Around 5% of EGFR gene alterations in non-small cell lung cancer (NSCLC) involve exon 18. Limited prospective data on the therapeutic actionability of individual exon 18 alterations with specific EGFR tyrosine kinase inhibitors (TKIs) are available to guide clinical decision making for these patients.
We conducted a literature search on PubMed using search terms “exon 18” OR “uncommon” OR “non-common” OR “rare” AND “EGFR” AND “NSCLC” OR “lung” for studies published in English on/before 6 February, 2021, that reported patient-level outcomes from NSCLC patients with defined exon 18 alterations treated with a single named EGFR TKI, with reported progression free survival (PFS) data. We extracted and analysed demographic and clinical data.
Forty-five publications, containing 143 patient-level reports, met the eligibility criteria. 64 patients had a single EGFR exon 18 alteration (37 being G719X). 79 patients had compound EGFR alterations (75 doublet and 4 triplet). For the whole cohort, treatment with afatinib was associated with the highest reported median(m) PFS (17 months; n=15), followed by erlotinib (8.4 months; n=49), gefitinib (7.0 months; n=70), osimertinib (7.0 months; n=6) and icotinib (2.3 months; n=3). Pairwise analysis suggested afatinib was associated with higher mPFS compared with gefitinib or erlotinib (both: p=0.01), but should be interpreted on the light of the selection/publication bias. Reported PFS exceeded 2 years in 13 cases, these being G719X (N=6 and 16.2% of all G719X cases), compound (N=6) or L692F (N=1) alterations, and all treated with first/second generation TKIs. This individual patient data and mutation level resolution presented suggest limited data supporting the actionability of certain rare alterations, heterogeneity in reported outcomes for patients with more prevalent alterations, and potential differences in alteration-specific drug sensitivity.
Reported patient level outcomes for distinct exon 18 mutations strongly imply distinct actionability with EGFR TKIs. In concert with reported cohort/trial and preclinical data, our data provide an additional resource to help clinical decision making for patients with these rare EGFR alterations.
Clinical trial identification
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G.J. Doherty: Other, Institutional, Advisory Board, Speaker: AstraZeneca; Other, Institutional, Advisory Board, Speaker: Amgen; Other, Institutional, Advisory Board, Speaker: Boehringer Ingelheim; Other, Institutional, Advisory Board, Speaker: Bayer; Other, Institutional, Advisory Board, Speaker: Roche. All other authors have declared no conflicts of interest.