EGFR TKI sequencing: does order matter?€¦ · Girard. Future Oncol 2018. Epub ahead of print....

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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.

Transcript of EGFR TKI sequencing: does order matter?€¦ · Girard. Future Oncol 2018. Epub ahead of print....

  • 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

    *

    PF

    S (

    month

    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

    IC50

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    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

    PF

    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

    Resp

    on

    se r

    ate

    (%

    )

    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

    Pro

    ba

    bilit

    y o

    f P

    FS

    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

    (n=225)

    Osimertinib

    (n=279)

    Erlotinib or

    gefitinib

    (n=277)

    Treatment

    discontinuation

    rate

    6.2% 6.3% 9.7% 6.7% 10% 14%

    Most common

    Grade ≥3 AEs

    Diarrhoea 12%

    Rash/acne 9%

    Liver enzyme

    elevation 9%

    Rash/acne 3%

    Acne 14%

    Diarrhoea 8%

    Paronychia 7%

    Liver enzyme

    elevation 12%

    Dyspnoea 3%

    Diarrhoea 2%

    Decreased

    appetite 2%

    Rash/acne 7%

    Liver enzyme

    elevation 12%

    Second- or third-generation TKIs versus first-generation TKIs

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    Hirsh, et al. J Clin Oncol 2016;34(Suppl.): Abstract 9046.

    Treatment-related AEs in patients who

    had a dose reduction from 40 mg (n=63)

    0

    20

    40

    60

    80

    100

    Any Diarrhoea Rash/acne Stomatitis Nail effect

    Pati

    en

    ts (

    %)

    0

    20

    40

    60

    80

    100

    Any Diarrhoea Rash/acne Stomatitis Nail effect

    Pati

    en

    ts (

    %)

    All grades Grade ≥3

    Befo

    re r

    ed

    ucti

    on

    (≥40 m

    g)

    Aft

    er

    red

    ucti

    on

    (<40 m

    g)

    PFS in patients who received a dose reduction

    within the first 6 months of treatment

    45 34 28 22 15 11 10 9 7 3 1 0 0 47

    113 97 78 66 45 32 23 17 12 6 3 2 1 0

    Es

    tim

    ate

    d P

    FS

    pro

    ba

    bil

    ity 1.0

    0.8

    0.6

    0.4

    0.2

    0

    0 3 6 9 12 15 18 21 24 27 30 33 36 39

    Months No. at risk:

  • 16

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    TKIs are standard up front

    Evidence #1

    Not all TKIs are equal

    Evidence #2

    Biology drives sequence

    Evidence #3

    Please see slide notes for copyright acknowledgements

  • 17

    • Impact of specific EGFR mutations and clinical characteristics on outcomes after treatment with EGFR TKIs versus chemotherapy in EGFRm+ lung cancer: a meta-analysis

    EGFRm+, epidermal growth factor receptor mutation positive.

    Lee, et al. J Clin Oncol 2015;33:1958–65.

    Trial HR 95% Cl HR 95% Cl

    Exon 19 deletions Exon 21 L858R substitution

    ENSURE 0.20 0.12–0.33 0.54 0.32–0.91

    EURTAC 0.27 0.17–0.43 0.53 0.29–0.97

    LUX-Lung 3 0.28 0.18–0.44 0.73 0.46–1.16

    LUX-Lung 6 0.20 0.13–0.32 0.32 0.19–0.54

    NEJ002 0.24 0.15–0.38 0.33 0.20–0.54

    OPTIMAL 0.13 0.07–0.24 0.26 0.14–0.48

    WJTOG 3405 0.42 0.26–0.66 0.69 0.44–1.07

    AII 0.24 0.20–0.29 0.48 0.39–0.58

    TKI Chemotherapy TKI Chemotherapy

    First-line: PFS efficacy of TKIs is different in EGFR del19/L858R mutations

    Please see slide notes for copyright acknowledgements

  • 18

    Kato, et al. Value Health 2015;18:A436 (Abstract PCN40).

