefits of temsirolimus in extending life-expectancy compared to standard existing therapy is a devastating and cruel blow to patients and their families. Temsirolimus, despite being found to be clinically effective, has been deemed not to be cost-effective in the current assessment.

Similarly disappointing news was announced in Scotland, as the Scottish Medicines Consortium (SMC) published its guidance on the use of GSK's Tyverb (lapatinib) and Eli Lilly's Alimta (pemetrexed), ruling that in both cases the manufacturer did not present a sufficiently robust economic case to gain acceptance. Lapatinib is approved in Europe, in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer, while pemetrexed is indicated, in combination with cisplatin, for the first-line treatment of patients with locally-advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Despite clinical evidence that the two drugs can extend patients' lives by around two months and six weeks, respectively, the price that this comes at is still not seen as cost-effective.

Matthew Dennis - Editor, Cancer Drug News

Wednesday, February 4, 2009

ATLAS meets primary endpoint

The Phase III ATLAS (AVF3671g) study investigating Tarceva (erlotinib) in combination with Avastin (bevacizumab) as maintenance therapy following initial treatment with bevacizumab plus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) has met its primary endpoint. The trial was stopped early on the recommendation of an independent Data Safety Monitoring Board after a preplanned interim analysis showed that combining erlotinib and bevacizumab significantly extended the time patients lived without their disease advancing, as defined by progression-free survival (PFS), compared to bevacizumab plus placebo. A preliminary safety analysis showed adverse events were consistent with previous erlotinib and bevacizumab studies, as well as trials evaluating the two medicines together, and no new safety signals were observed.

The global, multi-centre, randomised, double-blind, placebo-controlled study enrolled 1,157 patients with locally-advanced, recurrent or metastatic NSCLC. In order to evaluate patients who are often excluded from bevacizumab-based trials, patients with treated brain metastases, tumours of squamous cell histology that were not centrally located in the lung and those taking blood-thinning medications were eligible for this trial. Subjects were initially treated with four cycles of bevacizumab in combination with the investigators' choice of platinum-based CT regimens (carboplatin+gemcitabine, carboplatin+paclitaxel, carboplatin+docetaxel, cisplatin+vinorelbine, cisplatin+docetaxel or cisplatin+gemcitabine). If their cancer did not progress and they did not experience significant toxicity, patients were then randomised (n=768) to receive maintenance therapy with bevacizumab+erlotinib or bevacizumab+placebo until disease progression.

The study's primary endpoint of PFS, as determined by investigators, was defined as the length of time from randomisation to disease progression or death from any cause. PFS assessment began from the start of the maintenance phase of the study after initial treatment with four cycles of bevacizumab and CT. Secondary endpoints included overall survival (OS), incidence of all adverse events and selected Grade 3 or greater adverse events and incidence of treatment discontinuation for reasons other than disease progression.

An earlier study, called BeTa Lung, which evaluated bevacizumab in combination with erlotinib in patients with advanced NSCLC whose disease had progressed following platinum-based CT, failed to meet its primary endpoint of improving OS compared to erlotinib in combination with placebo. However, there was clear evidence of clinical activity, with improvements in the secondary endpoints of PFS and response rate when bevacizumab was added to erlotinib compared to erlotinib alone. An additional trial, called SATURN, showed that erlotinib delayed disease progression when given as a single agent immediately following treatment with CT, compared to placebo. In ATLAS, patients were initially treated with bevacizumab plus CT followed by the addition of erlotinib to bevacizumab in the maintenance phase. Genentech plans to discuss these data with the FDA to determine next steps.

Avastin is currently approved as first-line treatment in combination with carboplatin and paclitaxel for patients with locally-advanced, non-squamous NSCLC, based on a 25 per cent improvement in OS compared to CT alone (hazard ratio=0.80). Tarceva is currently approved as a treatment for patients with advanced NSCLC who have progressed following treatment with at least one prior CT regimen, based on a 37 per cent improvement in OS compared to placebo (hazard ratio=0.73). OSI Pharmaceuticals markets Tarceva through partnerships with Genentech in the US and Roche throughout the rest of the world. Avastin is jointly marketed by Genentech and Roche.

Matthew Dennis - Editor, Cancer Drug News

Pfizer to benefit from Wyeth acquisition

A definitive merger agreement has been entered into under which Pfizer will acquire Wyeth in a cash-and-stock transaction, currently valued at US$50.19 per share, or a total of approximately US$68 billion. The Boards of Directors of both companies have approved the combination, which will create one of the most diversified companies in the global healthcare industry.

Under the terms of the transaction, each outstanding share of Wyeth common stock will be converted into the right to receive US$33.00 in cash and 0.985 of a share of Pfizer common stock, subject to the terms of the merger agreement. Based on the closing price of Pfizer stock as of 23rd January, the stock component is valued at US$17.19 per share. The transaction provides immediate value to Wyeth shareholders through the cash component, as well as continued participation in the future prospects expected to result from the combination through their ownership of approximately 16 per cent of Pfizer’s shares. The transaction will be financed through a combination of cash, debt and stock. A consortium of banks has provided commitments for a total of US$22.5 billion in debt. Pfizer and Wyeth expect the transaction to close at the end of the third quarter or during the fourth quarter 2009.

The new company will be an industry leader in human, animal and consumer health. With the combined biopharmaceuticals business, it will lead in primary and specialty care as well as in small and large molecules. Its geographic presence in most of the world’s developed and developing countries will be unrivalled. Wyeth already has a leadership position in growth areas, such as vaccines, nutritionals and biologics. But what will Pfizer be getting for its money?

In the oncology area, Wyeth currently markets the following products: Torisel (temsirolimus) for the treatment of advanced renal cell carcinoma, and also filed in the EU for mantle cell lymphoma; Neumega (oprelvekin) for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with non-myeloid malignancies who are at high risk of severe thrombocytopenia; Mylotarg (gemtuzumab ozogamicin) for the treatment of patients with CD33+ acute myeloid leukaemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy; and Relistor (methylnaltrexone) subcutaneous injection for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. These will be combined with Pfizer's marketed products, which include Camptosar (irinotecan) for colorectal cancer; Sutent (sunitinib) for gastrointestinal stromal tumours and renal cell carcinoma; and Aromasin (exemestane) for breast cancer.

But what about future products? Wyeth's R&D pipeline includes the following oncology compounds: bosutinib, in Phase III for chronic myelogenous leukaemia and Phase II for breast cancer combination therapy; inotuzumab ozogamicin in Phase III for follicular non-Hodgkin's lymphoma (NHL) and Phase II for diffuse large B-cell lymphoma/NHL; and neratinib (HKI-272), which is in late-stage trials for breast cancer. Although Pfizer has many novel drugs in Phase I and II development, its current Phase III pipeline mainly consists of new indications for sunitinib. The main benefit to come from the acquisition of Wyeth will be Pfizer's increased exposure to areas of the oncology market that it does not currently serve, such as haematological cancers and supportive products.

Matthew Dennis - Editor, Cancer Drug News