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A. Vivancos
Author of
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.07 - Mechanisms of Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer (ID 1365)
11:50 - 12:01 | Author(s): A. Vivancos
- Abstract
Background:
AZD9291 is an irreversible, mutant-selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed to have potency against both EGFR-sensitizing mutations and T790M. In the ongoing Phase I study of AZD9291 (AURA, NCT01802632), the response rate in patients with T790M positive lung cancer with disease progression on previous EGFR-TKI was >60%, with a preliminary median progression-free survival of >10 months. The molecular mechanisms underlying acquired resistance to AZD9291 are currently under investigation.
Methods:
Plasma genotyping was performed on patients from AURA who had progressed on AZD9291 if they had detectable T790M pre-AZD9291, as assessed by tumor or plasma genotyping, and if they had plasma collected at progression available for analysis. Cell-free DNA (cfDNA) was extracted from plasma taken at progression. Droplet digital PCR (ddPCR) was performed for EGFR exon 19 deletions, L858R, T790M, and C797S. For further exploration, next-generation sequencing (NGS) of an amplicon panel was performed on available progression cfDNA. Lastly, targeted NGS was performed on available resistance biopsy specimens.
Results:
Plasma specimens were available following disease progression on AZD9291 from 40 patients with tumors positive for T790M through tumor (33) or plasma genotyping (7). Twenty-six progression cfDNA specimens were positive for an EGFR-sensitizing mutation by ddPCR, and were deemed eligible for initial resistance analysis. Of these, 12 (46%) had no detectable T790M in plasma despite presence of the EGFR-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism. Seven patients had detectable C797S on ddPCR (27%), all with detectable T790M; of 14 with detectable T790M at resistance, C797S was only detected with EGFR exon 19 deletions (7/9) and not L858R (0/5, p=0.02). Plasma NGS was performed on 12 cases with acquired resistance that were T790M positive pretreatment. Exon 19 deletion/T790M/C797S were detected in four cases, with two of these harboring two different DNA mutations encoding for C797S. One case lost T790M and exhibited HER2 copy number gain (6.3 copies); a tumor biopsy from a separate case underwent aCGH at Institute Gustave Roussy and was also found to have focal HER2 amplification with loss of T790M. Targeted NGS was performed on resistance biopsies from a total of 10 patients from four centers with T790M positive biopsies pre-AZD9291. Six cases maintained T790M, with three harboring exon 19 del/T790M/C797S. In four cases with loss of T790M, one harbored BRAF V600E and one harbored PIK3CA E545K.
Conclusion:
Complementary genomic analysis of plasma and tumor DNA provides insight into the diverse molecular mechanisms of acquired resistance to AZD9291 in EGFR-mutant lung cancer. Our studies show that a majority of cases maintained T790M at resistance, at times acquiring a new C797S mutation in those with EGFR exon 19 deletion. Loss of T790M at progression may be mediated by overgrowth of cells harboring HER2 amplification, BRAF V600E, or PIK3CA mutations. These data highlight the need for investigation of combination therapies to effectively prevent or treat the complexity of drug resistance in EGFR-mutant lung cancer.