    Agent Study HR

    (95% CI)

    Del19 HR

    (95% CI)

    Afatinib

    LUX-Lung 3 0.53 (0.36–0.79) 1.30 (0.80–2.11)

    LUX-Lung 6 0.64 (0.44–0.94) 1.22 (0.81–1.83)

    Total 0.59 (0.45–0.77) 1.25 (0.91–1.71)

    Erlotinib

    ENSURE 0.79 (0.48–1.30) 1.05 (0.60–1.84)

    EURTAC 0.94 (0.57–1.54) 1.00 (0.56–1.79)

    OPTIMAL 1.52 (0.91–2.52) 0.92 (0.55–1.54)

    Total 1.04 (0.71–1.51) 0.98 (0.72–1.35)

    Gefitinib

    IPASS 0.86 (0.61–1.22) 1.40 (0.91–2.15)

    NEJ002 0.83 (0.52–1.34) 0.82 (0.49–1.38)

    WJTOG3405 1.19 (0.65–2.18) 1.11 (0.60–2.05)

    Total 0.90 (0.70–1.17) 1.11 (0.81–1.54)

    First-line: OS Efficacy of TKIs Is Different in EGFR del19/L858R Mutations

    L858R

    0.01 100 0.1 1 10

    0.01 100 0.1 1 10

    0.01 100 0.1 1 10 0.01 100 0.1 1 10

    100 0.1 1 10 0.01

    100 0.1 1 10 0.01

    Favours chemotherapy

    Favours chemotherapy

    Favours chemotherapy Favours chemotherapy

    Favours chemotherapy

    Favours chemotherapy Favours afatinib Favours afatinib

    Favours erlotinib Favours erlotinib

    Favours gefitinib Favours gefitinib

  • 19

    Yang, et al. Lancet Oncol 2015;16:830–8.

    T790M

    (n=14)

    Exon

    20 ins

    (n=23)

    Mut/

    dup

    exon

    18-21

    (n=38)

    G719X

    (n=18)

    L861Q

    (n=16)

    S768I

    (n=8)

    Response

    rate (%) 14.3 8.7 71.1 77.8 56.3 100.0

    PFS (months) 2.9 2.7 10.7 13.8 8.2 14.7

    OS (months) 14.9 9.2 19.4 26.9 17.1 NE

    Note: A patient may be presented in more than one category.

    Group 3 (n=20): Exon 20 insertions

    Group 2 (n=14): T790M mutations

    Group 1 (n=33): Exon 18-21: G719, L861Q

    Ma

    xim

    um

    ch

    an

    ge

    fro

    m b

    as

    eli

    ne

    (%

    )

    120

    100

    80

    60

    40

    20

    0

    –20

    –40

    –60

    –80

    –100 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

    0

    5

    10

    15

    20

    25

    30

    35

    40

    PF

    S (m

    on

    ths

    )

    Patient index sorted by maximum percent decrease in descending order

    First-line: afatinib is effective for uncommon EGFR mutations • Clinical activity of afatinib in patients with advanced NSCLC harbouring uncommon

    EGFR mutations: a combined post hoc analysis of LUX-Lung 2, 3, and 6

    Please see slide notes for copyright acknowledgements

  • 20

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    TKIs are standard up front

    Evidence #1

    Not all TKIs are equal

    Evidence #2

    Biology drives sequence

    Evidence #3

    Please see slide notes for copyright acknowledgements

  • 21

    MET, MET proto-oncogene.

    Yu, et al. Clin Cancer Res 2013;19:2240–7.

    Molecular mechanisms of acquired resistance to first-/second-generation EGFR TKIs

    • 155 EGFR-mutant NSCLC patients, acquired resistance after TKI

    • Molecular analyses on re-biopsy specimen

    MET amplification 3%

    Small cell + MET 1% Small cell 1%

    Small cell + T790M 2%

    MET + T790M 3%

    HER2 T790M 4%

    T790M

    60%

    HER2 8%

    Unknown 18%

    Please see slide notes for copyright acknowledgements

  • 22

    12.74%

    29.04%

    5.10%

    53.21%

    Initial diagnosis J170 Relapse

    Chemotherapy

    ETV6, WNK1-WAC,

    MYO18B

    Molecular mechanisms of acquired resistance to first-/second-generation EGFR TKIs

    Funding

    Activating

    Mutation Resistance

    Passenger

    Pathogenic AML Normal

    Type cellulaire Mutations

    Recurrence

    HSC, haematopoietic stem cell.

