P1.01-50 Impact of Concomitant HER2 Alterations in Mediating Clinical Outcomes of EGFR-Mutant Patients to Different Generation of EGFR-TKIs

Abstract

The 2nd generation EGFR-TKI are selective and potent irreversible pan-HER inhibitors. Given their effect on HER2 besides EGFR, we investigated the role of HER2 co-alterations in mediating the clinical outcomes of EGFR-mutant non-small cell lung cancers to 2nd generation or other generation EGFR-TKIs. Plasma/tissue samples from advanced NSCLC before and after 1L EGFR-TKI treatment were sequenced using 168-/520-cancer-related gene panels, respectively. Clinical records of 94 EGFR-mutant pts (92 adenocarcinomas and 2 adenosquamous cell carcinomas) after 1st/3rd (n=73) or 2nd generation (afatinib, n=16; dacomitinib, n=5) EGFR-TKI treatment were collected for clinical outcomes evaluation. Event-time distributions were estimated using Kaplan-Meier and compared with long-rank test. Among the 94 pts identified as EGFR-positive at baseline, 8 (8.5%) had concurrent HER2 gain-of-function alterations (amplification or active mutation). Survival analysis showed that for those with concomitant EGFR and HER2 alterations at baseline, pts achieved favorable PFS (23.2 vs 5.6 months, p=0.04) to 2nd generation (n=2) than to 1st/3rd generation EGFR-TKI (n=6) as 1L treatment. And for those receiving 1L 1st/3rd generation EGFR-TKI (n=73), the presence of baseline HER2 alterations (n=6) was associated with shorter PFS (5.6 vs 9.8 months, p=0.16) and OS (15.7 vs 21.0 months, p=0.06) than absence of HER2 (n=67), although the difference was not significant due to a small sample size. In addition, we found all the samples (n=21) obtained from pts after 2nd generation EGFR-TKI resistance were HER2-negative, but pts progressed on 1st or 3rd generation EGFR-TKI with HER2 as the only resistance mechanism were observed in our study cohort. Our findings suggested that, for EGFR-mutant pts combined with HER2 alterations at baseline or those resistant to 1L treatment of 1st/3rd EGFR-TKI due to HER2 alterations only, 2nd EGFR-TKI might be a better choice. Our findings suggested that, for EGFR-mutant pts combined with HER2 alterations at baseline or those resistant to 1L treatment of 1st/3rd EGFR-TKI due to HER2 alterations only, 2nd EGFR-TKI might be a better choice.