Questa è la versione dell’autore dell’opera:
LUX-Lung: determining the best EGFR inhibitor in NSCLC?
Rossi A, Di Maio M. Lancet Oncol. 2015 Feb;16(2):118-9. doi:
10.1016/S1470-2045(14)71196-9. Epub 2015 Jan 12. PubMed
PMID: 25589190.
La versione definitiva è disponibile alla URL:
Magic mirror in my hand, which is the best EGFR-TKI in the land?
Antonio Rossi, MD,1 Massimo Di Maio, MD2
1Division of Medical Oncology, S.G. Moscati Hospital, Avellino- Italy
2Department of Oncology, University of Turin, A.O.U. San Luigi Gonzaga, Orbassano, Turin – Italy
Correspondence to: Antonio Rossi, M.D.
Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta, 8 83100 – Avellino (Italy) phone: + 39 0825 203573 fax: + 39 0825 203556 e-mail: [email protected]
Since first reports, many publications showed data on incidence and characteristics of epidermal growth factor receptor (EGFR) mutations in patients with non-small-cell lung cancer (NSCLC), and their correlation with outcome in patients receiving tyrosine kinase inhibitors (TKIs).1
In this issue of The Lancet Oncology, Yang and colleagues report overall survival (OS), a secondary endpoint, of two phase III trials, LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6). Both trials compared afatinib, a second-generation EGFR-TKI, with platinum-based first-line chemotherapy in patients with lung adenocarcinoma harbouring EGFR mutations2. In each
trial, both in intent-to-treat population and in patients with tumours harbouring common mutations (Del19/L858R), OS difference between arms was statistically non-significant. This was not surprising, and in line with no significant OS difference reported with gefitinib and erlotinib, first-generation EGFR-TKIs, in the same setting.3
However, in both trials, exploratory subgroup analyses showed a statistically significant OS improvement with afatinib in patients with tumours harbouring Del19, while no OS difference was reported in cases with L858R.2 Furthermore, in the pooled exploratory
analysis based on the combined individual data of patients with tumours harbouring common mutations from both trials, afatinib was associated with a significant OS benefit. Should afatinib be considered the only EGFR-TKI associated with a significant OS benefit, and in particular the first choice for lung adenocarcinoma harbouring EGFR Del19? From a methodological point of view, subgroup and post-hoc analyses can be informative, but should be interpreted with caution.4 Progression-free survival was chosen as primary
endpoint in all trials conducted in this setting, and even the authors of LL3 and LL6, not surprisingly, stated in the trial protocols that the OS difference was expected to be masked by treatments received after progression. However, even with no OS difference between arms, median OS reported with all the three EGFR-TKIs had never been observed before in advanced NSCLC, emphasizing their great impact in this subpopulation of patients with
oncogene-addicted tumours. Crossover rate was high for afatinib and erlotinib, and very high for gefitinib, making the statistical power for OS analyses very low.5 Finding an OS
benefit with afatinib does not definitely prove that a similar benefit is not produced by gefitinib or erlotinib. Let’s imagine conducting three parallel, randomized trials with a similar design, all with low statistical power. If the trials are testing the same drug, and only one produces a positive result, the difference would be easily ascribed to the low power. Unfortunately, if the three trials are similar but testing different drugs, we cannot be absolutely sure if the difference are drug-related or simply due to chance.
Apart from chance, there are other possible explanations for the OS results obtained with afatinib. The number of patients in LL3 and LL6 trials was larger than those randomized in each trial investigating gefitinib or erlotinib (also because most studies with these EGFR-TKIs were stopped early, after interim analyses), and this implies a difference in statistical power. Afatinib is active also against HER2, the preferred dimerization partner of EGFR, and through its irreversible, covalent binding leads to longer suppression of receptor kinase activity than with reversible first-generation EGFR-TKIs, because kinase activity is suppressed until new receptors are synthesized.6 Furthermore, the percentage of patients
randomized to afatinib and receiving further EGFR-TKIs in subsequent treatment lines, thus prolonging the overall exposure to EGFR inhibition, could potentially have produced OS benefits. This hypothesis had already been proposed also for reversible EGFR-TKIs.7
As emphasized by the authors themselves, the impressive OS advantage reported in patients with lung adenocarcinoma harbouring Del19 mutations definitely shows that the two common mutations (Del19 and L858R) are two “different” NSCLC diseases. However, also this issue was already suggested with other EGFR-TKIs.8, 9
All in all, are these data sufficient to answer to the title question: “You, my first-generation EGFR-TKIs, are fair so true, but afatinib is better than you”? Ideally, only a head-to-head trial could definitely answer. LUX-Lung 7 (NCT01466660), a phase IIb randomized trial
comparing afatinib and gefitinib as first-line treatment of lung adenocarcinoma with EGFR common mutations, should provide the first comparative evidence of efficacy and safety in this setting. In the absence of direct comparisons, for each patient, the choice among the available EGFR-TKIs should take into account all the clinically relevant endpoints, including disease control, survival prolongation, tolerability, and quality of life.
Conflict of interest statement
Dr Antonio Rossi reports personal fees from AstraZeneca and Boehringer Ingelheim; Dr Massimo Di Maio reports personal fees from AstraZeneca and Boehringer Ingelheim.
References
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2. Yang JCH, Wu YL, Schuler M, et al. Effect of afatinib on overall survival of patients with
EGFR mutation-positive lung adenocarcinoma: outcomes of the two randomised Phase
III trials LUX-Lung 3 and LUX-Lung 6. Lancet Oncol 2014; published online.
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9. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006; 12: 3908-3914.
