June 02, 2016
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Afatinib may be preferred first-line NSCLC treatment

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First-line treatment with afatinib significantly prolonged time-to-treatment failure compared with gefitinib for treatment-naive patients with EGFR–mutated non–small cell lung cancer, according to the results of a randomized trial.

Afatinib (Gilotrif, Boehringer Ingelheim) also significantly extended PFS, but the difference was less than 1 month.

Afatinib and gefitinib (Iressa, AstraZeneca) are approved as first-line treatment options for NSCLC harboring EGFR mutations.

Keunchil Park, MD, PhD, professor at Samsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, South Korea, and colleagues sought to compare the safety and efficacy of the two agents in treatment-naive patients.

The researchers conducted the phase 2b, international, open label LUX-Lung 7 trial, which included data from 319 patients (median age, 63 years; range, 30-89) with stage IIIB or stage IV NSCLC and common EGFR mutations (exon 19 deletion or Leu858Arg). They randomly assigned patients to daily afatinib (40 mg; n = 160) or gefitinib (250 mg; n = 159).

Treatment continued until disease progression; however, investigators could extend treatment beyond progression if they felt it was beneficial.

PFS, OS and time-to-treatment-failure served as coprimary endpoints.

Median follow-up was 27.3 months (interquartile range, 15.3-33.9).

Median PFS was 11 months in patients assigned afatinib, compared with 10.9 months with gefitinib. Although this was a small difference, it met statistical significance (HR = 0.73; 95% CI, 0.57-0.95).

Treatment with afatinib resulted in a significantly longer time-to-treatment failure (13.7 months vs. 11.5 months; HR = 0.73; 95% CI, 0.58-0.92).

OS data were not mature at the time of reporting. Median OS at the time of the primary analysis was 27.9 months (95% CI, 25.1-32.2) for afatinib and 25 months (95% CI, 20.6-29.3) for gefitinib (HR = 0.87; 95% CI, 0.66-1.15).

Seventy percent of patients (n = 112) assigned afatinib and 56% of patients (n = 89) assigned gefitinib achieved an objective tumor response, with patients in the afatinib arm achieving a longer median duration of response (10.1 months vs. 8.4 months).

Both arms had similar rates of adverse events of any grade (afatinib, 99% vs. gefitinib, 100%) and grade 3 or higher adverse events (57% vs. 52%). The most frequent grade 3 or higher adverse events included diarrhea (13% vs. 1%), rash or acne (9% vs. 3%), and elevations of the liver enzymes (0% vs. 9%).

Seventeen patients (11%) assigned afatinib and seven patients (4%) assigned gefitinib discontinued therapy due to serious treatment-related adverse events, and ten patients in each arm discontinued due to drug-related adverse events.

Sixty-three patients (39%) assigned afatinib received a dose reduction to 30 mg, of whom 21 (13%) had a further dose reduction to 20 mg.

Twenty-five patients died during treatment (afatinib, n = 15; gefitinib, n = 10). One patient in the gefitinib arm died of drug-related renal and hepatic failure. The researchers deemed the other fatalities unrelated to treatment.

The researchers acknowledged study limitations, including the lack of mature OS data and the potential for bias introduced by the open-label study design.

“Although an exploratory trial, the totality of data reported herein indicates that afatinib might offer improved efficacy compared with gefitinib, while conferring a predictable tolerability profile,” Park and colleagues wrote. “Our findings suggest that first-generation and second-generation EGFR–targeted drugs might not be interchangeable.”

The findings of this trial may have worldwide implications, Makoto Maemondo, MD, PhD, of Miyagi Cancer Center in Natori, Japan, wrote in an accompanying editorial.

“In the LUX-Lung 7 study, afatinib was compared with gefitinib, which has been mainly used in east Asia, whereas erlotinib [Tarceva; Genentech/Roche, Astellas Oncology] is the most commonly used EGFR TKI in Europe and the United States,” Maemondo wrote. “The Asian studies directly compared erlotinib vs. gefitinib and showed the two drugs were similar in terms of OS and PFS. Thus, afatinib activity might be considered superior to that of first-generation EFGR TKIs.” – by Cameron Kelsall

Disclosure: Boehringer Ingelheim funded this study. Park reports grant support from AstraZeneca, as well as personal fees from AstraZeneca, Boehringer Ingelheim, Clovis, Eli Lilly, Hanmi, Kyowa Hakko Kirin, Ono, Novartis and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures. Maemondo reports lecture fees from AstraZeneca, Boehringer Ingelheim and Chugai.