CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.
Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).
This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).
The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.
LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).
Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).
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The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.
In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.
Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.
Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.
"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.
In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.
Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).
There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.
Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.