First-Line Afatinib Supported for Select Advanced Lung Cancer Patients

First-line afatinib may improve overall survival for advanced lung adenocarcinoma patients with a del19 EGFR mutation

medwireNews: Mature results from the LUX-Lung 3 and 6 adenocarcinoma trials indicate that afatinib significantly improves overall survival (OS) for treatment-naive patients with an Epidermal growth factor receptor (EGFR) deletion (del)19 mutation compared with chemotherapy.

However, neither phase III trial found a significant OS benefit for the second-generation Tyrosine kinase inhibitor (TKI) versus a cisplatin-based doublet regimen for the overall populations of EGFR-positive patients with stage IIIB or IV disease or for patient subgroups with the Leu858Arg EGFR mutation.

“This finding suggests that among standard first-line EGFR tyrosine kinase inhibitors, afatinib should be the preferred option for patients with EGFR del19-positive lung adenocarcinoma”, the authors suggest in The Lancet Oncology.

Median OS was 28.2 months for LUX-Lung 3 patients regardless of whether they were randomly assigned to receive afatinib (n=230) or pemetrexed–cisplatin (n=115), report lead author James Chih-Hsin Yang, from National Taiwan University Hospital in Taipei, and team.

But among the 169 patients with a del19 mutation, OS was significantly higher among those given afatinib than pemetrexed–cisplatin, at 33.3 versus 21.1 months and a hazard ratio of 0.54.

Similarly, median OS did not significantly differ for the LUX-Lung 6 patients given afatinib (n=242) versus those given gemcitabine–cisplatin (n=122; 23.1 vs 23.5 months), except for the subgroup of 186 patients with a del19 mutation who had a significantly better outcome with afatinib (31.4 vs 18.4 months).

The researchers note that all the LUX-Lung 6 patients were Asian, as were the majority of LUX-Lung 3 patients, but that the del19 mutation-associated benefit for afatinib was also found in non-Asian participants, “supporting the applicability of the findings to all patients with EGFR mutation-positive disease, irrespective of ethnic origin.”

Hypothesising that the del19 mutation confers specific biological properties that affect response to EGFR TKIs, and afatinib in particular, the team concludes: “[T]hese findings suggest that patients with lung adenocarcinoma harbouring EGFR del19 and Leu858Arg Mutations should be stratified and analysed separately in future clinical trials.”

Writing in an accompanying comment, Antonio Rossi, from SG Moscati Hospital in Avellino, Italy, and Massimo Di Maio, from the University of Turin in Italy, note that the lack of OS benefit for afatinib over cisplatin-based chemotherapy for the total populations of the two trials is “not surprising” and in line with results for first-generation EGFR TKIs.

However, they caution that it is unclear whether afatinib is the only TKI to increase median OS in del19 patients as this outcome has not been reported for first-generation TKIs, also noting that second-line treatments make analysis of OS difficult.

The commentators therefore say that only a head-to-head trial can determine whether afatinib is better than first-generation EGFR inhibitors for lung adenocarcinoma. “[L]UX-lung 7, a phase 2b randomised trial comparing afatinib with gefitinib for first-line treatment of lung adenocarcinoma with EGFR common mutations, should provide the first comparative evidence of efficacy and safety in this setting”, they conclude.

References

Yang J C-H, Wu Y-L, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; Published online 11 January. DOI: dx.doi.org/10.1016/S1470-2045(14)71173-8

Rossi A, Di Maio M. LUX-Lung: determining the best EGFR inhibitor in NSCLC? Lancet Oncol 2015; Published online 11 January. DOI: dx.doi.org/10.1016/S1470-2045(14)71196-9

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