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
EGFR mutations
Common mutationsMechanisms of resistance to EGFR TKIs
Outline: Long-term management EGFR mutated NSCLC patients
Current EGFR TKI Resistance Management
Oligo-metastatic disease resistance
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
EGFR mutations
• Found in 10% - 15% of all lung cancer patients and 85% who clinically respond to EGFR TKIs
• Found more commonly in never-smokers, adenocarcinomas, BAC, women, Asians
• Predominantly located in EGFR exons 19 - 21
• EGFR mutations are not the same. There are sensitive mutations and acquired resistance mutations (T790M).
• 85% of EGFR mutations are either deletion exon 19 or L858 mutation.
Pao, Miller. J Clin Oncol. 2005;23:2556-2568; Wu et al. J Thorac Oncol. 2007;2:430-439.
The relative frequencies of the various mechanisms of acquired resistance.
Yu H A et al. Clin Cancer Res 2013;19:2240-2247
EGFR T790M: Frequently Found inTumor Cells From Patients With Acquired Resistance
to EGFR TKIs
Pao W, et al. PLoS Med. 2005;2:e73; Balak MN, et al. Clin Cancer Res. 2006;12:6494-6501.
T790M blocks erlotinib binding and leads to a resistant phenotype
Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008
EGFR mutations
Common mutationsMechanisms of resistance to EGFR TKIs
Outline: Long-term management EGFR mutated NSCLC patients
Current EGFR TKI Resistance Management
Oligo-metastatic disease resistance
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
EGFR mutant on TKI develops oligometastatic PD
• Continue EGFR TKI • Utilize radiation therapy or surgical resection• Close monitoring
• Several studies demonstrate additional PFS benefit (6.2-10 months) and possibly OS (41 months) benefit with this strategy.
Weickhardt et al. JTO 7: 1807-1814, 2012; Yu et al. ASCO 2012 abstract 7527, JCO 30 , 2012
Weickhardt et al. JTO 7: 1807-1814, 2012
EGFR mutation and ALK mutation patients with oligo-progressive disease + local therapy have PFS benefit
EGFR Mutant Disease Progression on EGFR TKI
Molecular:-Unknown
(other pathways)-MET-PIK3CA-SCLC-HER2
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
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
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel.
1:1
Chemotherapy-naïve advanced
NSCLCN=1949
No PDN=889
4 cycles of first-line platinum
doublet chemotherapy*
Placebo PD
Erlotinib150 mg/day
PD
Mandatory tumor sampling
SATURN: Treatment Schema
Stratification factors:
• EGFR IHC (positive vs negative vs indeterminate)
• Stage (IIIB vs IV)
• ECOG PS (0 vs 1)
• Chemotherapy regimen (cisplatin/gemcitabine vs carboplatin/docetaxel vs others)
• Smoking history (current vs former vs never)
• Region
Co-primary endpoints:
• PFS in all patients• PFS in patients with EGFR IHC+ tumors
Secondary endpoints:
• OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC– tumors, biomarker analyses, safety, time to symptom progression, and QOL
Cappuzzo. ASCO. 2009 (abstr 8001).
SATURN: PFS by EGFR Mutation Status
• About 50% of all tumors were able to be sequenced for EGFR mutation
Time (Weeks)
Pat
ien
ts W
ith
ou
t P
rog
ress
ion
(%
)
Pat
ien
ts W
ith
ou
t P
rog
ress
ion
(%
)
PFS: Wild-Type EGFR PFS: Mutated EGFR
HR=0.78 (0.63-0.96)P=0.0185
HR=0.10 (0.04-0.25) P<0.0001
0
20
40
60
80
100
0 8 16 24 32 40 48 56 640
20
40
60
80
100
Erlotinib (N=22)
Placebo (N=27)
Erlotinib (N=199)
Placebo (N=189)
Cappuzzo. ASCO. 2009 (abstr 8001).
