Clinical Outcomes of Compound EGFR Mutations in Non-Small Cell Lung Cancer: A National, Retrospective, Multicenter Study.

Background: Compound EGFR mutations are found in a rare proportion of non-small cell lung cancer (NSCLC). Currently there is no clear recommendation regarding the best therapeutic strategy in this setting. Chemotherapy, and tyrosine kinase inhibitors (TKI) are often used as first or second line of treatment. Recently, an in vitro structure-based classification of EGFR mutations showed a promising way of predicting response to treatment (Robichaux JC, Nature 2021).

Methods: We conducted a multicenter, retrospective, nationwide study of patients with advanced non-small cell lung cancer (NSCLC) harboring compound EGFR mutations. The common T790M mutation and exon 20 insertions were excluded. Compound EGFR mutations were structure-based classified as classical mutations and P-loop and αC-helix compressing (PACC) mutations or unclassified mutations. Clinical data and outcome of selected patients were collected. Overall survival (OS) and progression free survival (PFS) according to structure-based classification and exon-based classification were reported, overall survival being the primary objective.

Results: Eighty-one patients were enrolled in the analysis, including 24 patients in "classical mutations" group, 36 in the PACC group, and 21 as unclassified group. Median overall survival (OS) of the population was 42 months (95% CI, 25.5-64.4), significantly different according to structure-based classification (69.5 m in unclassified group, vs 47 m in classical mutations group and 24,3 in PACC mutations group, P = .01). There was no significant difference in OS according to the type of first-line treatment in the overall population or the presence or not of a frequent mutation (L858R or Del19). The median progression free survival in the first line setting (PFS1L) was shorter in the chemotherapy group (7.1 m.; 95% CI, 1.9-12.2) than in the TKI group (12.6 m.; 95% CI, 8.6-17), P = .005. In the PACC group, PFS1L was higher in the osimertinib group compared to other treatments, HR 0.34 (95% CI, 0.12-0.99), P=.027, whereas no difference was observed in other structure-based groups.

Conclusions: This study demonstrates that treatment with TKIs is associated with favorable outcomes in patients with compound EGFR mutations. Structure-based configuration of EGFR might also be considered when selecting a first-line TKI.