EGFR+ mNSCLC WILL FIND THE BACK ROADS
Despite advancements, EGFR+ mNSCLC still outmaneuvers today's strategies, leaving patients with limited PFS and at risk of disease progression.1-8
Poor EGFR+ outcomes
THE EGFR+ mNSCLC LANDSCAPE HAS CHALLENGES TO NAVIGATE
Despite advances in 1L treatment options, disease progression is inevitable and PFS outcomes are limited1-7,9,10
| 1L treatments for EGFR+ mNSCLC | mPFS, months (BICR analysis) |
| EGFR TKIs2-5,9,10 | 9.2 to 17.7 |
| EGFR TKIs + VEGF inhibitor6,7 | 16.5 to 16.9 |
PFS ranges for EGFR TKIs and EGFR TKIs + VEGF inhibitor are based on Phase 2b and Phase 3 clinical trials evaluating 1st-, 2nd-, and 3rd-generation EGFR TKIs.2-8,10
Immunotherapy is not a recommended treatment strategy in EGFR+ NSCLC in certain settings based on NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).11
Burden of EGFR+ mNSCLC mutations
Less than 1/5 of patients with EGFR+ mutations in mNSCLC will survive 5 years, as demonstrated by real-world data.12
Real-world OS Following EGFR TKI Treatment12*
*Based on a real-world analysis of 2,833 adult patients with confirmed EGFR mutations treated with a 1st-, 2nd-, and 3rd-generation EGFR TKI in the advanced NSCLC Flatiron registry EHR database between January 1, 2011, and May 21, 2020.12
†Real-world OS based on prognostic value analysis.12
25% to 39% of patients with EGFR+ mNSCLC never
receive 2L therapy, according to multiple studies 13-15
Range includes patients who died or discontinued the assigned therapy without receiving 2L therapy during follow-up.
Learn more about the underlying mechanism in
EGFR+ mNSCLC from an expert in the field.
Featuring Dr. Joshua Sabari, thoracic medical oncologist at New York University Langone's Perlmutter Cancer Center.
Drivers of progression
EGFR+ mNSCLC OUTMANEUVERS CURRENT APPROACHES
Resistance mechanisms may have implications for EGFR TKI treatment outcomes5,16
EGFR-dependent
“on-target” mechanisms5,16
- EGFR mutations
- EGFR amplification
EGFR-independent
“off-target” mechanisms5,16
- MET and HER2 amplification
- Bypass and downstream alterations (KRAS, BRAF, PIK3CA, FGFR1)
- Oncogenic fusions (ALK, BRAF, RET, ROS1)
- Cell-cycle gene alterations
- Histologic transformations
Patients may not respond to EGFR TKIs due to intrinsic resistance or may develop acquired resistance with EGFR TKI exposure5,16,17
MET amplification
MET amplification is a common mechanism of off-target acquired resistance to 3rd-generation EGFR TKIs, accounting for up to 50% of all cases5,18-21*
MET activates downstream pathways that can bypass EGFR signaling18
Amplification of MET is associated with disease progression in mNSCLC5
*The detection rate of MET amplification can differ based on the sensitivity of the employed testing method and the specific cutoff point in each study.
EGFR C797S
Most common tertiary EGFR mutation found in patients treated with 3rd-generation EGFR TKIs22
Impairs covalent bond formation between EGFR TKIs and the EGFR binding domain22,23
PIK3CA
PIK3CA alterations occur in 3% to 12% of patients following EGFR TKI5
Associated with 1st- and 3rd-generation EGFR TKI resistance5
May coexist with EGFR mutations24
Some FDA-approved EGFR TKIs have activity for HER2,
HER3, or HER4, but they do not target MET25-27
Unmet needs
STAYING AHEAD OF EGFR+ mNSCLC
Navigating the current challenges:
There remains an unmet need in addressing PFS outcomes in EGFR + mNSCLC
- mPFS for 1L EGFR TKIs ranges from 9.2 to 17.7 months2-5,9,10
- mPFS for EGFR TKIs + VEGF inhibitor ranges from 16.5 to 16.9 months6,7
Common off-target mechanisms of resistance are still a risk for patients
- Progression is inevitable for patients with EGFR+ mNSCLC, with MET amplification occurring in up to 50% of patients5,17-21*
- Currently approved EGFR TKIs address only EGFR+ NSCLC resistance mechanisms that alter the tyrosine kinase domain of EGFR5,16
*The detection rate of MET amplification can differ based on the sensitivity of the employed testing method and the specific cutoff point in each study.
Brain metastases pose a significant challenge in the current paradigm
- Brain metastases in patients with EGFR-mutated NSCLC are difficult to treat, and are associated with increased mortality28,29
- Improved strategies for managing intracranial activity are needed to maximize the benefit not only viscerally outside the brain, but also in the CNS where these types of cancer often grow28,29
We must find a way to stay ahead of EGFR+ mNSCLC
from the start
STAY AHEAD OF EGFR+ mNSCLC WITH US
1L, first line; 2L, second line; ALK, anaplastic lymphoma kinase; BICR, blinded independent review committee; BRAF, B-Raf; CI, confidence interval; CNS, central nervous system; EGFR, epidermal growth factor receptor; EHR, electronic health records; FDA, U.S. Food and Drug Administration; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; HER4, human epidermal growth factor receptor 4; KRAS, Kirsten rat sarcoma virus; MET, mesenchymal-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; mPFS, median progression-free survival; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
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11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V2.2024. National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed February 14, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
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19. Yu HA, Kerr K, Rolfo CD, et al. Detection of MET amplification (METamp) in patients with EGFR mutant (m) NSCLC after first-line (1L) osimertinib (abstract). 2023 American Society of Clinical Oncology Annual Meeting. June 2-6, 2023; Chicago, IL. Abstract 9074.
20. Ramalingam SS, Zhang N, Yu J, et al. Real-world landscape of EGFR C797X mutation as a resistance mechanism to osimertinib in non-small cell lung cancer (abstract). J Thorac Oncol. 2022;17(9S):S670S68. Abstract MA07.13.
21. Besse B, Baik CS, Marmarelis ME, et al. Predictive biomarkers for treatment with amivantamab plus lazertinib among EGFR-mutated NSCLC in the post-osimertinib setting: analysis of tissue IHC and ctDNA NGS (abstract). 2023 American Society of Clinical Oncology Annual Meeting. June 2-6, 2023; Chicago, IL. Abstract 9013.
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24. Wang L, Hu H, Pan Y, et al. PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. PLoS One. 2014:9(2):e88291.
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29. Ernani V, Stinchcombe TE. Management of brain metastases in non–small-cell lung cancer. J Oncol Pract. 2019;15(11):563-570.