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EGFR TKI sequencing: does order matter? · PDF file Girard. Future Oncol 2018. Epub ahead of print. Wild-type EGFR Intrinsic mutant EGFR e.g. Acquired T790M EGFR Second-generation

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  • EGFR TKI sequencing: does order matter?

    Nicolas Girard

    Thorax Institut Curie-Montsouris, Paris, France

    In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (Stage IIIb/IV) with activating mutations of EGFR

    (exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with

    locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for

    whom immunotherapy is not suitable.

  • 2

    Disclosures • Consultancy, symposia and research for Boehringer Ingelheim

    • Consultancy, symposia, research and hospitality for Roche

    • Consultancy, research and symposia for AstraZeneca

  • 3

    Indications:

    In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (Stage IIIb/IV) with activating mutations of EGFR (exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for whom immunotherapy is not suitable.

    Posology:

    The recommended dose is 40 mg once daily, orally. Maximum daily dose in squamous cell carcinoma of the lung is 50 mg, orally. Not recommended in patients with an eGFR

  • 4

    EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    TKIs are standard up front

    Evidence #1

    Please see slide notes for copyright acknowledgements

  • 5

    First- and second-generation EGFR TKIs are standard in the first-line treatment of NSCLC harbouring common EGFR mutations

    *PFS not reported for common mutations only. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; .

    Gefitinib. Summary of Product Characteristics, 2010; Maemondo M, et al. N Engl J Med 2010;362:2380–8; Mitsudomi T, et al. Lancet Oncol 2010;11:121–8; Mok TS, et al. N Engl J Med 2009;361:947–57;

    Rosell, et al. Lancet Oncol 2012;13:239–46; Sequist, et al. J Clin Oncol 2013;31:3327–34; Wu, et al. Lancet Oncol 2014;15:213–22; Wu, et al. Ann Oncol 2015;26:1883–9; Zhou, et al. Lancet Oncol 2011;12:735–

    42.

    *

    * 9.7

    11

    13.1

    9.2

    10.8 9.5

    13.6

    11

    5.2 5.5 4.6

    6.3 5.4

    6.3 6.9

    5.6

    0

    2

    4

    6

    8

    10

    12

    14

    16

    *

    Better PFS versus platinum-based chemotherapy

    Gefitinib* Erlotinib Afatinib Platinum-based chemotherapy

    *

    P F

    S (

    m o n th

    s )

  • 6

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    Not all TKIs are equal

    Evidence #2

    TKIs are standard up front

    Evidence #1

    Please see slide notes for copyright acknowledgements

  • 7

    HER2, human epidermal growth factor 2.

    Girard. Future Oncol 2018. Epub ahead of print.

    Wild-type EGFR

    Intrinsic mutant

    EGFR Acquired T790M EGFR

    Second-generation TKI

    Third-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

    First-generation TKI Activity range Erlotinib

    Gefitinib

    Afatinib

    Dacomitinib

    Osimertinib

    K

    ErbB heterodimers,

    e.g. HER2: ErbB3

    Range

    First-, second- and third-generation EGFR TKIs are not equal: activity against EGFR mutations

    Please see slide notes for copyright acknowledgements

  • 8

    IC50, half-maximal inhibitory concentration.

    Cross, et al. Cancer Discov 2014;4:1046–61; Hirano, et al. Oncotarget 2015;6:38789–803; Li, et al. Oncogene 2008;27:4702–11.

    EGFR mutant: L858R, exon 19 del Wild-type EGFR T790M

    First-, second- and third-generation EGFR TKIs are not equal: activity against EGFR mutations

    Afatinib

    EGFRm

    Wild-type

    T790M

    Osimertinib

    EGFRm

    Wild-type

    T790M

    100×

    10×

    Gefitinib

    EGFRm

    Wild-type

    T790M

    IC 5 0

  • 9

    BCRP, breast cancer resistance protein; CYP, cytochrome P450 enzyme; UGT, UDP-glycosyltransferase.

    Cross, et al. Cancer Discov 2014;4:1046–61; Li, et al. Oncogene 2008;27:4702–11; Peters, et al. Cancer Treat Rev 2014;40:917–26;

    TAGRISSO. Prescribing Information, March 2017.

    First-, second- and third-generation EGFR TKIs are not equal: metabolism

    Enzymes involved in the metabolism of oral EGFR TKIs

    May inhibit May induce Drug

    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

  • 10

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    Not all TKIs are equal

    Evidence #2

    TKIs are standard up front

    Evidence #1

    Please see slide notes for copyright acknowledgements

  • 11

    CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat.

    Corral, et al. Ann Onc 2017;28(Suppl. 2):ii28.

    First- and second-generation EGFR TKIs are not equal: antitumour activity • Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive

    NSCLC (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

    Afatinib

    (n=160)

    Gefitinib

    (n=159)

    Median, months 11.0 10.9

    HR (95% CI)

    p value

    0.74 (0.57–0.95)

    0.0178

    P F

    S (

    % )

    100

    80

    60

    40

    20

    0

    Months

    0 3 6 9 12 15 18 21 24 27 30 33 26 39 42 45 48 51

    160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0

    159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0

    Afatinib

    Gefitinib

    27%

    16%

    16% 8%

    70% 75%

    69%

    56%

    66%

    42%

    0.00

    0.20

    0.40

    0.60

    0.80

    ITT Del19 L858R

    R e s p

    o n

    s e r

    a te

    ( %

    )

    Gefitinib Afatinib

    p=0.002 p=0.150 p=0.003

  • 12

    First- and second-generation EGFR TKIs are not equal: antitumour activity

    ARCHER 1050: Dacomitinib vs Gefitinib (excluding CNS metastases)

    Daco (n=227) Gef (n=225)

    Number of events,

    n (%) 136 (59.9%) 179 (79.6%)

    Median PFS

    (95% Cl)

    14.7

    (11.1–16.6)

    9.2

    (9.1–11.0)

    HR (95% Cl) 0.59 (0.47–0.74)

    p

  • 13

    First- and third-generation EGFR TKIs are not equal: antitumour activity

    Date cut-off 12 Jun 2017. Tick marks indicate censored data.

    Soria, et al. N Engl J Med 2018;378:113–25.

    PFS in FLAURA

    No. at risk

    Osimertinib 279 259 229 200 170 132 66 22 3 0

    Erlotinib or Gefitinib 277 235 192 138 101 69 28 5 1 0

    P ro

    b a

    b il it

    y o

    f P

    F S

    Months

    0 3 6 9 12 15 18 21 24 27 0

    0.2

    0.4

    0.6

    0.8

    1.0 Osimertinib (n=279)

    Erlotinib or gefitinib

    (n=277)

    Median PFS (95% Cl) 17.7 (15.1–21.4) 9.7 (8.5–11.0)

    HR (95% Cl) 0.45 (0.36–0.57)

    p

  • 14

    AE, adverse event.

    1. Park, et al. Lancet Oncol 2016;17:577–89; 2. Paz-Ares, et al. Ann Oncol 2017;28:270–7; 3. Wu, et al. Lancet Oncol 2017;18:1454–66; 4. Soria, et al. N Engl J Med

    2018;378:113–25.

    First-, second- and third-generation EGFR TKIs do not have equal safety

    LUX-Lung 71,2 ARCHER 10503 FLAURA4

    Afatinib

    (n=160)

    Gefitinib

    (n=159)

    Dacomitinib

    (n=227)

    Gefitinib

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