CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.
First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.
Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.
Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.
Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.
Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.
Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).
Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.
"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."
Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.
The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m2 on day 1 plus docetaxel 75 mg/m2 on day 1; cisplatin 75 mg/m2 on day 1 plus gemcitabine 1,250 mg/m2 on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m2 on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m2 on days 1 and 8.
The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.
The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.
Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.