New Agent Improves Intracranial PFS for Lung Cancer and Brain Metastases
Virginia Powers, Ph.D.
Intracranial progression-free survival (iPFS) was more than doubled with icotinib compared to whole brain irradiation (WBI) plus standard chemotherapy, according to the results from a phase 3 trial that were presented at the 17th World Lung Cancer Conference, the Annual Meeting of the International Association for the Study of Lung Cancer (IASLC), in Vienna.
Icotinib significantly improved median iPFS, the trial’s primary endpoint, to 10 months compared with 4.8 months in patients treated with WBI and chemotherapy. Secondary endpoints of the trial, including progression-free survival (PFS) and the objective response rate (ORR), were also significantly improved with icotinib over WBI/chemotherapy. Median PFS was 6.8 versus 3.4 months, respectively.
The intracranial ORR was 67.1 percent versus 40.9 percent, and the overall ORR was 55.0 percent versus 11.1 percent with icotinib compared with WBI/chemotherapy, respectively.
“Whole brain irradiation is a standard of care for brain metastasis, which results in median survival of only four to six months. Small molecule inhibitors of epidermal growth factor receptor, including icotinib, achieved very successful results, although the combination of WBI with gefitinib or erlotinib remains controversial,” said Yi Long Wu, M.D., Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, China.
“There were no data from prospective randomized clinical trials exploring the efficacy of EGFR TKIs on brain metastases,” he added.
Wu and colleagues conducted the BRAIN trial in patients with advanced NSCLC plus EGFR sensitive mutations and who had at least three brain lesions. Patients were randomized to icotinib (85 patients) or WBI plus chemotherapy (91 patients). WBI was delivered at 30 Gy/3Gy for 10 fractions plus concurrent or sequential doublet chemotherapy for four to six cycles, and icotinib was administered at 125 mg orally thrice daily until disease progression. Icotinib could be continued beyond progression where clinical benefit was observed by the investigator, and crossover to icotinib from WBI was allowed.
The trial enrolled 176 patients from 17 sites throughout China from December, 2012 to June, 2015. The median age of the patients was 58 years and 32 percent were male, 87 percent of patients had PS 1, 96.8 percent of patients had adenocarcinoma, and 16.5 percent of patients had symptomatic brain metastases. Somewhat atypically, 70.9 percent of patients were non-smokers. Analysis of the mutation status revealed that 52.9 percent of patients’ tumors had EGFR exon 19 mutation, 42.4 percent harbored EGFR exon 21 (L858R) mutations, and 4.7 percent of patients had uncommon diverse EGFR mutations.
No significant difference was observed in median overall survival between treatment arms; median OS was 18.0 versus 20.5 months in the respective groups.
Wu pointed out that the overall disease control rate (DCR) was 78.8 percent versus 54.8 percent with icotinib as compared with WBI/chemotherapy — a difference of 24.0 percent. The intracranial DCR was 84.7 percent in patients given icotinib compared with 67.3 percent in patients who received WBI/chemotherapy, a difference of 17.5 percent favoring icotinib.
These findings were presented during the Presidential Symposium where an audience member commented that these results were observed in an Asian patient population and, as with several TKIs, may not be the same in non-Asian patients. Wu responded, “Icotinib should be evaluated in a non-Asian population, but I think that there will be no difference as long as the EGFR mutations are present in the patients.”
Icotinib was very well tolerated with just seven patients (8.2 percent) experiencing Grade 3 or higher adverse events (AEs) compared with 28 of patients (26.2 percent) receiving WBI/chemotherapy. The most common adverse events in the icotinib arm were increased liver transaminase and rash, whereas hematologic toxicity was the most commonly reported AE in the WBI/chemotherapy arm.
“These data from BRAIN represent the first phase 3 results comparing an EGFR TKI with WBI and show that icotinib was superior to WBI in terms of intracranial and overall PFS and showed superior response and disease control compared with WBI,” Wu said. Icotinib is currently indicated as a second-line or third-line treatment for the treatment of EGFR mutation-positive, advanced, or metastatic non-small cell lung cancer in patients who have failed at least one prior treatment with chemotherapy. “Icotinib should be used in first-line treatment for advanced EGFR mutated NSCLC with brain metastases,” advised Wu.