molecular profile for nsclc egfrmut patients after ... · marcelo cruz, m.d. developmental...
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Molecular profile for NSCLC EGFRmut patientsafter progression of disease with TKis
Marcelo Cruz, M.D.
Developmental Therapeutics Program
Division of Hematology/Oncology
Northwestern University
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Disclosures
• Clinical Research: Roche, Eli Lilly, Novartis, BMS, AZ
• Honorarium: Roche, AstraZeneca, Sanofi, Amgen. Lilly, BI, Agendia
I received honoraria for this activity
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Massimo Cristofanilli
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RCT of 1st and 2nd generation EGFR TKIs x Chemofor EGFRmut NSCLC
Morgillo F et al .ESMO 2016
EGFR-TKI x ChemoPFS ~ 10 months x 6 months Response Rate ~ 70 % x 30%
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Definition of Acquired Resistance to EGFR TKIs: • Previous therapy with EGFR TKI
• One of the following:• EGFRmut sensitive to EGFR TKi• Clinical benefit with EGFR TKI defined as:
• Partial or Complete Response (RECIST or WHO), or• Durable Stable Disease (≥ 6 months)
• Progression of Disease (RECIST or WHO) during continuous therapy with EGFR TKI during the last 30 days
• No systemic therapt between the EGFR TKI and the new therapy
Jackman et al., JCO 2010
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Morgillo F et al .ESMO 2016
Mechanisms of Acquired Resistance to EGFR TKIs
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“Progress in Science depends on new techniques,
new discoveries and new ideas,
probably in that order”
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Resistance to First Line EGFR TKis
N= 258
T790M:60%
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N Engl J Med. 2005 Feb 24;352(8):786-92
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• CASE REPORT A 71-year-old former smoker with NSCLC
• Transbronchial tumor-biopsy specimen:
• deletion, delL747–S752 identical to a previously described EGFR mutation that is associated with responsiveness to gefitinib.
• The patient had a clinical and radiographic response to gefitinibmonotherapy for 24 months
N Engl J Med. 2005 Feb 24;352(8):786-92
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• The authors hypothesized that the patient’s relapse may have been due to an acquired, second mutation in the EGFR gene that conferred resistance to gefitinib
Rebiopsy
N Engl J Med. 2005 Feb 24;352(8):786-92
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• DNA at first biopsy x Rebiopsy:
• sequencing of exon 20 demonstrates a novel Cytosine-to-Thymidine base-pair change resulting in the aminoacid change: methionine was substituted for threonine at position 790 (T790M) in the catalytic cleft of the EGFR TK domain
N Engl J Med. 2005 Feb 24;352(8):786-92
T790M restores TK affinity to ATP which turns this TK 5x more active than the WT cinase
Yun C at al. PNAS, 2008
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Molecular profile pos-PD EGFRmut after Tki exposure
2005 2017 – AURA Trial 2018 – FLAURA Trial
To identify EGFR T790M mutations after PD to EGFR-targeted TKIs:- Rebiopsy- cfDNA methods; tumor sample is recommended if the plasma result is negative.
2018 – ASCO, NCCN Guideline