Department of Thoracic/Head & Neck Medical Oncology Management of EGFR-Mutant NSCLC Resistant to EGFR-TKI therapy Anne S. Tsao, M.D. Associate Professor The University of Texas MD ANDERSON CANCER CENTER Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program
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Department of Thoracic/Head & Neck Medical Oncology
Management of EGFR-Mutant NSCLC Resistant to EGFR-TKI therapy
Anne S. Tsao, M.D.
Associate Professor
The University of TexasMD ANDERSON CANCER CENTER
Director, Mesothelioma Program
Director, Thoracic Chemo-XRT Program
EGFR mutations
Common mutationsMechanisms of resistance to EGFR TKIs
Clinical PD appearance:- Rapid disease PD globally-Slow growth globally-Growth in several areas, but not all
Flare of Disease after EGFR TKI discontinuation in acquired resistance
• Rapid disease acceleration leading to hospitalization and/or death after EGFR TKI cessation occurs in up to 23% (n=14) of patients in MSKCC series (n=61).
Riely et al. Clinical Cancer Research 2007, Chaft et al. CCR 17 (19): 6298-6303, 2011
Current Options in EGFR TKI resistant patient with EGFR mutation
Chemotherapy
Chemotherapy + EGFR TKI combination
Chemotherapy
Chemotherapy with intermittent EGFR TKI
EGFR TKI
Chemo is safeChemo then maintenance erlotinib is safe
Goldberg et al. ASCO 2012 Abstract 7524, Yoshimura N. et al. JTO 8 (1):96-101, 2013; Faehling et al. ASCO 2012 Abstract 7572; Oxnard et al. ASCO 2012 Abstract 7547
ASPIRATION Phase II Asian multicenter trial for NSCLC EGFR mutation patientsusing continuation erlotinib beyond PD1
Enrollment: April 2011 – Dec 2014 Plan 207 patients
2 Trials to compare ongoing EGFR TKI for Acquired Resistance
Chemo is safeChemo then maintenance erlotinib is safe
Chemo + EGFR TKIs are safe
Chemotherapy
Chemotherapy + EGFR TKI combination
Chemotherapy
Chemotherapy with intermittent EGFR TKI
EGFR TKI SATURN
INTACT I, IITRIBUTE, TALENT
FAST ACT
Potential Antagonism Chemo + EGFR TKI
• There are concerns over combining erlotinib-chemo as erlotinib arrests the cancer cells in the G1 checkpoint and chemo usually works best in the mitotic phase.
Solit et al, Clin Can Res 2005; Davies A et al. CLC 7 (6): 385-388, 2006; Encyclopedia of Science Cell Biology http://www.daviddarling.info/encyclopedia/C/cell_cycle.html
First-Line Asian Sequential Erlotinib plus chemo Trial (FASTACT)
• For local oligo-PD, continue EGFR TKI and apply local therapy.
• For more global PD: 4 options until future trials elaborate on acquired resistance– Chemo– Chemo + EGFR TKI– Chemo then EGFR TKI– Chemo intercalated with EGFR TKI
• Ultimately – Re-biopsy and molecular profile will determine the optimal therapy
EGFR mutations
Common mutationsMechanisms of resistance to EGFR TKIs
• Front-line afatinib improved QOL, RR, DCR, and median PFS over cisplatin-pemetrexed in both the overall EGFR mutation population and in the common EGFR mutation (del19/L858) patients.
• Subgroup analysis showed benefit across most of the subgroups.
• No new safety signals with diarrhea and rash as the most frequent AEs.
Yang et al. ASCO 2012 Abstract LBA7500
• Afatinib was approved July 12, 2013 by the FDA for first-line NSCLC patients with EGFR mutations (del exon 19 and exon 21 L858R) as detected by an FDA-approved assay.
• It remains unknown which EGFR TKI (erlotinib, gefitinib, or afatinib) should be used first or whether these agents can be sequenced in the EGFR mutation population.
• Additional studies are needed to clarify this issue.
• Afatinib is currently under development in combination with cetuximab for resistant EGFR T790 mutant patients.
• Future more broad application of afatinib is anticipated.
Summary Afatinib
Regales et al. JCI 2009
Combination of Afatinib and Cetuximab is effective against EGFR T790M
A randomized phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced, EGFR mutation positive NSCLC
Lynch, T. IASLC Targeted Therapies Meeting Feb 2013
CO-1686 is a novel TKI specifically targeting mutated EGFR
• Novel, oral, selective covalent inhibitor of EGFR mutations in NSCLC• Inhibits key activating and T790M resistance mutations• Minimal activity against wild type EGFR
• First-in-human study ongoing in EGFR-mutation positive pts with recurrent advanced NSCLC, started with free base capsule formulation, hydrobromide salt form of CO-1686 with improved drug availability and reduced variability completed dose escalation.
