Even if Tarceva is approved, Iressa is expected to be the leading epidermal growth factor inhibitor for treating nonsmall cell lung cancer.
by Med Ad News Staff
Tarceva could be cleared in the second half of 2004, but analysts say the drug will not overtake Iressa as the leading epidermal growth factor receptor inhibitor for the treatment of nonsmall cell lung cancer. As the drug first to market, Iressa has gained force. Analysts expect Iressa sales of more than $500 million in 2005 and Tarceva sales in the $100 million to $300 million range in the same year. Iressa will have been available in Japan at least two years before and in the United States at least one year before Tarceva may gain its first approval anywhere.
Tarceva is being jointly developed by Genentech Inc., Roche, and OSI Pharmaceuticals Inc. The product is in Phase III clinical trials as monotherapy and combination treatment in second-line and third-line settings for nonsmall cell lung cancer. Analysts believe that results from these trials, which are due in the first quarter of 2004, will significantly boost Tarceva's marketability. Tarceva is in clinical trials for other cancers, including bronchioloalveolar cell, pancreatic, ovarian, breast, advanced head and neck, and malignant glioma.
Iressa initially was approved in Japan for the first-line treatment of nonsmall cell lung cancer in the third quarter of 2002. In the United States, Iressa was approved in May 2003 as third-line monotherapy after failure of platinum-based and docetaxel chemotherapies in late-stage patients with no remaining treatment options.
Merrill Lynch analysts forecast Iressa U.S. sales of $233 million in 2003, $424 million in 2004, $541 million in 2005, and $659 million in 2006. Iressa was restricted to third-line therapy in the United States because of safety concerns. The drug has been linked to a serious side effect known as interstitial lung disease, a condition that causes inflammation, scarring, and tissue damage in the lungs. Despite the safety issues, Iressa is generating good sales growth. Iressa controlled 70% of the nonsmall cell lung cancer market 12 months into its Japanese launch. Four months into the U.S. launch, sales were averaging $2.5 million a week. Total Iressa sales amounted to $67 million in 2002.
Merrill Lynch (ml.com) projects Tarceva worldwide sales of $268 million in 2005 and $490 million in 2006.
Iressa is the only inhibitor to epidermal growth factor receptor - or EGFR - approved for the treatment of advanced or metastatic nonsmall cell lung cancer in the United States, Japan, and Australia. Iressa was developed to block growth stimulatory signals in cancer cells. These signals are mediated in part by enzymes called tyrosine kinases. Iressa blocks several of these tyrosine kinases, including the one associated with epidermal growth factor receptor.
Tarceva is a small molecule designed to target the human epidermal growth factor receptor 1 pathway, which is critical to cell growth in many cancers. HER1, also known as epidermal growth factor receptor, is a key component of the HER signaling pathway, which often is involved in the formation and growth of numerous cancers. Tarceva is designed to inhibit the tyrosine kinase activity of the HER1 signaling pathway inside the cell, which blocks tumor cell growth.
There are about 1.6 billion U.S. cases of nonsmall lung cancer, of which 1.3 billion have been diagnosed. Lung cancer is the single-largest cause of cancer deaths in the United States and is responsible for almost 30% of cancer deaths in the country. Analysts believe that even the third-line therapy market for nonsmall cell lung cancer could have sales potential of more than $1 billion.
The marketer of Tarceva, AstraZeneca (astrazeneca.com), continues to explore Iressa's uses in several different forms of cancer. Iressa is in Phase II clinical trials for the treatment of colorectal cancer and breast cancer. In addition, Phase III clinical trials are exploring Iressa for the treatment of head and neck cancer.
Genentech, Roche (roche.com), and OSI (osipharm.com) are developing Tarceva in nonsmall cell lung cancer trials that include a Phase III study of Tarceva as a single agent in second-line and third-line settings, and a Phase II study of Tarceva as a single agent in bronchioloalveolar cell carcinoma.
