Afatinib Active in NSCLC Tumours Harbouring Specific Rare EGFR Mutations

Response to afatinib in patients with advanced non-small-cell lung cancer with uncommon epidermal growth factor receptor mutations varies according to mutation type

medwireNews: Afatinib shows activity in non-small-cell lung cancer (NSCLC) tumours with uncommon epidermal growth factor receptor (EGFR) mutations, although patients with certain mutation types respond better than others, suggests a post-hoc analysis of data from three trials.

The best response was noted in patients harbouring point mutations or duplications in exons 18 to 21, with poorer responses in those with de novo Thr790Met mutations and insertion mutations in exon 20, the researchers report in The Lancet Oncology.

Using data from the phase II LUX-Lung 2 and the phase III LUX-Lung 3 and 6 trials, they identified 75 stage IIIb or IV lung adenocarcinoma patients with uncommon EGFR mutations, defined as any other than the exon 19 deletion or the Leu858Arg point mutation in exon 21, from the 600 who received afatinib across the three trials.

Of the 38 patients with mutations or duplications in exons 18 to 21 (group 1), 71.1% had an objective response – this compared with a rate of 14.3% for the 14 participants with de novo Thr790Met mutations in exon 20 (group 2) and 8.7% of the 23 with insertion mutations in exon 20 (group 3).

Median progression-free (PFS) was 10.7, 2.9 and 2.7 months for patients in group 1, 2 and 3, respectively. And median overall survival (OS) was 19.4, 14.9 and 9.2 months, respectively.

The results suggest that group 1 mutations could be “categorised as receptive to EGFR inhibitors and support the use of afatinib in these patients but not in those patients with group 2 or 3 mutations”, say the researchers.

Among patients with tumours harbouring the most frequent among the uncommon EGFR mutations in lung adenocarcinoma, objective responses were observed in all eight patients with Ser768Ile mutations, 77.8% of the 18 patients with Gly719Xaa mutations and 56.3% of the 16 patients with Leu861Gln mutations.

Patients harbouring Ser768Ile mutations also had longer PFS than carriers of Gly719Xaa and Leu861Gln mutations, at 14.7 versus 13.8 and 8.2 months, respectively, the team reports. Median OS was not estimable for participants with Ser768Ile mutations, and was 26.9 and 17.1 months for those with Gly719Xaa and Leu861Gln mutations, respectively.

“Our findings show that it is important to assess uncommon EGFR mutations independently or appropriately grouped, and not as a whole group (ie, uncommon) because mutation-specific responses may not be identified and activity in certain mutations might be masked by a lack of response in others,” conclude Yi-Long Wu, from Guangdong General Hospital and Guangdong Academy of Medical Sciences in Guangzhou, China, and colleagues.


Yang J, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.Lancet Oncol 2015; Advance online publication 4 June. doi:

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