The oral EGFR blocker afatinib was superior to standard chemotherapy at prolonging progression-free survival in patients with advanced non–small-cell lung cancers that harbor EGFR mutations, according to a report in the Journal of Clinical Oncology.
Patients who received afatinib in this international, industry-sponsored phase-III clinical trial (NCT00949650) also showed statistically significant and clinically meaningful improvements in lung cancer symptoms and a higher treatment response rate than did those who received a regimen of cisplatin plus pemetrexed, which is widely considered to be the optimal combination chemotherapy, said Dr. Lecia V. Sequist of Massachusetts General Hospital and Harvard Medical School, Boston, and her associates.
Afatinib should now be considered a standard therapeutic option for such patients, they noted.
Dr. Lecia Sequist
Mutations in the EGFR (epidermal growth factor receptor) gene, found in a subset of lung adenocarcinomas, make the tumors uniquely susceptible to selective EGFR blockers. Previous trials have demonstrated tumor shrinkage and durable responses to treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib, and afatinib has also shown promise.
In what they described as the largest prospective, randomized trial of afatinib to date, Dr. Sequist and her colleagues compared first-line afatinib against combination cisplatin plus pemetrexed in 340 patients treated at 133 medical centers in Asia, Europe, North America, South America, and Australia during a 2-year period. All the patients had advanced treatment-naive disease with proven EGFR mutations.
The patients were randomly assigned to receive either daily oral afatinib (229 patients) or monthly IV chemotherapy (111 patients) until the cancer progressed, and underwent periodic CT or MRI imaging to track progression.
After a median follow-up of 16 months, the primary endpoint of progression-free survival was significantly longer with afatinib (11.1 months) than with cisplatin plus pemetrexed (6.9 months) in an analysis conducted by independent reviewers. This endpoint also was significantly longer with afatinib (11.1 months) than with cisplatin plus pemetrexed (6.7 months) in an analysis conducted by the trial investigators, Dr. Sequist and her associates said (J. Clin. Oncol. 2013;31:3327-34).
This benefit in progression-free survival was robust across most clinically relevant subgroups of patients, regardless of age, sex, race, or Eastern Cooperative Oncology Group status.
The treatment response rate also was significantly higher with afatinib (56%) than with chemotherapy (23%) in the independent analysis, as well as in the trial investigators’ analysis (69% and 44%, respectively).
In addition, a higher proportion of patients achieved disease control with afatinib (90%) than with chemotherapy (81%). And the median duration of disease control was 13.6 months for afatinib, compared with 8.1 months for chemotherapy.
Patients reported that the time to meaningful worsening of cough and dyspnea was significantly longer with afatinib than with chemotherapy, and the time to meaningful worsening of pain was longer but not to a significant degree.
At the time of data analysis, only 28% of the study population had died, and median survival had not yet been reached for either group. The data on overall survival therefore are considered preliminary. Overall survival was not significantly different between the afatinib group (16.6 months) and the chemotherapy group (14.8 months).
"Both treatments were well tolerated, and adverse effects were manageable with dose reductions and delays. Treatment-related adverse effects of grade 3 or greater occurred in 112 patients (49%) receiving afatinib and 53 patients (48%) receiving chemotherapy," the investigators said.
Treatment was discontinued because of adverse effects in 8% of patients receiving afatinib and 12% of those receiving chemotherapy.
Pharmacokinetic studies showed that dose modification of afatinib according to individual tolerability "optimized the exposure to afatinib and maintained efficacious plasma levels," they added.
This study was supported by Boehringer Ingelheim. Dr. Sequist reported ties to Boehringer Ingelheim, Clovis Oncology, Merrimack Pharmaceuticals, and Daiichi Sankyo, and her associates reported ties to numerous industry sources.