Abstract 1014P
Background
Almonertinib is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with demonstrated activity against EGFR sensitizing mutations and EGFR T790M mutation. Despite the success of almonertinib, acquired resistance inevitably occurs.
Methods
To identify mechanisms of resistance to almonertinib and characterize clinically, we identified patients with EGFR-mutant lung cancers who had next-generation sequencing performed on tumor tissue or plasma after developing acquired resistance to almonertinib.
Results
1) We collected post-almonertinib samples from 79 patients, the majority were female (n = 54, 68.4%), median age was 64 (range 27-83). All patients had an EGFR activating mutation. 2) When almonertinib was given as initial treatment, EGFR-dependent mutations which may lead to the acquired resistance were identified in 23.1% (9/39) patients, including C797S (1 pts), L833V (2 pts), L747P (1 pts), E709V (1 pts), EGFR amplification(6 pts). Bypass or downstream activating mutations were detected in 38.5% (15/39) patients, including EML4-ALK rearrangement (1 pts), MET amplification (8 pts), KRAS mutations (2 pts), MYC amplification (3 pts), PIK3CA mutations (2 pts), CDK4 amplification (2 pts) and CDK6 amplification (2 pts). 3) When almonertinib was given as second-line treatment, EGFR-dependent mutations which may lead to the acquired resistance were identified in 32.5% (13/40) patients, including C797S (1 pts), V834L (2 pts), G724S (2 pts), V769L (1 pts), L718Q (1 pts), E709V (1 pts) and EGFR amplification (7 pts). Bypass or downstream activating mutations were detected were in 27.5% (11/40) patients, including MET amplification (5 pts), ERBB2 amplification (2 pts), MYC amplification (1 pts), CDK4 amplification (3 pts), CDK6 amplification (2 pts), CCNE1 amplification (1 pts), BRAF V600E (1 pts), KRAS mutations (1 pts) and PIK3CA mutations (3 pts).
Conclusions
Hence, the resistance landscape to almonertinib is similar to osimertinib, repeated tumor biopsies, as well as plasma genotyping at the time of progression on almonertinib, are crucial steps in unraveling resistance mechanisms and guiding future treatments.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.