Department of Thoracic/Head & Neck

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.

12-00 12-02

Patient with EGFR mutation deletion exon 19

Newly diagnosed3-16-07

3 months of erlotinib6-18-07

Patient with L858 EGFR mutation

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







EGFR pathway


CO-1686


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 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



Chemotherapy


Chemotherapy


EGFR TKI SATURN


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

2 Trials to compare ongoing EGFR TKI for Acquired Resistance



Chemotherapy


Chemotherapy


EGFR TKI SATURN


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

FAST ACT 1 PFS favored GC-erlotinib

Lee J et al. ASCO 2012 Abstract 8031

FAST ACT-2

Mok T et al. ASCO 2012

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







EGFR pathway


CO-1686


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

[TITLE]

Yang et al. ASCO 2012 Abstract LBA7500


Phase III Lung LUX-3 Trial

1269 screened, 452 EGFR mutation (+) => 345 randomized

[TITLE]


ORR favored afatinib


PFS favored afatinib


PFS Independent Review Subgroup Analysis


PFS Common Mutants (Del 19/L858R)


QOL: EORTC QLQ C-30


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.


• 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

http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=+authorsfield:(Newton,+Robert+C)

http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=+authorsfield:(Scherle,+Peggy+A)

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







EGFR pathway


CO-1686


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


Abstract #7505 Phase II Onartuzumab

Met IHC Biomarker


“Met Diagnostic Positive” = >50% tumor cells with moderate or strong staining intensity93% had adequate tissue for analysis and 52% were “Met Diagnostic Positive”


MetMAb + erlotinib in ITT

PFS HR 1.09OS HR 0.8


MetMAb + erlotinib in Met Dx+ pts



MetMAb + erlotinib in Met Dx- pts



MetMAb benefit is not driven by EGFR mutation nor FISH status


PFS HR 1.71

OS HR 2.61

Met expression correlates to worse outcome in erlotinib + placebo treated pts.


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-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

Documents

Department of Thoracic/Head & Neck