Emerging Algorithm for Optimal Sequencing of EGFR TKIs in ......Emerging Algorithm for Optimal Sequencing of EGFR TKIs in EGFR Mutation‒Positive NSCLC Keunchil Park, MD, PhD

Emerging Algorithm for Optimal Sequencing of EGFR TKIs in

EGFR Mutation‒Positive NSCLC

Keunchil Park, MD, PhD

Samsung Medical Center,

Sungkyunkwan University School of Medicine

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Faculty Disclosure

• Consulting or Advisory Role: Astellas Pharma; AstraZeneca; Boehringer

Ingelheim; Clovis Oncology; Hanmi; Kyowa Hakko Kirin; Lilly; Novartis; Ono

Pharmaceutical; Roche

• Speakers' Bureau: Boehringer Ingelheim

• Research Funding: AstraZeneca

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Key Factors in First-line EGFR TKI Selection

Sequencemakes survival

Not all TKIs are equal

EfficacyDrug-druginteractions

Adverse eventprofile

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The Family of EGFR TKIs

Liao et al. Curr Opin Oncol. 2015;27:94.

Wild-type

EGFR

Intrinsic mutant

EGFR

Acquired T790M

EGFR

2nd-generation TKI

3rd-generation TKI

K K K K K K

K Kinase domain

Activity range

Activity

• Reversible binding to wild-type and mutant EGFR

• Inactive on T790M mutant

• Irreversible covalent binding to EGFR, ErbB2 and ErbB4 to inhibit all

ErbB Family signalling• Broader activity to overcome EGFR TKI‒resistant mutations

• Specificity for EGFR T790M mutant; EGFR

wild-type sparing• Irreversible covalent binding to mutant EGFR

EGFR inhibition

ErbB Family blockade

EGFR mutant‒specific

inhibitor

1st-generation TKI Activity rangeErlotinib

Gefitinib

Afatinib

Dacomitinib

Osimertinib

K

ErbB heterodimers

(eg, Her2: ErbB3)

Range

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Activity of First-, Second-, and Third-Generation EGFR

TKIs Against EGFR Mutations

Li et al. Oncogene. 2008;27:4702; Cross et al. Cancer Discov. 2014;4:1046; Hirano et al. Oncotarget. 2015;6:38789.

IC50 = half-maximal inhibitory concentration.

EGFR mutant: L858R, exon 19 delWild-type EGFR T790M

Gefitinib Afatinib Osimertinib

EGFRm

EGFRm

EGFRm

Wild-type

Wild-type

Wild-type

T790M

T790M

100×

10×

1×

T790M

IC50

(nM

)

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First- and Second-Generation EGFR TKIs Are Standard for First-line Treatment of NSCLC With Common EGFR Mutations

• Better PFS vs platinum-based chemotherapy

Chen et al. Ann Oncol. 2013;24:1615; Gefitinib Summary of Product Characteristics 2010; Han et al. J Clin Oncol. 2012;30:1122; Maemondo et al. N Engl J Med. 2010;362:2380;

Mok et al. N Engl J Med. 2009;361:947; Mitsudomi et al. Lancet Oncol. 2010;11:121; Rosell et al. Lancet Oncol. 2012;13:239; Sequist et al. J Clin Oncol. 2013;31:3327; Wu et al.

Lancet Oncol. 2014;15:213; Wu et al. Ann Oncol. 2015;26:1883; Zhou et al. Lancet Oncol. 2011;8:735.

aPFS not reported for common mutations only.

NSCLC = non‒small cell lung cancer.

GefitinibaErlotinib Platinum-based chemotherapy

10.411

13.1

9.2

10.8

9.7a

13.6

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5.2 5.54.6

6.35.4

6.3a6.9

5.6

Afatinib

month

s

EURTAC ENSURE OPTIMAL WJTOG NJE002 IPASS LL3 LL6 EURTAC ENSURE OPTIMAL WJTOG NJE002 IPASS LL3 LL6

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First- and Second-Generation EGFR TKIs Are Not Equal: Response Rate and PFS in LUX-Lung 7

LUX-Lung 7: Afatinib vs Gefitinib

Park et al. Lancet Oncol. 2016;17:577; Corral et al. ELCC 2017. Abstract 93PD.

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First- and Second-Generation EGFR TKIs Are Not Equal:

PFS in ARCHER 1050

ARCHER 1050: Dacomitinib vs Gefitinib (excluding CNS metastases)

Mok et al. ASCO 2017. Abstract LBA9007.

