Bases biológicas del cáncer de pulmón. Caracterización

molecular y su repercusión en las decisiones terapéuticas

Dr. Javier de Castro

Salamanca, 23 de mayo de 2019

Disclosure

Educational fees: Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Roche

Advisory board: Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Takeda

Osmani L et al, Semin Cancer Biol 2018; 52 (Pt 1): 103-109

El tratamiento del cáncer de pulmón en 2000

Tumores con mutación tratable

Inmunoterapia

TRATAMIENTO DEL CÁNCER DE PULMÓN NO MICROCÍTICO

CÁNCER DE PULMÓN

Paradigma del cáncer

Cáncer dePulmón

Enfermedad adicta a un oncogen

Heterogeneidad tumoral

Plasticidad

Diseminación sistémica

Potential new target “driver” genes in NSCLC

ADC = adenocarcinoma; ALK = anaplastic lymphoma kinase; Amp = amplification

ERBB2 = erb-b2 receptor tyrosine kinase 2; FGFR = fibroblast growth factor receptor

HER2 = human epidermal growth factor receptor 2; KIF5B = kinesin family member 5B

KRAS = kirsten rat sarcoma viral oncogene homologue

PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PTEN = phosphatase and tensin homologue; SQCC = squamous cell carcinoma

SQCC

ADC

Small cell

Squamous

Large cell and others

Adeno

CAUCASIAN

Unknown

EGFR

KRAS

BRAFERBB2

ALK

PIK3CAROS

KIF5B-RET

FGFR 1-3

UNKNOWN

EGFRAmp

ERBB2

BRAF

PIK3CA

PTEN

NOTCH

AKT 1-3

RAS

ASIAN

UNKNOWN

ROS

ALK

BRAF

HER2

EGFR

KRAS

EGFR activating mutations tend to cluster at exons 18 through 21 in NSCLC

*Literature review as reported in COSMIC (Catalogue Of Somatic Mutations In Cancer) database; may vary depending on study and population factors. †Sensitizing mutations that confer sensitivity to first- and second-generation TKIsEGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.1. Shigematsu H, et al. J Natl Cancer Inst. 2005;97(5):339-346. 2. Lynch TJ, et al. N Engl J Med. 2004;350(21):2129-2139. 3. Paez JG, et al. Science. 2004;304(5676):1497-1500. 4. Siegelin MD, et al. Lab Invest. 2014;94(2):129-137.

FLAURA primary endpoint: PFS by investigatorassessment

Soria JC, et al. N Engl J Med. 2018;378(2):113-125.2. OheY, et al. Presented at: European Society of Medical Oncology Asia Congress; 17-19 November 2017; Singapore. Abstract 413O.

Turajlic S et al, Nat Rev Genet. 2019

RESULTS: ACQUIRED RESISTANCE MECHANISMS WITH COMPARATOR EGFR-TKI (n=129)*/OSIMERTINIB (n=91)

Ramalingam S et al, ESMO 2018

Combination osimertinib and gefitinib in trans C797S+T790M: a case report

Arulananda , JTO 2017

Turajlic S et al, Nat Rev Genet. 2019

Turajlic S et al, Nat Rev Genet. 2019

CTC = circulating tumour cell

Haber & Velculescu. Cancer Disc June 2014

Biopsia Líquida

Herbreteau G et al, J Thorac Dis 2019;11(Suppl 1):S113-S126

Herbreteau G et al, J Thorac Dis 2019;11(Suppl 1):S113-S126

Biopsia Líquida

Herbreteau G et al, J Thorac Dis 2019;11(Suppl 1):S113-S126

Biopsia Líquida(Técnicas de detección)

AURA3: osimertinib benefit in patients with plasma T790M-positive status is similar to patients with tumor tissue T790M-positive status

PFS is defined as time from randomization until date of objective disease progression or death. Progression included deaths in the absence of RECIST progression. Osimertinib administered 80 mg orally once daily. Platinum-pemetrexed group treatment consisted of: pemetrexed 500 mg/m2 + carboplatin AUC5 or cisplatin 75 mg/m2 Q3W for up to 6 cycles + optional maintenance pemetrexed for patients whose disease had not progressed after 4 cycles of platinum-pemetrexed. RECIST v1.1 assessments performed every 6 weeks until objective disease progression.*PFS adjusted for ethnicity. All patients were selected using a tumor tissue test for EGFR T790M (by cobas® EGFR Mutation Test) from a biopsy after disease progression prior to study entry. †Response did not require confirmation per RECIST v1.1.CI, confidence interval; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors1. Mok TS, et al. N Engl J Med. 2017;376:629-640. 2. Suppl. Info for: Mok TS, et al. N Engl J Med. 2017;376:629-640.

Median 5 co-mutations: 60% TP53, 12% PIK3CA, 10% RB1, 9% CTNNB1. Ampl.: ERBB2 4%, MET 2%

TP53 associated with worse OS

Transformación en Carcinoma microcítico

Westover – Ann Oncol 2018 * Marcoux – JCO 2019 * Lee – JCO 2017 * Yu- CCR 2018

EGFR mut. with Rb and p53 mut: x 43 risk of SCLC

Today it is easier to predict what patients maydevelop histologic transformation baseline

Baseline

Acquired

~18 months after diagnosis

• Exposición al radón

• Asbesto/metales pesados

• Combustión de cocinas

• Factores hormonales

• Fumador pasivo

¿Otros factores de Riesgo?