• Early evidence of efficacy presented at ASCO 2013, WCLC 2013, free base dosed to 900 mg BID
• Roche Molecular Systems companion diagnostic collaboration• Potential for use as first-line therapy
Modified from Soria WCLC 2013
Phase I Schema
Dose 1 (n=3)
Phase IIExpansion Phase
Dose 2 (n=3)
Dose 4 (n=3)
Dose 6 (n=6)
Dose 5 (n=3-6); MTD
Dose 3 (n=3)
40 T790M pts
Target Exposure
45
Phase 2 Cohort A-T790M : 1. Disease progression while on treatment with EGFR-directed therapy. Prior CT including intervening CT before planned initiation of CO-1686, is allowed (washout for EGFR TKI min 3 days, chemo 14 d)Phase 2 Cohort B-T790M 1. Disease progression while on treatment with the first single agent EGFR-directed therapy within the last 30 days, with no intervening treatment before planned initiation of CO-1686 .
92 patients will be enrolled into Phase 1 (57 on CO-1686 free base and approximately 35 on CO-1686 HBr).
CO-1686 freebase demonstrated limited and low-grade adverse events in patients
GRADE 1
GRADE 2
GRADE 3
% patients with eventSoria WCLC 2013
*
67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID
EGFRi immediately before CO-1686 *
1 2 2 2 4 2 2 1 1
Weeks on treatment
******
*
Number of Previous EGFR TKI
lines
6
22 15 1824 11 8 21 30
8 of 9 patients progressed on TKI immediately prior to CO-1686
*
Soria WCLC 2013
Promising clinical activity observed with
CO-1686 – no evidence of WT inhibition• 67% RECIST response rate in evaluable T790M+
patients treated at 900mg BID (free base)
• A hydrobromide (HBr) formulation of CO-1686 with improved exposure has been introduced and a RP2D of 750mg BID has been identified
• CO-1686 is well tolerated with no acneiform rash, consistent with absence of WT-EGFR inhibition• AEs all grades: nausea-25%, fatigue-21%, impaired glucose
tolerance/hyperglycemia 21%
• The pivotal phase 2/3 TIGER program starts 1H14• Efficacy updates at ELCC2014 and ASCO2014
Modified from Soria WCLC 2013
CO-1686 phase 2/3 development: TIGER program
TIGER: Third-generation Inhibitor of mutant EGFR in lung cancER All are global studies in mutant EGFR NSCLC:
− TIGER1: Phase 2/3 randomized registration study in newly-diagnosed patients (vs. erlotinib)
− TIGER2: Phase 2 registration study in 2nd line T790M+ patients directly progressing on first TKI
− TIGER3: Phase 2 registration study in later-line T790M+ patients, progressing on second or later TKI or subsequent chemotherapy
− TIGER4: Phase 2 study in 2nd or later-line patients with T790M detected with a blood/plasma assay
− TIGER5: Phase 3 randomized confirmatory study in 2nd or later-line patients (vs. chemo)
EGFR mutations
Common mutationsMechanisms of resistance to EGFR TKIs
Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI
Novel agents that target
EGFR pathway
AfatinibAfatinib-cetuximab for T790M
CO-1686
MetMAb (onartuzumab)Met inhibition
ASCO 2011 Abstract #7505 MetMab Onartuzumab
Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations.
Met expression is associated with a worse prognosis in NSCLC
MetMab is an anti-Met one-armed antibody that inhibits hepatocyte growth factor (HGF)-mediated activation
Spigel et al. ASCO 2011 Abstract 7505
MetMAb
Met
HGF HGF
Met
GrowthMigrationSurvival
Noactivity
Spigel et al. ASCO 2011 Abstract 7505
Abstract #7505 Phase II Onartuzumab
Met IHC Biomarker
Spigel et al. ASCO 2011 Abstract 7505
“Met Diagnostic Positive” = >50% tumor cells with moderate or strong staining intensity93% had adequate tissue for analysis and 52% were “Met Diagnostic Positive”
Spigel et al. ASCO 2011 Abstract 7505
MetMAb + erlotinib in ITT
PFS HR 1.09OS HR 0.8
Spigel et al. ASCO 2011 Abstract 7505
MetMAb + erlotinib in Met Dx+ pts
PFS HR 0.53 OS HR 0.37
Spigel et al. ASCO 2011 Abstract 7505
MetMAb + erlotinib in Met Dx- pts
PFS HR 1.82OS HR 1.78
Spigel et al. ASCO 2011 Abstract 7505
MetMAb benefit is not driven by EGFR mutation nor FISH status
Spigel et al. ASCO 2011 Abstract 7505
PFS HR 1.71
OS HR 2.61
Met expression correlates to worse outcome in erlotinib + placebo treated pts.
Spigel et al. ASCO 2011 Abstract 7505
Most commonly reported AE frequency > 10%
Phase II
• Met IHC expression inversely correlates with prognosis.
• MetMAb + erlotinib was well-tolerated with no new safety signals.
• MetMAb + erlotinib improved PFS and OS in Met Diagnostic Positive patients.
• A phase III study of MetMAb + erlotinib in Met Diagnostic positive patients started enrollment January 2012 and has completed accrual.
Tsao Conclusions on Clinical Management for EGFR mutation patients with Acquired Resistance
Feb 2013
Oligo-PD Continue EGFR TKI + localized therapy
Global PD
ChemoChemo then EGFR TKIChemo + EGFR TKIChemo intercalated with EGFR TKI