biomarcadores e imunoterapia - .atividade clínica dos inibidores de pd-1/pd-l1. ... pd-l1 ihc assay

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  • Biomarcadores e Imunoterapia:

    alm do PD-L1

    Luiz Henrique Araujo, MD, PhD

    Instituto COI de Educao e Pesquisa

    Instituto Nacional do Cncer (INCA)

  • Sumrio

    Introduo

    Expresso tumoral de PD-L1

    Carga mutacional

    Perfil mutacional

    Outros biomarcadores

    Concluses

  • Sumrio

    Introduo

    Expresso tumoral de PD-L1

    Carga mutacional

    Perfil mutacional

    Outros biomarcadores

    Concluses

  • Primary sensitivity = biomarkers

    Atividade clnica dos inibidores de PD-1/PD-L1

  • Superviso imunolgica contra o cncer

    Imagem adaptada de Mellman I et al.

    APC = clulas apresentadoras de antgenos; MHC = complexo principal de histocompatibilidade; TCR = receptor dos linfcitos T.

    1. Mellman I et al. Nature. 2011;480(7378):480-489. 2. Dunn GP et al. Nat Immunol. 2002;3(11):991-998.

    MHC

    APC

    TCR

    Clulas T

    Clula tumoral

    Antgeno especfico ao tumor

    Microambiente tumoralTecido linfide

    Ativao e expanso clonal

  • Uso de PD-L1 como biomarcador clnico

    Topalian SL, et al. Nature Rev Cancer. 2016, 16:275-287

  • Expresso de PD-L1 heterognea e varia de acordo com a plataforma

    E1L3N SP142

    Negative

    Positive

    1 mm

    H&E

    JMcLaughlin,K Schalper and D Rimm (Yale Pathology)

  • DrugPD-L1 IHC

    AssayPD-L1 scoring

    Cut-offs reported in

    clinical trials

    FDA Diagnostic

    Status

    Nivolumab 28-8 Tumor cells 1%, 5%, 10% Complementary

    Pembrolizumab 22C3 Tumor cells (TPS) 1%, 50% Companion

    Atezolizumab SP142Tumor cells (TC) 1%, 5%, 50%

    ComplementaryImmune cells (IC) 1%, 5%, 10%

    Durvalumab SP263 Tumor cells 25% Unknown

    Avelumab 73-10 Tumor cells 1%, 50%, 80% Unknown

    TPS: tumor proportional score; TC: staining on tumor cell; IC: staining on immune cells

    Diferentes anticorpos e plataformas

  • BLUEPRINT-2: Comparao entre 5 ensaios

    Each circle represents the mean of all scores (glass slide & digital combined)

    SP142

    28-8H & E

    73-10

    22C3

    SP263

  • Regulao da expresso de PD-L1

    Pardoll D. Nat Rev Cancer 2012; 12: 252-64

  • SG com pembrolizumabe em CPNPC avanado

    Fase 2/3 (KEYNOTE-010)

    Roy S. Herbst, presented at ESMO ASIA 2015; Lancet 2015

    Median OS Pembro PDL1 50% = 14.9 and 17.3 mo Median OS Pembro PDL 1% = 10.4 and 12.7 mo

    2 vs 10 mg/kg: HR 1.122 vs 10 mg/kg: HR 1.17

    Pembro 10 mg/kg

    Docetaxel

    Pembro 2 mg/kg

    Pembro 10 mg/kg

    Docetaxel

    Pembro 2 mg/kg

    1-yr OS rate = 34.6%

    1-yr OS rate = 52.3%

    1-yr OS rate = 43.2%

    Inclusion criteria: PD-L1 TPS 1%

  • 1. Reck M et al. N Engl J Med. 2016; DOI: 10.1056/NEJMoa160677.

    2. Reck M et al. Ann Oncol. 2016;27(suppl 6):LBA8 PR.

    3. Keytruda [package insert]. Kenilworth, NJ, USA: Merck Sharp & Dohme Corp.; 2016.

    Data cutoff date: May 9, 2016.

    From the N Engl J Med. Reck,M. et al. Pembrolizumab versus chemotherapy for PD-L1positive non small-

    cell lung cancer. 2016;375:1823-1833. 2016 Massachusetts Medical Society. Adapted with permission from

    Massachusetts Medical Society.

    KEYNOTE-024 (NCT02142738) demonstrated that pembrolizumab had superior efficacy over platinum-based chemotherapy as first-line therapy for

    patients with advanced NSCLC with PD-L1 TPS 50%1,2

    JR Brahmer, WCLC 2017

    KEYNOTE-024 (NCT02142738): Efficacy Outcomes

  • Sumrio

    Introduo

    Expresso tumoral de PD-L1

    Carga mutacional

    Perfil mutacional

    Outros biomarcadores

    Concluses

  • NSCLC is among the most deranged neoplasias (average ~ 10

    somatic mutations/Mb)

  • Taxa de mutaes no-sinnimas como biomarcador para

    imunoterapia

    CANCER IMMUNOLOGY

    Mutational landscapedeterminessensitivity toPD-1blockadeinnonsmall cell lungcancerNaiyer A. Rizvi ,1,2* M atthew D. Hellmann,1,2* Alexandra Snyder,1,2,3* Pia Kvistbor g,4

    Vladimir M akarov,3 Jonathan J. Havel,3 W ill iam Lee,5 Jianda Yuan,6 Phi ll ip W ong,6

