Abstract 1264P
Background
Widespread adoption of tumor sequencing in NSCLC patients has revealed a broad spectrum of oncogenic EGFR non-classical mutations (NCMs), including PACC (P loop and αC helix compressing) and other groups, in addition to classical mutations L858R and Ex19del.
Methods
Analysis of 11,434 sequenced cases of newly diagnosed and treatment naïve EGFRm NSCLC within the GuardantINFORMtm clinical-genomic database (1L treatment information in 3,276 patients) reveals a broad spectrum of NCMs and allows association of discrete groups of mutations with real-world treatment practices and therapeutic outcomes.
Results
There are greater than 100 validated oncogenic EGFR mutations expressed in NSCLC. NCMs comprise at least 22% of newly diagnosed EGFRm NSCLC and can be cohesively grouped into families based on structural properties and pharmacology. Treatment practices for patients with NCMs remain heterogenous: 36% of patients received osimertinib or afatinib and 60% of patients received chemotherapy and/or immunotherapy. Preclinical data demonstrated weaker potency for osimertinib against NCMs compared with classical mutations, and patients expressing NCMs discontinue osimertinib sooner than patients expressing classical mutations. L858R patients with NCM co-expression discontinue osimertinib therapy sooner than patients expressing L858R alone.
Conclusions
Compared to NSCLC patients expressing classical EGFR mutations, patients expressing NCMs discontinue EGFR inhibitor treatment sooner, and chemotherapy remains the most common treatment, with poor patient outcomes. Moreover, the co-expression of osimertinib-resistant NCMs with L858R may contribute to inferior outcomes versus patients with L858R alone. These real-world data underscore the unmet medical need of patients expressing NCMs, and the opportunity for a 4th-generation TKI that potently inhibits NCMs in the newly diagnosed setting. Table: 1264P
EGFR mutation | Median real-world time to treatment discontinuation (rwTTD (mo)) – 1L NSCLC | ||
chemotherapy/immunotherapy | osimertinib | afatinib | |
NCM | 4.2 (n=325) | 6.0 (n=104) | 8.0 (n=90) |
Classical | 2.8 (n=370) (Ex19del or L858R alone) | 13.8 (n=1696) (Ex19del or L858R alone)14.7 (n=1054) (Ex19del, alone)10.8 (n=642) (L858R, alone)5.0 (n=62) (L858R + NCM) | 9.3 (n=72) (Ex19del or L858R alone) |
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Black Diamond Therapeutics.
Funding
Black Diamond Therapeutics.
Disclosure
J.V. Heymach, M. Nilsson, Y.Y. Elamin, X. Le: Financial Interests, Institutional, Research Funding: BDTX. E. Dardenne, C. Guzman, S. Eathiraj, E. Buck: Financial Interests, Institutional, Full or part-time Employment: BDTX. J. Liao, N. Zhang: Financial Interests, Institutional, Full or part-time Employment: GH.
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