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The Lancet Oncology

Monday, July 13, 2009

Erlotinib Improves Overall Survival After Initial Chemotherapy in Patients with Advanced Lung Cancer

Results from SATURN, a pivotal Phase III study, met a key secondary endpoint of extending overall survival in patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib (Tarceva®, Genentech/Roche; OSI) immediately after their initial chemotherapy. A statistically significant improvement in overall survival was seen in the pre-planned final analysis of the total patient population in the study. The new data will be presented during the 13th World Conference on Lung Cancer to be held July 31 – August 4, 2009 in San Francisco.

Lung cancer is the most common cancer worldwide with 1.5 million new cases annually and NSCLC accounts for 85 – 90% of all lung cancers. Non-small cell lung cancer (NSCLC) progresses rapidly and survival rates are generally very poor. Most people are diagnosed with advanced stage disease and less than 5% of these advanced NSCLC patients survive for five years. Extending the time patients live and managing side effects are key treatment goals.

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States. In 2009, approximately 159,000 Americans will die from the disease.
Treating patients immediately following first-line chemotherapy versus waiting for the cancer to grow or spread before giving additional treatment represents a new approach in advanced NSCLC.

A new approach
Erlotinib is, as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor, different from conventional chemotherapies.
Over-expression of EGFR is common in several solid tumors, such as colorectal cancer, lung carcinomas, and cancers of the head and neck. It correlates with increased metastasis, decreased survival and a poor prognosis. EGFR protects malignant tumors cells from the cytotoxic effects of chemotherapy and radiotherapy, making these treatments less effective.

HER1 and EGFR receptors are directly involved in inter-cellular signaling in systems governing cell division and proliferation. By interfering with the function of these receptors, which are highly active and often over-expressed in rapidly dividing tumor cells, erlotinib inhibits EGFR-receptor tyrosine kinase activity, and may help to initiate pathways of apoptotic cell death. The interference with the cell signaling pathways involved in cell proliferation represents a novel approach to the treatment of solid tumors.

Today, erlotinib is the first and only EGFR oral targeted agent in second line with a proven and significant survival and symptom benefit in a broad range of patients with advanced lung cancer without the side effects associated with chemotherapy. The drug has been approved in the EU since September 2005 and in the US since November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Patient benefit
In the landmark registration study BR.21, a randomised controlled phase III clinical trial comparing erlotinib with placebo/best supportive care in patients with locally advanced or metastatic non-small lung cancer which took place in 17 countries around the world, erlotinib delivered effectiveness comparable to chemotherapy and significantly improves overall quality of life.

The registration study underlined that more patients on erlotinib had improvement in cough, pain, shortness of breath and overall physical function versus patients on placebo. In addition erlotinib did not induce the distressing side-effects associated with chemotherapy, such as nausea and vomiting. An added benefit, improving adherence, is that erlotinib is convenient as patients can take a tablet once a day at home rather than receive intravenous treatments in a hospital.

Global trial
SATURN, a global multicentre, double blind, randomized, prospective phase III study was designed to evaluate the efficacy of erlotinib vs. placebo in patients with advanced, recurrent or metastatic NSCLC who had not progressed following first line platinum-based chemotherapy. The study involved more than 880 patients from approximately 160 centers; 438 received erlotinib and 451 placebo.

The study met its primary endpoint demonstrating a statistically significant extension of the time patients live without their disease worsening; there was a 41% increase compared with placebo (hazard ratio= 0.71, p-value <0.0001).>

“This study has now not only confirmed that immediate treatment with Tarceva after initial chemotherapy delayed the progression of disease, but also importantly helped patients in the study live longer,” said Professor Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, Milan and principal investigator of the SATURN study. “This is good news for doctors and their patients since advanced lung cancer is one of the most challenging cancers to treat and is often associated with a very short life-expectancy.”

Commenting on the study, William M. Burns, CEO Division Roche Pharmaceuticals said, “This is the second set of data from large studies that has shown Tarceva helps patients with advanced lung cancer to live longer. These results confirm that Tarceva has an important role to play in improving the lives of patients earlier in the management of this devastating disease.”

Erlotinib is already a well established treatment in second-line management of advanced NSCLC after the failure of chemotherapy and is proven to extend survival for a broad range of patients in this setting. Most recently, presentation of the SATURN primary endpoint data analysis at ASCO 2009 showed that patients who received treatment with erlotinib immediately after initial chemotherapy if their cancer had not progressed had a 41% improvement in the length of time they lived without their disease getting worse compared to placebo.

Outcome confirmed
During the Annual Society of Clinical Oncology (ASCO) Vincent A. Miller, MD., a medical oncologist from the Memorial Sloan-Kettering Cancer Center, presented results from the phase III ATLAS study supported findings in the SATURN study.

The ATLAS study, a global multicentre, randomised, double blind, placebo controlled study that enrolled 1,160 patients with locally advanced, recurrent or metastatic NSCLC, was designed to evaluate bevacizumab (Avastin®, Genentech/Roche) in combination with erlotinib (150 mg daily) versus bevacizumab alone, following bevacizumab in combination with a platin-containing doublet chemotherapy, in patients with stage IIIb/IV NSCLC.

The study showed that combined treatment with bevacizumab and erlotinib, immediately following initial therapy with bevacizumab plus chemotherapy was highly effective and significantly delayed disease progression for patients with advanced NSCLC, without the need for chemotherapy.

The positive results from these trials were encouraging because previous Phase III studies in which erlotinib was used as first-line therapy in combination with cytotoxic drugs (the TRIBUTE and TALENT studies) failed to demonstrate a survival advantage when erlotinib was added to conventional treatment regimens.

The overall survival data fron SATURN will be used to support the European and US applications for use of erlotinib as a first-line maintenance treatment for patients with advanced NSCLC. These applications were made to the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in March 2009 and are based on the pivotal Phase III SATURN trial. The FDA Prescription Drug User Fee Act (PDUFA) review date will be on or about January 18, 2010.

Commenting on the overal product development, Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals, Roche's US partner, said:"We are pleased with the launch of Tarceva in the U.S. to date and we continue to believe that Tarceva will emerge as a fundamentally important new agent in changing the paradigm for the treatment of cancer patients around the world. With our partners, Genentech and Roche, we are committed to executing a post-approval development plan, studying Tarceva in earlier stage lung cancer patients, in patients with other tumor types and combinations with other targeted therapies."

For more information:

ASCO 2009 Annual meeting:

Also read these PubMed abstracts:

Information for your patient:

Images courtesy American Society of Clinical oncology (ASCO)

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