121P Clinical outcomes of compound EGFR mutation in non-small cell lung cancer: A national, retrospective, multicenter study

Compound EGFR mutations are a rare and heterogeneous subtype of non-small cell lung cancer (NSCLC). Currently there is no clear recommendation regarding the best therapeutic strategy to treat these patients. Chemotherapy, tyrosine kinase inhibitors (TKIs) and immunotherapies are often used as first or second line of treatment. Recently, a structure-based classification of EGFR mutations showed a novel and promising way of predicting response to treatment (Robichaux JC, Nature 2021). We conducted a multicenter, retrospective, nationwide study of patients with metastatic NSCLC harboring compound EGFR mutations. The common mutation T790M and exon 20 insertions were excluded. Point mutation within exon 20 were included. Compound EGFR mutations were classified into two main groups according to structure-based classification: group 1 for classical mutations and group 2 for PACC (P-loop and αC-helix compressing) mutation. Clinical data were collected. We enrolled 47 patients in the analysis.16 patients were included in “classical mutations” group, 25 patients in the PACC group and 6 patients could not be classified. The median overall survival of the population was 37.2 m. [27-53.5]. The median progression free survival in the first-line setting (PFS1L) was shorter in the chemotherapy group (3.7 m.; 95% CI [3-NA]) than in the TKI group (11.2 m.; 95% CI [7.4-17], p=0.004). The median PFS1L was significantly longer in all TKI groups taken individually vs chemotherapy (1G TKI, 7.4 m., 95% CI [4.9-27.4]; afatinib, 13.2 m., 95% CI [7.5-NA]; osimertinib, 10.3 m., 95% CI [8.6-NA]; p=0.04). The median PFS2L treatment was significantly shorter in patients treated with chemotherapy (4 m. 95% CI [3.0-8.6]) compared to osimertinib (8.8 m. 95% CI [7.1-NA], p=0.01). According to structure-based classification, median PFS1L to afatinib was 10.1 m. for classical mutations group vs. 17 m. for the PACC mutations group with, p=0.09. This study shows that treatment with TKIs in either first or second line is associated with favorable outcome in patients presenting compound EGFR mutation. Structure-based configuration of EGFR compound mutation might also be considered for selecting TKI in first line.