Afatinib (Gilotrif) is an oral selective ErbB family inhibitor that irreversibly blocks signaling from EGFR/ErbB1, HER2/ErbB2, and ErbB4 and has exhibited broad-spectrum activity against EGFR mutations in preclinical studies. A phase II study of afatinib in EGFR-mutation positive lung adenocarcinoma showed high response rates and progression-free survival.

In a phase III study (LUX-Lung 3) reported in the Journal of Clinical Oncology, Lecia V. Sequist, MD, of Massachusetts General Hospital and Harvard Medical School and colleagues found that first-line afatinib increased progression-free survival compared with standard cisplatin plus pemetrexed (Alimta) chemotherapy in a predominantly East Asian population of patients with EGFR-mutant stage IIIB/IV lung adenocarcinoma.¹

Study Details

In this international study, 345 patients with EGFR-mutant advanced lung adenocarcinoma were randomly assigned (2:1) to afatinib at 40 mg/d (n = 230) or six cycles of cisplatin plus pemetrexed (n = 115) at standard doses given every 21 days.

The afatinib and chemotherapy groups were generally well-matched for age (median, 61.5 vs 61 years), sex (64% vs 67% female), race (72% East Asian in both, 26.5% vs 26% white), smoking status (67% vs 70% never, 30% vs 28% former), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 in 100% vs 99%), adenocarcinoma stage (IIIB with pleural effusion in 9% vs 15%, IV in 91% vs 85%), and EGFR mutations (exon 19 deletion in 49% vs 59%, L858R in 40% vs 41%, and other in 11% vs 10%).

Prolonged Progression-free Survival

Median follow-up at the time of primary analysis was 16.4 months. Median progression-free survival on independent review was 11.1 months in the afatinib group and 6.9 months in the chemotherapy group (hazard ratio [HR] = 0.58, P = .001). Median progression-free survival among those with the most common activating EGFR mutations—ie, exon 19 deletions and L858R mutations (n = 308)—was 13.6 months in the afatinib group and 6.9 months in the chemotherapy group (HR = 0.47, P = .001). Subgroup analyses showed the progression-free survival benefit for afatinib persisted among most subgroups examined (by age, sex, race, and ECOG performance status).

Response rates on independent review were 56% with afatinib and 23% with chemotherapy (P = .001) and median durations of response were 11.1 and 5.5 months, respectively. Overall survival data are considered preliminary, and median overall survival had not been reached in either group. Overall survival did not significantly differ between the afatinib and chemotherapy groups (HR = 1.12, P = .60; 25th percentile, 16.6 vs 14.8 months).

At disease progression, most patients in the afatinib group crossed over to chemotherapy (62%) and most in the chemotherapy group crossed over to EGFR tyrosine kinase inhibitor treatment (65%). With regard to patient-reported outcomes, afatinib treatment was associated with significant delay to clinically meaningful worsening of cough (HR = 0.60, P = .007) and dyspnea (HR = 0.68, P = .01) compared with chemotherapy.

Adverse Events

The most common treatment-related adverse events of any grade were diarrhea (95% vs 15%), rash/acne (90% vs 6%), stomatitis/mucositis (72% vs 15%), and paronychia (57% vs 0%) in the afatinib group and nausea (66% vs 18%), decreased appetite (53% vs 21%), fatigue (47% vs 18%), and vomiting (42% vs 17%) in the chemotherapy group. The most common grade 3 or higher adverse events were rash/acne (16% vs 0%), diarrhea (14% vs 0%), paronychia (11% vs 0%), and stomatitis/mucositis (9% vs 1%) in the afatinib group and neutropenia (18% vs < 1%), fatigue (13% vs 1%), and leukopenia (8% vs < 1%) in the chemotherapy group.

Treatment was discontinued due to treatment-related adverse events in 8% of afatinib patients and in 12% of chemotherapy patients. Three cases of potentially treatment-related interstitial lung disease-like events and four potentially treatment-related deaths (due to respiratory decompensation in two patients, sepsis in one, and unknown cause in one) were observed among afatinib patients. There were no treatment-related fatal toxicities in the chemotherapy group.

The investigators concluded, “[P] atients with lung adenocarcinoma with EGFR mutations have significant [progression-free survival], tumor response, and lung cancer–related symptom benefits when treated with first-line afatinib compared with cisplatin plus pemetrexed. Afatinib could be considered a standard option for such patients.” ■

Disclosure: The study was supported by Boehringer Ingelheim. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Sequist LV, Yang J-CH, Yamamoto N, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol July 1, 2013.