AT WCLC 2016
VIENNA (FRONTLINE MEDICAL NEWS) – Icotinib proved significantly more effective and less toxic than standard therapy with whole-brain irradiation and chemotherapy in patients with multiple brain metastases from epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer in the phase III BRAIN trial.
“With favorable objective response and disease control rates, icotinib was superior to whole-brain irradiation with chemotherapy, and therefore icotinib should be used as first-line therapy for advanced EGFR-mutant non–small cell lung cancers with brain metastases,” Yi-long Wu, MD, said in presenting the BRAIN results at the World Congress on Lung Cancer.
The catch is that icotinib, which was developed in China, isn’t marketed outside the Far East. But two EGFR tyrosine kinase inhibitors (TKIs) accessible to physicians elsewhere in the world – gefitinib (Iressa) and erlotinib (Tarceva) – are the subject of ongoing phase III clinical trials in patients with brain metastases from EGFR-mutated non–small cell lung cancer (NSCLC) on the basis of strongly favorable preliminary data.
Patients with brain metastases are often excluded from participation in clinical trials because their prognosis is so poor. BRAIN is the first phase III trial to report results comparing an EGFR tyrosine kinase inhibitor (TKI) – icotinib – to whole-brain irradiation (WBI) plus chemotherapy, regarded in National Comprehensive Cancer Network guidelines as standard therapy in the setting of brain metastases from NSCLC, noted Dr. Wu of the Guangdong Lung Cancer Institute in Guangzhou, China.
BRAIN was a multicenter Chinese trial in which investigators randomized 158 patients with three or more brain metastases from EGFR-mutated NSCLC to oral icotinib at 125 mg t.i.d. or to WBI with four to six cycles of concurrent or sequential platinum-based chemotherapy.
Icotinib outperformed standard therapy with WBI plus chemotherapy on multiple efficacy endpoints. Median intracranial progression-free survival was 10 months with icotinib, compared with only 4.8 months in patients on WBI with chemotherapy. At 6 months, 72% of patients assigned to icotinib remained free of intracranial disease progression, compared with just 48% of controls on WBI and chemotherapy. Six-month overall PFS, intracranial as well as extracranial, was 6.8 months with icotinib and 3.4 months in the WBI group. The intracranial and overall objective response rates were 67% and 55%, respectively, with icotinib, compared with 41% and 11% with WBI.
In addition, the EGFR TKI had a significantly better safety profile: grade 3 or worse toxicities occurred in just 8% of the icotinib group, compared with 26% of controls on standard therapy, Dr. Wu reported at the meeting sponsored by the International Association for the Study of Lung Cancer.
There was, however, no significant difference between the two study arms in overall survival: 18 months with icotinib, 20.5 months with standard therapy, noted Dr. Wu, who is president of the Chinese Society of Clinical Oncology.
Discussant Jacek Jassem, MD, said “This is potentially, and likely, a practice-changing study.” He added that he’s looking forward to planned future presentation of neurotoxicity and quality of life data from BRAIN. Those important endpoints are also incorporated in the ongoing phase III trials of gefitinib and erlotinib, EGFR TKIs which are far more readily accessible at present to physicians outside the Far East.
Dr. Jassem called WBI a therapy with “considerable neurotoxicity and questionable efficacy.” He predicted it’s likely that physicians will use WBI more sparingly in the future, not only in patients with EGFR-mutated primary tumors but also in other settings. Already, based upon the BRAIN results, the role of WBI has been considerably diminished.
“Whole-brain radiotherapy for brain metastases from EGFR-mutated non–small cell lung cancer is a vanishing approach. The remaining role in this setting is as salvage in cases of symptomatic primary or secondary resistance to EGFR TKIs,” said Dr. Jassem, head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.
By way of background, he noted that 10%-15% of patients already have brain metastases at the time of diagnosis of NSCLC, and 40% develop them eventually. EGFR-mutated primary tumors are particularly likely to metastasize to the brain.
Remaining questions in the wake of the BRAIN trial include the efficacy of gefitinib and erlotinib versus WBI plus chemotherapy, as well as the broader question of the efficacy of EGFR TKIs in non-Asian patients with brain metastases.
“Most of the studies of EGFR TKIs have been in East Asian populations. These agents are particularly active in East Asians. There’s a question as to whether the BRAIN results can be applied to other populations,” Dr. Jassem said.
The BRAIN study was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu reported serving as a consultant to AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi. Dr. Jassem reported having no financial conflicts of interest.