    Ding, et al. Nature 2015;481:506–10.

    Please see slide notes for copyright acknowledgements

  • 23

    PD, progressive disease.

    Mok, et al. N Engl J Med 2017;376:629–40.

    Osimertinib standard of care for T790M+ acquired resistance to first-/second-generation EGFR TKIs

    Patients in the population

    HR for PD or death, 0.30 (95% CI: 0.23–0.41)

    p

  • 24

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    TKIs are standard up front

    Evidence #1

    Not all TKIs are equal

    Evidence #2

    Biology drives sequence

    Evidence #3

    Biological monitoring is key

    Evidence #4

    Please see slide notes for copyright acknowledgements

  • 25

    Chouaid, et al. Lung Cancer 2014;86:170–3; Kawamura T, et al. Cancer Sci 2016;107:1001–5.

    Identification of T790M at acquired resistance, is tissue re-biopsy feasible?

    Re-biopsy could not be done in 18% of cases, mainly because of anticoagulation that the

    patient’s physician considered to be a contraindication. One patient refused re-biopsy.

    Among the 82 patients who underwent re-biopsy, the sample could be analysed

    histologically in 94% of cases. Cytologic samples represented only.

    Re-biopsy methods (n=82)

    Surgery

    Adrenalectomy 1

    Lung surgery 3

    Node surgery 1

    Biopsy

    Bronchial + E-BUS 43

    Pulmonary under CT 19

    Liver 2

    Bone 6

    Skin 2

    Cytology

    Nodes 3

    Pleura 2

    Ineligible for trial:

    poor PS: n=10;

    comorbidity: n=7;

    elderly: n=2

    Ineligible for re-biopsy:

    inaccessible tumour sites:

    n=19 (18 brain

    metastases and

    one lung lesion

  • 26

    FDA, US Food and Drug Administration; FFPE, formalin-fixed, paraffin-embedded.

    Oxnard, et al. J Clin Oncol 2016;34:3375–82.

    Proposed algorithm for use of plasma genotyping for EGFR T790M

    Acquired resistance

    to EGFR TKI

    All patients undergo

    biopsy,

    FDA-approved

    FFPE assay for T790M

    T790M+

    T790M–

    Third-generation

    EGFR TKI

    Chemotherapy

    Acquired resistance

    to EGFR TKI

    FDA-approved plasma

    assay for T790M and

    sensitising mutations

    T790M+

    T790M–

    Skip biopsy, start third-generation

    EGFR TKI

    Biopsy, FDA-approved

    FFPE assay for

    T790M

    T790M+

    T790M–

    Third-generation

    EGFR TKI

    Chemotherapy

    A

    B

    Please see slide notes for copyright acknowledgements

  • 27

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    TKIs are standard up front

    Evidence #1

    Not all TKIs are equal

    Evidence #2

    Biology drives sequence

    Evidence #3

    Biological monitoring is key

    Evidence #4

    Sequence makes survival

    Evidence #5

    Please see slide notes for copyright acknowledgements

  • 28

    What is OS in EGFR-mutant NSCLC?

    Addition of the PFS of

    all treatment lines

    At each patient level:

    NEED for the swimmer plot of individual patients

    NOT the sum of median PFS in trials

    Number of lines TKIs, chemotherapy, other

    x

  • 29

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    First-/second-

    generation TKI

    Chemotherapy First-/second-generation TKI

    Girard. Future Oncol 2018. Epub ahead of print.

    Please see slide notes for copyright acknowledgements

  • 30

    Yang, et al. Ann Oncol 2015;16:141–51.