CNS = central nervous system; ITT = intent-to-treat; CI, confidence interval.

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First and Third-Generation EGFR TKIs Are Not Equal:

PFS in FLAURA

Ramalingam et al. ESMO 2017. Abstract LBA2.

FLAURA: Osimertinib vs Gefitinib or Erlotinib

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Safety

Second- or Third-Generation TKIs vs First-Generation TKIs

1. Park et al. Lancet Oncol. 2016;17:577; 2. Paz-Ares et al. Ann Oncol. 2017;28:270; 3. Mok et al. ASCO 2017. Abstract LBA9007; 4. Ramalingam et al. ESMO 2017. Abstract

LBA2.

LUX-Lung 71,2 ARCHER 10503 FLAURA4

Afatinib

(n=160)

Gefitinib

(n=159)

Dacomitinib

(n=227)

Gefitinib

(n=225)

Osimertinib

(n=279)

Treatment

discontinuation

rate

6.3% 6.3% 9.7% 6.6%13.0%

(any)

Most common

grade ≥3 AEs

Diarrhoea: 12%

Rash/acne: 9%

Liver enzyme

elevation: 9%

Rash/acne: 3%

Acne: 14%

Diarrhoea: 9%

Paronychia: 8%

Liver enzyme

elevation: 9%

Paronychia: 1%

Diarrhoea: 2%

Decreased

appetite: 3%

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Dose Reduction of Afatinib Reduced Drug-Related AEs

Without Compromising Efficacy

Hirsch V, et al. ASCO 2016 poster presentation: 369.

PFS = progression-free survival; HR = hazard ratio; CI = confidence interval.

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DDIs of First-, Second-, and Third-Generation EGFR TKIs

Cross et al. Cancer Discov. 2014;4:1046; Li et al. Oncogene. 2008;27:4702; Peters et al. Cancer Treat Rev. 2014;40:917; TAGRISSO Prescribing Information. March 2017.

Enzymes Involved in the Metabolism of Oral EGFR TKIs

May Inhibit May InduceDrug

Metabolised by CYP Enzymes

3A4 3A5 2D6 1A1 1A2 1B1 2C8 2C9

Gefitinib +++ ++ +++ ++ + -

CYP2C19 (w)

CYP2D6 (w)

UGT1A9, BRCP

Erlotinib +++ +++ + + ++ + + +

CYP3A4 (m)

CYP2C8 (m)

CYP1A1 (s)

UGT1A1 (s)

CYP1A1

CYP1A2

Afatinib - - - - - - - - - -

Dacomitinib ++ ++ + CYP2D6 (s)

Osimertinib +++ +++ - - - - - - BCRP

CYP3A4

CYP1A2

CYP2C

DDI = drug-drug interaction; CYP = cytochrome P450 enzyme; BCRP = breast cancer resistance protein; UGT = UDP-glycosyltransferase.

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OS With Afatinib in EGFR-Mutant NSCLC

Yang et al. Lancet Oncol. 2015;16:141.

Common Mutations (del19/L858R) (n=307)

aOnly 6 patients in the afatinib arm were treated with osimertinib because of lack of availibility (trial recruitment was from August 2009 to February 2011).

NSCLC = non‒small cell lung cancer.

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Molecular Mechanisms of Acquired Resistance to

First-/Second-Generation EGFR TKIs

Yu HA et al. Clin Cancer Res. 2013;19:2240.

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OS in Patients Treated With Third-Generation TKIs

Subsequently in LUX-Lung 7

Corral et al. ELCC 2017. Abstract 93PD.

NE = not estimable.

20%/17% who discontinued afatinib/gefitinib received third-generation TKIs (osimertinib, olmutinib,

rociletinib)

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Treatment Sequences in EGFR-Mutant NSCLC After

First-line EGFR TKI

1st-/2nd-generation

TKI

OsimertinibT790M

+

T790M

-

Other

Chemotherapy 1st-/2nd-generation TKI

MET/HER2 inhibitor

Chemotherapy

Except if molecular target

Osimertinib Chemotherapy

Except if molecular target

NEED MATURE OS AND TREATMENT SEQUENCES FROM AURA3 and FLAURA (med PFS = 18.9 months)

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Emerging Algorithm for Optimal Sequencing of EGFR TKIs in ......Emerging Algorithm for Optimal Sequencing of EGFR TKIs in EGFR Mutation‒Positive NSCLC Keunchil Park, MD, PhD