Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
Molecular profile for NSCLC EGFRmut patientsafter progression of disease with TKis
Marcelo Cruz, M.D.
Developmental Therapeutics Program
Division of Hematology/Oncology
Northwestern University
Disclosures
• Clinical Research: Roche, Eli Lilly, Novartis, BMS, AZ
• Honorarium: Roche, AstraZeneca, Sanofi, Amgen. Lilly, BI, Agendia
I received honoraria for this activity
Massimo Cristofanilli
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%
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
Morgillo F et al .ESMO 2016
Mechanisms of Acquired Resistance to EGFR TKIs
“Progress in Science depends on new techniques,
new discoveries and new ideas,
probably in that order”
Resistance to First Line EGFR TKis
N= 258
T790M:60%
N Engl J Med. 2005 Feb 24;352(8):786-92
• 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
• 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
• 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
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