    OS in EGFR-mutant NSCLC: LUX-LUNG 3 trial

    Common mutations

    Afatinib

    (n=203)

    Cis/Pem

    (n=104)

    Median,

    months 31.6 28.2

    HR (95% CI) 0.78 (0.58–1.06)

    Common mutations (Del19/L858R)

    (n=307)

    Es

    tim

    ate

    d O

    S (

    pro

    ba

    bilit

    y)

    OS (months)

    0

    0

    1

    1

    9

    5

    32

    10

    49

    20

    58

    26

    90

    35

    101

    40

    108

    47

    121

    52

    133

    55

    143

    63

    162

    71

    171

    81

    181

    86

    188

    92

    197

    98

    203

    104

    No. at risk:

    Afatinib

    Cis/Pem

    1.0

    0.8

    0.6

    0.4

    0.2

    0

    0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

    Afatinib

    Cisplatin/pemetrexed

    Please see slide notes for copyright acknowledgements

  • 31

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    T790M+

    Osimertinib Chemotherapy? TKI?

    First-/second-

    generation TKI Except if molecular target

    Girard. Future Oncol 2018. Epub ahead of print.

    Please see slide notes for copyright acknowledgements

  • 32

    PD-1, programmed death-1; PD-L1, programmed death ligand-1.

    Mok, et al. N Engl J Med 2017;376:629–40.

    Ongoing osimertinib treatment at time of data cut-off (n=166)

    Discontinue treatment (n=113)

    • Objective PD (n=77)

    • AE (n=18)

    • Subject decision (n=9)

    • Other (n=8)

    • Severe protocol non-compliance (n=1)

    AURA3: treatment beyond osimertinib

    Anticancer treatment post-discontinuation of osimertinib (n=67)

    • Platinum-containing chemotherapy regimen (n=48) • Non-platinum-containing chemotherapy regimen (n=18) • Radiotherapy (n=17)

    • EGFR TKI (n=9)

    • EGFR TKI + non-PD-1/PD-L1 (n=6)

    • PD-1/PD-L1 (n=4)

  • 33

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    Osimertinib T790M+

    T790M–

    Other MET/HER2 inhibitor

    Chemotherapy?

    Except if molecular target

    TKI?

    First-/second-generation TKI

    First-/second-

    generation TKI

    Chemotherapy

    Girard. Future Oncol 2018. Epub ahead of print.

    Please see slide notes for copyright acknowledgements

  • 34

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    OS DATA

    FROM AURA-3

    NOT YET AVAILABLE

    FACT #1:

    Osimertinib T790M+

    T790M–

    Other MET/HER2 inhibitor

    Chemotherapy?

    Except if molecular target

    TKI?

    First-/second-generation TKI Chemotherapy

    First-/second-

    generation TKI

    Girard. Future Oncol 2018. Epub ahead of print.

    Please see slide notes for copyright acknowledgements

  • 35

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    CHALLENGE IS TO ENSURE ACCESS

    FOR A MAJORITY OF PATIENTS

    TO FURTHER LINES OF TREATMENT

    FACT #2:

    Osimertinib T790M+

    T790M–

    Other MET/HER2 inhibitor

    Chemotherapy?

    Except if molecular target

    TKI?

    First-/second-generation TKI Chemotherapy

    First-/second-

    generation TKI

    Girard. Future Oncol 2018. Epub ahead of print.

    Please see slide notes for copyright acknowledgements

  • 36

    Sequist, et al. Ann Oncol 2017;28(Suppl. 5): v460-v496 10.1093/annonc/mdx380

    OS in patients treated with osimertinib subsequently in LUX-Lung 3, 6 and 7

    No. at risk:

    Afatinib 37 37 37 37 37 37 36 35 28 20 12 3 0

    Es

    tim

    ate

    d O

    S p

    rob

    ab

    ilit

    y

    Time to death (months)

    0.8

    1.0

    0.6

    0.4

    0.2

    0

    0 72 6 12 18 24 30 36 42 48 54 60 66

    Median follow-up = 4.7 years

  • 37

    Analysis of treatment sequence: first-/second-generation TKIs followed by third-generation TKIs