Time (Weeks)
0 8 16 24 32 40 48 56 64
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
Continuing EGFR TKI +/- Chemo may have benefit
Trial PatientsContinued EGFR TKI +
chemo
Goldberg et al. 34 chemo + E44 chemo
RR improvedNo PFS or OS difference
Faehling et al. 27 chemo + EGFR TKI14 chemo
Improved OS
Yoshimura et al. 27 pemetrexed + EGFR TKI ORR 26%, DCR 78%Median PFS 7 months
Median OS 11.4 months
Delayed additional therapy
Oxnard et al. 42 EGFR TKI 45% > 3 months19% > 12 months
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
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)
1:1
Untreated NSCLC IIIB/IVNo prior EGFR
TKI
Platinum (d1) Gemcitabine (d1, 8)
+ PlaceboD15-28 Q4weeks
x 6 cycles
Placebo
Platinum (d1) Gemcitabine (d1, 8)
+ ErlotinibD15-28 Q4weeks
x 6 cycles
Erlotinib
1o endpoint: 8-week non-PD rate2nd: PFS, 16-week non-PD rate, ORR, TTP, OS
Lee J et al. ASCO 2012 Abstract 8031
n=154
Mok T et al. ASCO 2012
FAST ACT II: ITT PFS favors erlotinib-GC
Critique: •FAST ACT 2 has a maintenance portion with the EGFR TKI and this affects clinical outcomes
• SATURN maintenance trial proves PFS benefit in EGFR mutant patients
Tsao Summary on Acquired Resistance
• 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
Outline: Long-term management EGFR mutated NSCLC patients
Current EGFR TKI Resistance Management
Oligo-metastatic disease resistance
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
Novel agents targeting EGFR TKI resistant disease
Agent Inhibitor type Preclinical benefit against T790M
Clinical Trial phase
Dacomitinib(Pfizer)
Irreversible TKI of EGFR, HER2, HER 4
yes II, III
Afatinib(Boehringer Ingelheim)
Irreversible TKI of EGFR, HER2, HER4
yes II, III
CO-1686(Clovis)
Selective covalent inhibitor EGFR mutations
yes I/II (T790M selection)
AZD9291 Irreversible TKI to mutant EGFR
yes I
Onartuzumab(Genentech)
Monoclonal antibody that targets MET receptor
n/a II, III
Tivantinib (ArQule) MET-R TKI n/a II, III
Volitinib (AZ) cMET TKI n/a I
Ariad 26113 EGFR, ALK, ROS1 I
Yang et al. ASCO 2012 Abstract LBA7500
Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation (+) => 345 randomized
Summary LUNG LUX-3
• 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
Afatanib/Cetuximab
• No DLTs at afatinib 40mg po daily plus cetuximab 250 mg/m2 or 500mg/m2 IV q2 weeks
• Expansion cohort dosing: afatinib 40mg po daily + cetuximab 500mg/m2 IV q2 weeks
• Data on the first 100 patients available
Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012
Responses at MTD by T790M mutation
Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012
Eligibility:•Recurrent or advanced NSCLC•Sensitizing EGFR mutation (i.e., exon 19 deletion, L858R)•Chemotherapy and TKI-naïve•PS 0-2
Afatinib PO 40mg daily
+Cetuximab
IV 500mg/m2 Q2 weeks
N=138
Afatinib PO 40mg daily
N=138
Primary Endpoint:Progression-Free Survival
Secondary Endpoints:ORR, OS, Safety, Tolerability, QOL
Exploratory Biomarkers:Pre-and post-Rx T790M testing, whole exome sequencing, HER2 and MET FISH
Initial Evaluation:PET-CT Brain CT or MRI ECG, Echo/MUGA Tumor molecular analysis
CT scans q8 wks
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
Outline: Long-term management EGFR mutated NSCLC patients
Current EGFR TKI Resistance Management
Oligo-metastatic disease resistance
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
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
PFS HR 1.71
OS HR 2.61
Met expression correlates to worse outcome in erlotinib + placebo treated pts.
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-PDContinue EGFR TKI +
localized therapy
Global PD
Chemo
Chemo then EGFR TKI
Chemo + EGFR TKI
Chemo intercalated with EGFR TKI
Tsao Conclusions: Molecular Age Will Come
Molecular Rebiopsy:-Unknown
(other pathways)-MET-PIK3CA-SCLC-HER2
Sequist L et al. Sci Transl Med 2011;3:75ra26-75ra26
Future Clinical Options for T790M or Met pathway acquired resistance
Agent Inhibitor type Preclinical benefit against T790M
Clinical Trial phase
Dacomitinib(Pfizer)
Irreversible TKI of EGFR, HER2, HER 4
yes II, III
Afatinib(Boehringer Ingelheim)
Irreversible TKI of EGFR, HER2, HER4
yes II, III
CO-1686(Clovis)
Selective covalent inhibitor EGFR mutations
yes I/II (T790M selection)
AZD9291 Irreversible TKI to mutant EGFR
yes I
Onartuzumab(Genentech)
Monoclonal antibody that targets MET receptor
n/a II, III
Tivantinib (ArQule) MET-R TKI n/a II, III
Volitinib (AZ) cMET TKI n/a I
Ariad 26113 EGFR, ALK, ROS1 I