Real-World Outcomes of T790M Mutation Testing and Sequential Osimertinib in EGFR-Positive Advanced Non-small Cell Lung Cancer: A Revisited Strategy.

Background: Epidermal growth factor receptor (EGFR)-driven non-small cell lung cancer (eLC) is a leading cause of death. The FLAURA study showed that upfront osimertinib (U-OSI) led to better overall survival (OS) than gefitinib or erlotinib, regardless of T790M status in advanced disease. However, if sequenced optimally, sequential OSI (S-OSI) in T790M-positive patients after first- or second-generation EGFR-tyrosine kinase inhibitors (F-S-EGFR-TKI) should theoretically lead to better OS than U-OSI.

Objective: To identify the best sequencing strategy in this group of patients.

Patients and methods: A multicentre retrospective study was conducted on treatment-naive eLC patients who had received an F-S- EGFR-TKI between 1 January 2016 and 31 December 2020 in three tertiary NHS hospitals in the UK. Compliance to national recommendation of T790M testing was analysed. Survival outcomes of T790M testing and S-OSI were estimated with the Kaplan-Meier and Cox Proportional Hazard models.

Results: In 84/122 evaluable patients, after F-S-EGFR-TKI, only 50% of the patients were offered a T790M biopsy, owing to rapid progression and reduced fitness. Of which, 59.5% of the patients tested positive and had S-OSI. Median OS for the T790M-tested cohort, regardless of positivity and S-OSI, was 54.0 months vs 8.9 months in those not tested (P = < 0.001). Median OS of S-OSI in T790M-positive patients was 64.0 months vs 34.9 months in the T790M-negative cohort (P < 0.0001). On multivariable analysis, S-OSI was associated with better OS (HR 1.841; 95% CI 1.052-3.221; P = 0.0325), whereas performance status (HR 2. 256; 95% CI 1.151-4.422, P = 0.0178), presence of baseline intracranial disease (HR 2 .022; 95% CI 1.144-3.575, P = 0. 0115), the male sex (HR 2.265; 95% CI 1.302-3.939; P = 0.0038) and non-exon 19 deletion mutations (HR 1.610; 95% CI 1.112-2.331, P = 0.0116) were associated with a higher risk of death.

Conclusions: High performance status and intracranial disease should be indications for U-OSI for a higher chance of response. For fitter patients, F-S-EGFR-TKI followed by T790M biopsy +/- S-OSI appears to confer better-than-expected OS in the entire cohort in the real-world setting, regardless of T790M positivity. Given the clinical benefit and potential cost-effectiveness of this approach, S-OSI should be considered a favourable option in this group of patients, especially in resource-deprived settings.