Icotinib Improves Intracranial PFS in EGFR-Mutant NSCLC and Brain Mets

Yi Long Wu, MD

Treatment with icotinib more than doubled intracranial progression-free survival (iPFS) compared with whole brain irradiation (WBI) combined with standard chemotherapy, according to phase III trial results 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 10.0 months compared with 4.8 months in patients treated with WBI and chemotherapy, HR = 0.56; 95% CI, 0.36-0.90 (P = .014). 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 (HR, 0.44; 95% CI, 0.31-0.63 [P < .001]).

The intracranial ORR was 67.1% versus 40.9% (P < .001), and the overall ORR was 55.0% versus 11.1% (P < .001) 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 4 to 6 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, MD, 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 3 brain lesions. Patients were randomized to icotinib (N = 85) or WBI plus chemotherapy (N = 91). WBI was delivered at 30 Gy/3Gy for 10 fractions plus concurrent or sequential doublet chemotherapy for 4 to 6 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% were male, 87% of patients had PS 1, 96.8% of patients had adenocarcinoma, and 16.5% of patients had symptomatic brain metastases. Somewhat atypically, 70.9% of patients were non-smokers. Analysis of the mutation status revealed that 52.9% of patients’ tumors had EGFR exon 19 mutation, 42.4% harbored EGFR exon 21 (L858R) mutations, and 4.7% 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, HR = 0.93 (P = .734).

Wu pointed out that the overall disease control rate (DCR) was 78.8% versus 54.8% with icotinib as compared with WBI/chemotherapy — a difference of 24.0% (P = .001). The intracranial DCR was 84.7% in patients given icotinib compared with 67.3% in patients who received WBI/chemotherapy, a difference of 17.5% favoring icotinib (P = .014).

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 7 patients (8.2%) experiencing Grade ≥3 adverse events (AEs) compared with 28 of patients (26.2%) 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 III 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.

Wu YL. BRAIN: A phase III trial comparing WBI and chemotherapy with icotinib in NSCLC with brain metastases harboring EGFR mutations (CTONG 1201). Abstract PR03.03. Presented at: 17th World Lung Cancer Conference, the Annual Meeting of the International Association for the Study of Lung Cancer (IASLC), Vienna.