    Median PFS in LUX-Lung 7

    Median PFS in AURA-3 (T790M+)

    OS in patients treated with

    osimertinib subsequently in

    LUX-Lung 3, 6, and 7

    10.1 months with osimertinib

    11.0 months with afatinib

    10.9 months with gefitinib

    1.0

    0.8

    0.6

    0.4

    0.2

    0

    0 3 6 9 12 15 18

    Months

    Osimertinib

    Platinum-pemetrexed

    1.0

    0.8

    0.6

    0.4

    0.2

    0

    0

    Time of PFS (mo)

    Esti

    mate

    d P

    FS

    pro

    ba

    bil

    ity

    3 6 9 12 15 18 21 24 27 30 33 36 39 42

    Afatinib Gefitinib

    Esti

    mate

    d P

    FS

    pro

    ba

    bil

    ity

    Sequist, et al. Ann Oncol 2017;28(Suppl. 5): v460-v496 10.1093/annonc/mdx380; Mok TS, et al. N Engl J Med 2017;376:629–40; Park K, et al. Lancet Oncol. 2016;17:577.

    Please see slide notes for copyright acknowledgements

  • 38

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    Osimertinib

    Osimertinib T790M+

    T790M–

    Other MET/HER2 inhibitor

    Chemotherapy

    Except if molecular target

    First-/second-generation TKI Chemotherapy

    First-/second-

    generation TKI

    Girard. Future Oncol 2018. Epub ahead of print.

    Please see slide notes for copyright acknowledgements

  • 39

    FLAURA: treatment beyond osimertinib Regimen Osimertinib (n=279) Erlotinib or gefitinib (n=277)

    First post-treatment anticancer therapy (including crossover osimertinib), n (%)

    Discontinued randomised trial treatment 138 (49) 213 (77)

    First post-treatment anticancer therapy 82 (29) 129 (47)

    No post-treatment anticancer therapy 56 (20) 84 (30)

    Ongoing randomised trial treatment 141 (51) 64 (23)

    First post-treatment anticancer therapy, n (%)

    EGFR-TKI 29 (21) 97 (46)

    PD-1/PD-L1 3 (2) 2 (1)

    Non-platinum chemotherapy 50 (36) 27 (13)

    Platinum-based chemotherapy 48 (35) 26 (12)

    Other targeted therapy 2 (1) 3 (1)

    Anti-VEGF 7 (5) 4 (2)

    Second post-treatment anticancer therapy, n (%)

    Second post-treatment anticancer therapy 24 (9) 39 (14)

    Only one post-treatment anticancer therapy 58 (21) 90 (32)

    Second post-treatment anticancer therapy, n (%)

    EGFR TKI 10 (7) 14 (7)

    PD-1/PD-L1 2 (1) 1 (

  • 40

    FLAURA: treatment beyond osimertinib Regimen Osimertinib (n=279) Erlotinib or gefitinib (n=277)

    First post-treatment anticancer therapy (including crossover osimertinib), n (%)

    Discontinued randomised trial treatment 138 (49) 213 (77)

    First post-treatment anticancer therapy 82 (29) 129 (47)

    No post-treatment anticancer therapy 56 (20) 84 (30)

    Ongoing randomised trial treatment 141 (51) 64 (23)

    First post-treatment anticancer therapy, n (%)

    EGFR-TKI 29 (21) 97 (46)

    PD-1/PD-L1 3 (2) 2 (1)

    Non-platinum chemotherapy 50 (36) 27 (13)

    Platinum-based chemotherapy 48 (35) 26 (12)

    Other targeted therapy 2 (1) 3 (1)

    Anti-VEGF 7 (5) 4 (2)

    Second post-treatment anticancer therapy, n (%)

    Second post-treatment anticancer therapy 24 (9) 39 (14)

    Only one post-treatment anticancer therapy 58 (21) 90 (32)

    Second post-treatment anticancer therapy, n (%)

    EGFR TKI 10 (7) 14 (7)

    PD-1/PD-L1 2 (1) 1 (

  • 41

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    Chemotherapy

    Except if molecular target

    Osimertinib T790M+

    T790M–

    Other MET/HER2 inhibitor

    Chemotherapy

    Except if molecular target

    First-/second-generation TKI Chemotherapy

    First-/second-

    generation TKI

    Girard. Future Oncol 2018. Epub ahead of print.