Cáncer de pulmón: Múltiples enfermedades infrecuentes

Supervivencia en ROS 1 y ALK +

Shaw – ELCC 2019 * Shaw – Ann Oncol 2019

ALK: PROFILE 1014

4y-OS: 56.6%

N=343 ALK

Crizotinib

Chemotherapy

ROS1: PROFILE 1001 N=51 ROS1

Similar 4-y OS in ALK- and ROS1-positive without lower subsequent treatment lines, better prognosis?

Solomon – JCO 2018

¿Cáncer de pulmón o Cáncer Agnóstico ?

Vaishnavi – Cancer Dsicovery 2015 * Hyman – ASCO 2017

Multiple NTRK 1/2/3 fusions across multiple tumours

Reck M et al, N Engl J Med 2017;377:849-61.

Cáncer dePulmón

Múltiples mutaciones no tratables

Microambiente tumoral

Epigenética

Diseminación metastásica

Cheung WKC and Nguyen DX, Oncogene 2015;34: 5771-5780

Altorki NK et al, Nature rev Cancer 2019

Altorki NK et al, Nature Rev Cancer 2019

Cancer immunotherapy: induction of long-term survival

Checkpoint inhibitors

Chemotherapy

Ove

rall

su

rviv

al

Nov-14 May-19

Brahmer J et al, ,WCLC 2017

KEYNOTE-024: Pembrolizumab vs. quimioterapia: OS

Reck M et al, Future Oncol. (2019) 15(12), 1363–1383

Fenotipos de la respuesta inmune frente al cáncer

Modified from Chen DS, Mellman I. Immunity 2013; Herbst et al Nature 2014; Hedge, Karanikas, Evers. Clin Cancer Res 2016

Cada fenotipo describe el nivel de presencia y actividad de células T dentro del microambiente tumoral y está asociado a mecanismos específicos de escape al sistema inmune

The nature of the TME influences immune cellcomposition and hampers antitumor immunity

Schaaf et al. Cell Death and Disease (2018) 9:115

¿Se puede mejorar el tratamiento del CPNMmen primera línea ?

5

50

100

QUIMIOTERAPIA

INMUNOTERAPIA 2ª L

INMUNOTERAPIA 1ª L

INMUNOTERAPIA + QT 1ª LAntiangiogénicosOTRAS OPCIONES

????

AÑOS

SUP

ERV

IVEN

CIA

KEYNOTE-010, Checkmate 017/057 , OAK

KEYNOTE-024

No escamoso Escamoso

EGFR, ALK, ROS1

Terapia Dirigida

PD-L1 +PD-L1 +/- PD-L1 + alto PD-L1 +PD-L1 +/- PD-L1 + alto

Keynote-042

Keynote-024

Keynote-042

Keynote-024

Keynote-042

Keynote-042

Keynote- 189

Impowe-150/130/132

Keynote- 407

Impowe-131

Checkmate-227 Checkmate-227

IO

Checkmate-227 Checkmate-227IO-IO

IO-QT

Inmunología y Cáncer

Chan TA et al, Annals of Oncology 30: 44–56, 2019

CheckMate 227: PFS Nivolumab + Ipilimumab vs Quimioterapia en pacientescon alta TMB (≥10 mut/Mb)a

Con una mediana de seguimiento de 13.6 meses para N+I y 13.2 m para QT

Chan TA et al, Annals of Oncology 30: 44–56, 2019

Altorki NK et al, Nature rev Cancer 2019

NGS=next-generation sequencing.

1. Frampton GM et al. Nat Biotechnol. 2013;31(11):1023-1031. 2. Zehir A et al. Nat Med. 2017;23(65):703-713.

Factor Parameter Recommendations*

Preanalytical

Sample processing• Standardise sample processing protocols• Minimise interlaboratory variability

Sequencing parameters

Genomic region covered• Select gene panels that screen for actionable mutations or biomarkers• Select panels with larger genome coverage (ideally 1 megabase or greater)

BioinformaticsStandardisation

of workflow

• Align panel-derived TMB values to a WES-derived reference standard to ensure consistency regardless of the assay

• Standardise mutation calling and filtering algorithms

Comparison of results

Calibration of outputs• Ensure reporting consistency by developing templates for clinically meaningful reporting (eg,

report TMB as mutations per megabase)• Allow calibration of results from different studies

NGS: un proceso complicado

Pitroda et al, Nature Rev Clin Oncol 2019

Cheung WKC and Nguyen DX, Oncogene 2015;34: 5771-5780

IMPORTANCIA DE LOS miRNA

Wu K-L et al, Int. J. Mol. Sci. 2019, 20, 1611;

Subtipos moleculares en carcinoma microcítico de pulmón

Rudin et al, Nature Rev Cancer 2019

Altorki NK et al, Nature rev Cancer 2019