June 1, 2009 (Orlando, Florida) — Two targeted therapies were better than 1 when used for the maintenance treatment of nonsmall-cell lung cancer (NSCLC) in the ATLAS trial, according to results presented here at the American Society of Clinical Oncology 45th Annual Meeting. Adding erlotinib (Tarceva) to bevacizumab (Avastin) for maintenance treatment, after a course of chemotherapy combined with bevacizumab, significantly improved progression-free survival.
In another phase 3 trial presented here, known as SATURN, maintenance therapy with erlotinib alone was better than placebo and significantly increased progression-free survival. This patient population of advanced NSCLC patients was similar to that in the ATLAS trial, but patients had received first-line treatment with chemotherapy alone. This trial was conducted mainly outside of the United States, where bevacizumab is not standard care.
The results suggest a new treatment paradigm: noncytotoxic maintenance therapy for NSCLC with targeted agents.
Although avoiding chemotherapy is an advantage, and both of these trials showed a significant increase in progression-free survival, there are no data available yet for overall survival. The expert discussing these presentations urged the audience to wait for survival data, because these targeted agents have their own set of adverse effects, some of which are serious.
"Yes, there are some patients who would benefit from this approach," said Nasser Hanna MD, from Indiana University in Indianapolis, "but this is definitely not for all patients, as many would be overtreated unnecessarily."
"An improvement in progression-free survival is less meaningful unless the treatment also results in a decrease in symptoms or complications, or an improvement in quality of life," Dr. Hanna explained. From the data presented so far from both of these trials, "it's not clear that they will live longer or live better with maintenance therapy."
Some of these patients might be better off enjoying a treatment-free holiday, he suggested, while being followed frequently and closely. There might be about 30% of patients who do not progress for 3 to 6 months and, in that time, "they can enjoy life," Dr. Hanna noted. Patients with advanced NSCLC have a very short life-expectancy, and currently "we really do not know if maintenance therapy will benefit them," he said.
ATLAS Results With 2 Targeted Agents
The ATLAS trial involved 768 patients with advanced NSCLC who were treated with 4 cycles of chemotherapy (various platinum-containing doublets) and bevacizumab. Patients who did not progress were then randomized to maintenance therapy with bevacizumab alone or bevacizumab plus erlotinib.
The results showed a significant increase in median progression-free survival — from 3.7 months for bevacizumab alone to 4.8 months for bevacizumab plus erlotinib (hazard ratio, 0.722; P =.0012), reported lead investigator Vincent Miller, MD, from the Memorial Sloan–Kettering Cancer Center in New York City.
Results that may be more meaningful to the practicing clinician, he said, show that at 3 months, progression-free survival was seen in 67.7% of patients in the combination group vs 53.4% in the bevacizumab-alone group; at 6 months, the figures for progression-free survival were 40.3% vs 28.4%, respectively.
In the United States, bevacizumab is already a core component of the treatment of advanced NSCLC, and this trial shows that adding another targeted agent to maintenance therapy can improve outcomes, Dr. Miller remarked. The combination was well tolerated, with no new safety signals, he added.
"These are intriguing data," commented Julie Brahmer, MD, assistant professor at the Johns Hopkins University in Baltimore, Maryland, who was not involved with the study. "These new data lead us to consider using this combination in patients after they have completed treatment with chemotherapy and bevacizumab."
"It is something to consider and to discuss with patients, but it is not something to use automatically in all patients," Dr. Brahmer added.
She pointed out that a previous study, known as the BeTa Lung study, also used a combination of erlotinib and bevacizumab, and although it also found an improvement in progression-free survival, ultimately there was no difference in overall survival. However, in that trial, the targeted agents were being used for second-line therapy, whereas in the ATLAS trial they were being used for maintenance therapy, she noted.
Dr. Miller agreed that the combination might not be suitable for all patients. "My feeling is that this is a strategy that will not be employed in all patients, but maybe in those who remain symptomatic, which would be about 1 patient out of every 2 or 3," he said.
There needs to be research now to find the patients who are most likely to benefit from the combination, and this will be based, in a large part, on the identification of genetic biomarkers, he said.
One of the most important biomarkers is epidermal growth-factor receptor (EGFR) mutation status, which appears to identify lung cancer patients who respond particularly well to EGFR inhibitors, such as erlotinib and gefitinib, as has been shown in other studies.
In the SATURN trial, which used erlotinib alone for maintenance therapy, there was a significant increase in progression-free survival for all patients taking erlotinib, compared with placebo. However, a subgroup analysis showed that for patients with tumors that had EGFR mutations (about 10% of the patient population), erlotinib had a "huge effect," explained lead author Federico Cappuzzo, MD, from the Istituto Clinico HumanitasIRCCS in Rozzano, Italy.
"This is the way forward toward personalized cancer care," said Bruce Johnson, MD, director of the Dana-Farber Harvard Medical Center Lung Cancer Program, in Boston, Massachusetts. He suggested that testing for EGFR mutations could identify patients for whom treatment with EGFR inhibitors would be most beneficial.
"Lung cancer is one of the most challenging cancers to treat, but the studies presented today highlight promising new targeted therapies," he noted while moderating a press briefing at which the ATLAS results were presented.
Dr. Miller reports receiving honoraria from Genentech. Dr. Brahmer has acted as an advisor to AstraZeneca, Eli Lilly, and ImClone. Dr. Cappuzzo has received honoraria from AstraZeneca, Boehringer, Eli Lilly, and Roche. Dr. Hanna has received honoraria from Eli Lily and Genentech, and research funding from Eli Lilly, AstraZeneca, Genentech, and Onyx. Dr. Johnson has acted as a consultant to Genzyme; holds stock ownership in Boston Scientific, Celgene, and Johnson & Johnson; and receives royalty payments on a license to Genzyme for carrying out EGFR mutation testing.
American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstracts LBA8002 and 8001. Presented May 31, 2009.
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