Survival outcomes of patients with uncommon EGFR mutations in surgically resected lung adenocarcinoma: A multi-institutional real-world database study (CReGYT-01 EGFR study)

Uncommon epidermal growth factor receptor (EGFR) mutations (UCM) account for approximately 10% of EGFR-mutant lung adenocarcinoma (LUAD) cases; however, their prognostic impact remains unclear. This study aimed to evaluate postoperative outcomes in patients with UCM compared to those with common mutations (CM) using a large multicenter database.

This retrospective study included 1,636 patients with EGFR-mutant LUAD who underwent complete resection between 2015 and 2018 at 21 Japanese institutions. Patients were classified into the CM and UCM groups. Recurrence-free survival (RFS), overall survival (OS), lung cancer-specific survival (LCSS), and survival after recurrence (SAR) were analyzed using univariable and multivariable analyses and the inverse probability of treatment weighting (IPTW) method.

Among the patients, 1,441 (88.1%) had CM and 195 (11.9%) had UCM. RFS was comparable between the groups. However, patients with UCM showed significantly shorter OS and LCSS than those with CM (OS: multivariable hazard ratio [HR] 1.538, 95% confidence interval [CI] 1.003-2.359; LCSS: multivariable HR 1.803, 95% CI 1.064-3.056). This trend was consistently validated using IPTW methods. SAR was also significantly shorter in patients with UCM. Subtype-specific analyses revealed that patients with exon 20 insertions (Ex20ins) had a significantly worse prognosis than those with other UCMs.

Patients with UCM had significantly worse OS, LCSS, and SAR than those with CM despite similar RFS. These survival disadvantages in UCM were strongly associated with the Ex20ins subtype. These findings highlight the urgent need for novel perioperative treatments for patients with UCM, especially Ex20ins.