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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling
Jonathan W Riess1, David R Gandara1, Garrett M Frampton2
1UC Davis Comprehensive Cancer Center, Sacramento, California.
Introduction:
EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC.
Methods:
Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes.
Results:
Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for five patients and none responded.
Conclusions:
In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.
Insights
EGFR exon 20 insertions (EGFRex20ins) are uncommon in non-small cell lung cancer (NSCLC) and do not respond to current EGFR TKIs. Comprehensive genomic profiling reveals diverse EGFRex20ins, highlighting the need for new therapeutic strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- EGFR exon 20 insertions (EGFRex20ins) are a rare subset of EGFR mutations in non-small cell lung cancer (NSCLC).
- These mutations confer relative resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs).
- Emerging data suggests potential benefit from newer-generation EGFR TKIs for patients with EGFRex20ins.
Purpose of the Study:
- To characterize the spectrum of EGFRex20ins and associated genomic alterations in a large NSCLC cohort.
- To evaluate the frequency of EGFRex20ins in EGFR-mutant NSCLC.
- To assess clinical outcomes in patients with EGFRex20ins treated with EGFR TKIs.
Main Methods:
- Hybrid capture-based comprehensive genomic profiling (CGP) was performed on 14,483 NSCLC specimens.
- CGP analyzed 236 or 315 cancer-related genes with high mean coverage depth (>650X).
- Clinical outcomes for patients receiving EGFR TKIs were collected and analyzed.
Main Results:
- EGFRex20ins were identified in 1.8% of NSCLC cases (263/14,483), representing 12% of EGFR-mutant NSCLC.
- Sixty-four unique EGFRex20ins were detected, with D770_N771>ASVDN and N771_P772>SVDNP being most common.
- No responses were observed in five patients treated with first- or second-generation EGFR TKIs; co-occurring alterations in TP53, CDKN2A, and RB1 were frequent.
Conclusions:
- EGFRex20ins occur more frequently than previously reported in EGFR-mutant NSCLC.
- Current EGFR TKIs demonstrate limited efficacy in patients with EGFRex20ins.
- The diversity and prevalence of EGFRex20ins underscore the need for developing targeted therapies for this patient population.
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