    Teresa S. Ho,6 M artin L. M i ller,7 Natasha Rekhtman,8 Andre L. M oreira,8

    Fawzia I brahim,1 Cameron Bruggeman,9 Bi llel Gasmi,10 Rober ta Zappasodi ,10

    Yuka M aeda,10 Chr is Sander,7 Edward B. Garon,11 Taha M erghoub,1,10

    Jedd D. W olchok,1,2,10 Ton N. Schumacher,4 Timothy A. Chan2,3,5

    Immune checkpoint inhibitors, which unleash a patient s own T cells to kill tumors, are

    revolut ionizing cancer treatment. To unravel the genomic determinants of response

    to this therapy, we used whole-exome sequencing of nonsmall cell lung cancers treated

    with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two

    independent cohorts, higher nonsynonymous mutation burden in tumors was associated

    with improved objective response, durable clinical benefit , and progression-free survival.

    Efficacy also correlated with the molecular smoking signature, higher neoantigen

    burden, and DNA repair pathway mutations; each factor was also associated with mutation

    burden. In one responder, neoant igen-specific CD8+ T cell responses paralleled tumor

    regression, suggest ing that ant iPD-1 therapy enhances neoantigen-specif ic T cell

    reactivity. Our results suggest that the genomic landscape of lung cancers shapes

    response to ant iPD-1 therapy.

    Today, more than a century since the initial

    observation that the immune system can re-

    ject human cancers (1), immune checkpoint

    inhibitorsaredemonstrating that adaptive

    immunity can be harnessed for the treat-

    ment of cancer (27). In advanced nonsmall cell

    lung cancer (NSCLC), therapies with an antibody

    targetingprogrammed cell death-1(antiPD-1) dem-

    onstrated response ratesof 17to 21%, with some

    responses being remarkably durable (3, 8).

    Understanding the molecular determinants of

    response to immunotherapies such as antiPD-1

    therapy is one of the critical challenges in oncol-

    ogy. Among the best responses have been in

    melanomas and NSCLCs, cancers largely caused

    by chronic exposure to mutagens [ultraviolet light

    (9) and carcinogens in cigarette smoke (10), re-

    spectively]. However, there is a large variability

    in mutation burden within tumor types, ranging

    from 10sto 1000sof mutations(1113). Thisrange

    is particularly broad in NSCLCs because tumors

    in never-smokers generally have few somatic mu-

    tations compared with tumors in smokers (14).

    We hypothesized that the mutational landscape

    of NSCLCs may influence response to antiPD-1

    therapy. To examinethishypothesis, wesequenced

    the exomes of NSCLCs from two independent

    cohorts of patients treated with pembrolizumab,

    a humanized immunoglobulin G (IgG) 4-kappa

    isotype antibody to PD-1(n = 16 and n = 18, re-

    spectively), and their matched normal DNA (fig.

    S1and table S1) (15).

    Overall, tumor DNAsequencinggenerated mean

    target coverage of 164x, and a mean of 94.5%of

    the target sequence wascovered to a depth of at

    least 10x; coverage and depth were similar be-

    tween cohorts, as well as between those with or

    without clinical benefit (fig. S2). We identified a

    median of 200 nonsynonymous mutations per

    sample(range11to 1192). Themedian number of

    exonic mutations per sample was 327 (range 45

    to 1732).Thequantity and rangeof mutationswere

    similar to published series of NSCLCs (16, 17)

    (fig. S3). Thetransition/transversion ratio (Ti/Tv)

    was 0.74 (fig. S4), also similar to previously de-

    scribed NSCLCs (1618). To ensureaccuracy of our

    sequencing data, targeted resequencing with an

    orthogonal method (Ampliseq) was performed

    using 376 randomly selected variants, and muta-

    tionswereconfirmed in 357of thosevariants (95%).

    Higher somatic nonsynonymous mutation

    burden was associated with clinical efficacy of

    pembrolizumab. In the discovery cohort (n = 16),

    the median number of nonsynonymous muta-

    tions was 302 in patients with durable clinical

    benefit (DCB) (partial or stable response lasting

    >6 months) versus 148 with no durable benefit

    (NDB) (Mann-Whitney P= 0.02) (Fig. 1A). Seventy-

    three percent of patients with high nonsynon-

    ymous burden (defined as above the median

    burden of thecohort, 209) experienced DCB, com-

    pared with 13% of those with low mutation bur-

    den (below median) (Fishersexact P= 0.04). Both

    confirmed objective response rate (ORR) and

    progression-free survival (PFS) were higher in

    patients with high nonsynonymousburden [ORR

    63% versus 0%, Fishers exact P = 0.03; median

    PFS14.5 versus 3.7 months, log-rank P = 0.01;

    hazard ratio (HR) 0.19, 95%confidence interval

    (CI) 0.05 to 0.70] (Fig. 1B and table S2).

    Thevalidation cohort included an independent

    set of 18 NSCLC samples from patients treated

    with pembrolizumab. The clinical characteristics

    were similar in both cohorts. The median non-

    synonymous mutation burden was 244 in tu-

    mors from patients with DCB compared to 125

    in those with NDB (Mann-Whitney P = 0.04)

    (Fig. 1C). The ratesof DCB and PFSwere again sig-

    nificantly greater in patients with a nonsynon-

    ymous mutation burden above 200, the median

    of the validation cohort (DCB 83% versus 22%,

    Fishersexact P= 0.04; median PFSnot reached

    versus 3.4 months, log-rank P = 0.006; HR 0.15,

    95% CI 0.0