Targeted cancer drugs such as Iressa and Tarceva are designed to focus only on the special biology of the cancer cell while leaving noncancerous cells unaffected. Although each targeted therapy may work a little differently, most focus their activity on proteins that stimulate cancer cell growth, such as epidermal growth factor. Lung, breast, ovarian, bladder, prostate, colorectal, kidney, and head and neck cancer overproduce epidermal growth factor proteins.
Several cancer drugs that target receptors for different growth proteins have revolutionized cancer treatment. The first such drug to be approved was Herceptin from Genentech (gene.com) for breast cancer. Herceptin is a humanized HER2 antibody to the HER2 protein, and targets the HER2 receptors in breast cancer cells. Gleevec from Novartis (novartis.com) targets tyrosine kinase, an intracellular protein that sends signals similar to the endothelial growth factor receptor. Gleevec has changed the way chronic myeloid leukemia is treated and has been shown to work in rare gastrointestinal stromal tumors.
Iressa was the third targeted cancer therapy to be approved by FDA. Analysts say failures by epidermal growth factor inhibitors in major clinical trials have diminished the promise of this drug class. If the results of the clinical trials involving Tarceva and Iressa are positive, however, both drugs still are likely to have some role in the management of cancer, most likely in combination with other innovative cancer drugs.
In October 2003, Genentech, OSI , and Roche reported that Tarceva missed the primary end point of the improvement of survival in two pivotal Phase III first-line nonsmall cell lung cancer trials. Clinical developers were not surprised by Tarceva's inability to meet the trials' primary end point because of Iressa's failure in a similar front-line nonsmall cell lung cancer trial in 2002.
"We are disappointed, but not completely surprised based on previously announced failures of EGFR inhibitors in this setting, that Tarceva in combination with chemotherapy did not improve overall survival as a first-line therapy in these studies," says Susan D. Hellmann, M.D., executive VP of development and product operations and chief medical officer at Genentech. "We believe that further work is needed to provide more insight into the role of EGFR inhibitors in this setting, either as a single agent or in combination with other targeted agents or chemotherapy."
The alliance among the three companies remains on track with the clinical development of Tarceva, and executives say the product may have utility in treating a variety of cancers. The two Phase III studies are part of a comprehensive development program in lung cancer, which includes a Phase III study of Tarceva as a single agent in a second-line setting and third-line setting, a Phase II study of Tarceva as a single agent in bronchioloalveolar cell carcinoma, and a Phase I/II trial of Tarceva in combination with Avastin, a vascular endothelial growth factor inhibitor in clinical development (see related story about Avastin on cover).
"It is important to note that Tarceva has shown activity in a number of solid tumor types, including relapsed nonsmall cell lung cancer, bronchioloalveolar cell carcinoma, and glioblastoma," says Colin Goddard, Ph.D., CEO of OSI. "Consequently, we remain optimistic about the alliance's prospects for success in the Phase III second-line/third-line monotherapy trial in nonsmall cell lung cancer and are encouraged by the response rates observed in the Phase I glioblastoma study, Phase II bronchioloalveolar cell carcinoma study, and in the combination trial with Genentech's Avastin."
The Phase III Tarceva second-line and third-line nonsmall cell lung cancer trials were expected to be completed by year-end 2003, with data being made public by the end of first-quarter 2004. Genentech began a Phase II study in glioblastoma in first-quarter 2003, an indication for which FDA has granted orphan-drug status. Tarceva is the first epidermal growth factor receptor inhibitor to receive this classification.
Analysts still have hope that Tarceva trials in the second-line and third-line settings for nonsmall cell lung cancer will demonstrate a survival advantage. If Tarceva does demonstrate a survival benefit, then this could give the product a marketing advantage over Iressa, which is being marketed by AstraZeneca without such a claim.
AstraZeneca's marketing strength will shield Iressa sales from the impact of Tarceva, but Tarceva conceivably could compete in other indications other than nonsmall cell lung cancer. "Tarceva could potentially enter every market that Iressa has an interest in and Tarceva may be used off-label where Iressa is used," says Kyung Lee, oncology analyst at Datamonitor (datamonitor.com). "However, Iressa has not shown any significant potential in any indication so far, so Tarceva's potential in these indications may also be limited."
