Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are a standard treatment in patients with lung adenocarcinomas. However, analysis of a large database of sequenced EGFR results and corresponding patient outcomes has revealed uncommon EGFR mutations that associate survival was improved following first-line chemotherapy compared with a TKI in these patients. Findings were presented at the ESMO 2018 Congress in Munich, Germany by first author Aurelien Brindel of the Pathology Department, Groupement Hospitalier Est in Bron, France.
Professor Brindel and colleagues conducted a retrospective study to determine the incidence of rare, uncommon EGFR mutations and to describe the association of these mutations to patient response and outcome following chemotherapy or TKI therapy.
The investigators performed 7539 molecular analyses covering exons 18 to 21 of the EGFR from 2009 to 2017 at the regional genomics facility of the Lyon University Hospital using techniques such as Sanger and next generation sequencing. This analysis comprised EGFR-mutant tumours excluding L858R, exon 19 deletions, T790M and exon 20 insertions. All mutations were reviewed by two pathologists, and clinical data were collected from the corresponding medical records of the patients.
Sequencing yielded 857 EGFR somatic mutations, of which 95 (11%) were considered to be uncommon EGFR-mutations. The majority of uncommon mutations included 47 (50%) exon 18 mutations, comprised of 15% E709X and 35% G719X alterations. Twenty-six (27%) exon 20 mutations were found that included 9% of S768I and 18% of A767_V769dup mutations. In addition, 22 (23%) L861Q in exon 21 mutations were detected. Of further interest were 27 (28%) samples, which presented another mutation, of which 9 contained L858R mutations.
The corresponding patient data showed that patients with uncommon mutations had longer median overall survival (OS) when treated with first-line chemotherapy than patients with similar mutations receiving a first-line TKI; median OS was 27.7 months; 95% confidence interval [CI] 21.6 - 35 with chemotherapy compared to 16.9 months; 95% CI, 13.6 - 25.9 with a TKI (p = 0.075, all mutations included).
The investigators further correlated OS with the type of mutation and found that exon 18 and exon 20 associated with a better prognosis, whereas L861Q was linked to a poorer prognosis.
The presence of a second rare EGFR mutation in the same tumour sample associated with better OS (p = 0.002).
Discussant Points
Dr Raffaele Califano of the Department of Medical Oncology, The Christie and Manchester University Hospital, Manchester, UK who discussed the study findings said that it provides further insight on incidence of uncommon mutations in Caucasian patients. However, there is no data on ORR and PFS, only one patient received osimertinib and there is no data provided on clinical characteristics according to type of mutations.
Conclusions
Uncommon somatic mutations need to be further investigated, as their clinical and therapeutic significance remains unknown, according to the investigators.
In this analysis, they found that chemotherapy tended to improve survival compared to TKI therapy in patients with lung adenocarcinoma, also presenting with uncommon EGFR mutations. Of note was that patients having specific mutations localised in exon 18 showed a better prognosis than others.
Further analysis in a larger cohort could help to optimise personalised treatment for each rare mutation.
Disclosure
This trial was sponsored by the French National Cancer Institute.
Reference
LBA60 – Brindel A, Althakfi W, Barritault M, et al. Uncommon EGFR mutations in lung adenocarcinomas: clinical features and response to tyrosine kinase inhibitors.