We read with interest the recently published paper by Truini and colleagues (1) describing the peculiar in vitro activity of afatinib on non–small cell lung cancer cell lines harboring the EGFR L747-A750>P mutation.

We reviewed our patient database and found 6 cases out of 265 with this specific EGFR mutation (2.2%), similar to the prevalence reported in the paper by Truini and colleagues. Here we report two of those cases, one treated in first-line with afatinib and the other with erlotinib followed by osimertinib at progression. A 68-year-old lady, never smoker, was diagnosed with stage IV lung adenocarcinoma in 2015. We started first-line treatment with afatinib with partial response (PR; only a small residual lesion in the site of primary right lower lobe tumor, complete response on the other sites; Fig. 1) with a progression-free survival (PFS) of 48 months. Treatment is still ongoing.

Figure 1.

CT scan showing the tumor mass (A) and the liver metastasis (C) at the time of the diagnosis and after almost 4 years of treatment (B and D).

Figure 1.

CT scan showing the tumor mass (A) and the liver metastasis (C) at the time of the diagnosis and after almost 4 years of treatment (B and D).

Close modal

A 52-year-old never smoker woman was diagnosed with metastatic lung adenocarcinoma in October 2017. First-line treatment with erlotinib was started in November 2017, with PR and subsequent progressive disease (PD) (PFS = 8 months). Because of the identification of T790M mutation, a second-line therapy with osimertinib was started. Best response was a PD with a PFS of 1.9 months. Patient died in December 2018 without receiving further anticancer therapies due to rapid clinical deterioration.

EGFR L747-A750>P mutation have been recently reported to show a unique pattern of sensitivity to the second-generation tyrosine kinase inhibitor (TKI) afatinib compared with erlotinib and osimertinib, conferring resistance to first- and third-generation TKIs, but not to second-generation ones (afatinib and dacomitinib). In line with this finding, patients with L747-A750>P mutation have inferior outcomes when treated with a first-generation TKI, compared with the more common E746-A750 mutants. Still, data regarding the outcome of these patients when treated with second- and third-generation TKIs are lacking.

Among common EGFR mutations, exon 19 deletions have been shown to be more sensitive to EGFR-TKIs, as compared with L858R mutations, regardless of the type of drug used (2). In the LUX LUNG 7 trial, median PFS in patients treated with afatinib was 10.9 and 12.7 months in patients with L858R and Del19 mutations, respectively (3). Similarly, in the FLAURA study, Osimertinib led to a median PFS of 14.4 versus 21.4 months in patients with L858R and Del19 mutations, respectively, while corresponding figures for standard EGFR-TKI (erlotinib or gefitinib) were 9.5 and 11.1 months (4).

The exceptional depth and duration of response of our afatinib-treated case, as opposed to the poor outcome of the patient treated with erlotinib followed by osimertinib, provides further clinical support to the preclinical study of Truini and colleagues, indicating that tumors harboring the EGFR exon 19, L747-A750>P mutation have an excellent and specific sensitivity to second-generation TKIs (such as afatinib). Therefore, knowing the specific exon 19 mutation at the time of diagnosis may help clinicians to choose among the available EGFR-TKIs the most appropriate for each patient.

A. Ardizzoni is an unpaid consultant/advisory board member for MSD, AstraZeneca, Novartis, Roche, and Bristol-Myers Squibb. No potential conflicts of interest were disclosed by the other authors.

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