Afatinib shows increased progression-free survival in non-small-cell lung cancer

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1. As a first-line treatment, afatinib shows increased progression-free survival as compared to cisplatin plus gemcitabine in Asian patients with EGFR mutation-positive non-small-cell lung cancer.  

2. Afatinib-treated patients had more diarrhea and rash but less nausea and vomiting compared to cisplatin plus gemcitabine-treated patients.  

Evidence Rating: 2 (Good)

Study Rundown: The prevalence of EGFR mutations in lung adenocarcinoma is roughly three times higher in East Asian populations as compared to non-Asian ones.   This study, also called the Lux-Lung 6 study, compared the efficacy and safety of the irreversible ErbB receptor (a principal component in the EGFR signaling pathway) inhibitor, afatinib against that of the mainstay, first-line therapy available in Asia, namely cisplatin plus gemcitabine.  They screened for patients who were chemotherapy-naive and had tumors with EGFR mutations (mostly Exon 19 deletion or Leu858Arg).  The study showed a nearly two-fold increase in average progression-free survival in the afantinib group as compared to the gemcitabine plus cisplatin group.  Furthermore, patients treated with afatinib were nearly three times as likely to have an objective response as compared to those treated with gemcitabine plus cisplatin.  Unfortunately, median overall survival was not different in the two groups.  There was a tradeoff in adverse side effects: diarrhea, rash, and stomatitis or mucositis were most common in the afatinib group while vomiting, nausea, leucopenia were most common in the gemcitabine plus cisplatin group.  There are three major limitations in this trial.  Firstly, it was open label, which makes it susceptible to investigator bias.  Secondly, there were more patients in the afatinib group with poorer performance status (80.2%) compared to the gemcitabine plus cisplatin group (66.4%).  While the authors argue that this would favor the latter treatment arm in terms of increasing survival, it should also be expected that treatment-naive patients who are initially worse would have more objective response to any therapy.  Finally, the pharmaceutical sponsor of this trial, Boehringer Ingelheim, was “responsible for trial design, the collection, analysis, and interpretation of data, and coordination of article preparation.”

Click to read the story in The Lancet Oncology

Relevant reading: Rational, biologically based treatment ofEGFR-mutant non-small-cell lung cancer

In-Depth [randomized, open-label, phase 3 trial]: This study was a randomized, open-label, phase 3 trial that included 364 patients from 36 centers in China, Thailand, and South Korea (roughly 90% of patients were Chinese).  These patients had tumors that were EGFR mutation positive by PCR. 242 patients were randomized to treatment with afatinib and the remaining 122 were assigned to treatment with gemcitabine plus cisplatin.  The two groups were matched in terms of age, sex, ethnicity, smoking history, cancer stage, and mutation type, but not functional performance status. The authors found that the median progression-free survival for the former and latter treatment arms were 11.0 months and 5.6 months, respectively (HR 0.28, 95% CI 0.2-0.39; p<0.0001).  66.9% of patients in the afatinib group had an objective response as compared to 23.0% in the gemcitabine plus cisplatin group (OR 7.28, 95% CI 4.36-12.18; p<0.0001).  However, overall survival was not different in the former (22.1 months) as compared to the latter (22.2 months) (HR 0.95, 95% CI 0.68-1.33, p=0.76).  The analysis was performed according to intention-to-treat and the median follow-up time was 16.6 months.  Survival was approximated using the Kaplan-Meier method and logistic regression was used to compare objective response rates.  Adverse effects were reported by patients using a standard questionnaire.

By Khang T. Dinh and Andrew Bishara

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