    Osimertinib

    Please see slide notes for copyright acknowledgements

  • 42

    Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI

    Chemotherapy

    Except if molecular target

    Osimertinib T790M+

    T790M–

    Other MET/HER2 inhibitor

    Chemotherapy

    Except if molecular target

    First-/second-generation TKI Chemotherapy

    First-/second-

    generation TKI

    Girard. Future Oncol 2018. Epub ahead of print.

    Osimertinib

    NEED MATURE OS AND TREATMENT SEQUENCES FROM FLAURA

    Please see slide notes for copyright acknowledgements

  • 43

    How to optimise sequence?

    • CNS disease and progression

    • Loss of patients from one line to another

    • Treatment beyond progression

    Optimisation

    of treatments

    • Anti-angiogenics

    • Anti-EGFR antibodies

    Understanding

    of biology

    • Resistance mechanisms to sequencing versus osimertinib

    • Impact of de novo T790M

    Clinical

    factors

  • 44

    Ramalingam, et al. J Clin Oncol 2018;36:841–9.

    Molecular characterization after osimertinib first-line failure (all T790M negative)

    Baseline EGFR mutation

    Post-dose plasma EGFR

    mutation

    (allelic fraction %)

    Post-dose

    plasma

    resistance aberration(s)

    identified

    (allelic fraction %, copies)

    Other post-

    dose plasma mutations

    identified

    (allelic fraction %)

    Total time

    receiving

    osimertinib (months)

    Ex19del* None detected JAK2 V617F

    (1.5%)

    None detected 29.9+

    Ex19del Ex19del (5.2%) EGFR C797S

    (3.0%)

    P53 R273H

    (6.6%), CTNNB1 G34V

    (6.5%)

    27.8+

    L858R L858R (16.7%) PIK3CA E545K (1.6%)

    P53 H179R (13.3%), PTEN

    Q171* (8.1%),

    NOTCH G2299G (4.6%)

    26.3

    Ex19del Ex19del

    (34.6%)

    MET CNV (3.0

    copies)

    RB1 R255*

    (64.1%), P53 pHis179fs

    (62.9%)

    26.3

    Ex19del None detected KRAS G12D (8.6%)

    CTNNB1 S37F (3.6%)

    24.9

    L858R and

    T790M

    L858R (4%) +

    T790M (5%)

    EGFR C797S

    (1%)

    NF2 T352M

    (1.5%)

    14.5

    Ex19del Ex19del (7.5%) KRAS CNV (3.7

    copies), EGFR CNV (3.0

    copies)

    P53 H175H

    (15.9%), RB1 pLys427fs

    (9.9%)

    14.3

    G719S and

    S768I

    G719S (6.9%) +

    S768I (5.7%)

    MEK1

    (MAP2K1)

    G128V (3.2%)

    SMAD4 G358E

    (4.6%),

    PDGFRA S961C (1.1%)

    5.6

    L858R None detected HER2 ex20 ins

    (12.3%), HER2 E1247K (4.2%)

    P53 R213*

    (6.3%), IDH2 R140Q (2.5%)

    1.2

    C797S 23%

    Met ampl 11%

    Her2 mut 11%

    Mek 11%

    JAK2 11%

    PIK3CA 11%

    Kras and EGFR ampl 11%

    Kras 11%

  • 45

    Girard. Future Oncol 2018. Epub ahead of print.

    Choosing the sequence in EGFR-mutant NSCLC

    Sequence makes survival

    Evidence #5

    TKIs are standard up front

    Evidence #1

    Not all TKIs are equal

    Evidence #2

    Biology drives sequence

    Evidence #3

    Biological monitoring is key

    Evidence #4

    Please see slide notes for copyright acknowledgements