ENFERMEDAD METASTÁSICA

Carcinoma No Microcítico de Pulmón

Xabier Mielgo Rubio MDUnidad de Oncología

Hospital Universitario Fundación Alcorcón

CONTENIDO

1. CNMP CON MUTACIONES DRIVER– EGFR– ALK– ROS1– KRAS G12C– RET

2. CNMP SIN MUTACIONES DRIVER– QT y antiangiogénicos– Inmunoterapia

2L 1L

CNMP CONmutaciones

driver

EGFR

Soria et al. N Eng J Med 20187; Ramaligangam SS et al at ESMO, LBA5 PR

FLAURA OS ANALYSIS

38,6 vs 31,9m; HR 0,79, p=0,0462

EGFR

Soria et al, N Eng J Med 2018; Ramaligangam SS et al at ESMO, LBA5_PR

FLAURA OS ANALYSISConfirms role of osimertinibas SoC 1L in commonEGFRm NSCLC

Prolongs survival, with betterCNS activity and bettertolerability than 1st G TKIs

Careful! only 30% of control arm received osimertinib and 30% did not receive further tx

EGFRGef VS Gef + Chemo

Noronha V et al at ASCO, Abs 9001

EGFR

Zhang V et al at WCLC, OA11:07

Updated NCT02148380

•Only PS 0 or 1 patiens taken, unlike Indian study

•Brain Metastases included

•Uncommon mutations not included

•Chemo Schedule every 4 weekly

•Small numbers in each subgroup

EGFR

Zhang V et al at WCLC, OA11:07

Updated NCT02148380

AE, n (%)AC + G (n=40) G (n=41)Al Grade 3-4 All Grade 3-4

Liver dysfunction 21 (52.5) 4 (10.0) 15 (36.6) 1 (2.4)

Neutropenia 17 (42.5) 4 (10.0) 3 (7.3) 0 (0.0)Astriction 19 (47.5) 0 (0.0) 5 (12.2) 0 (0.0)Fatigue 9 (22.5) 3 (7.5) 7 (17.1) 0 (0.0)Anemia 17 (42.5) 0 (0.0) 11 (26.8) 0 (0.0)Nausea 20 (50.0) 0 (0.0) 6 (14.6) 0 (0.0)Diarrhea 19 (46.3) 0 (0.0) 17 (41.5) 0 (0.0)Skin rash 24 (60.0) 4 (10.0) 22 (53.7) 4 (9.8)Anorexia 16 (40.0) 0 (0.0) 8 (19.5) 0 (0.0)Thrombocytopenia 10 (25.0) 0 (0.0) 2 (4.9) 0 (0.0)

Leucopenia 8 (20.0) 0 (0.0) 3 (7.3) 0 (0.0)

Impressive 3 year OS data, however the numbers are small

Active in patients with CNS metastases (number of patients not mentioned)

No data available on T790M mutation and postprogression therapies

Better toxicity profile than other studies

3rd study with OS and PFS benefitStrategy Trial Treatment Median PFS,

monthsPFS HR (95%

CI)Median OS,

monthsOS HR (95%

CI)

1st

generation EGFR TKI + chemothera

py

NEJ009 Gefitinib + carbo-pemetrexed vs.

gefitinib

20.9 vs.11.2 months

0.49 (0.39-0.63)

52.2 vs.38.8 months

0.60 (0.52-0.93)

Noronha Gefitinib + carbo-pemetrexed vs.

gefitinib

16 vs. 8 months

0.51 (0.39-0.66)

NR vs. 17 months

0.45 (0.31-0.65)

Current study

Zhang Gefitinib + carbo-pemetrexed vs.

gefitinib vsPemetrexedCarboplatin

17.5 vs11.9 vs 5.7

months

0.48(0.29-.78) 37.9 vs 25.8 months

0.56(0.34-091)

EGFR

Nakagawa K et al at ASCO, Abs 9000

RELAY

EGFR

Nakagawa K et al at ASCO, Abs 9000

RELAY

Confirms benefit of the strategyof EGFR TKI + antiangiogenesis

Impressive PFS

More toxicity because of more hypertension

¿alternative to the SoCosimertinib?

EGFR

Zhou Q et al at ESMO, 14800

CTONG 1509

Confirms benefit in PFS of thestrategy of EGFR TKI + antiangiogenesis (RELAY, JO25567, NEJ026

No new safey signals

¿erlotinib + bevacizumab/ramucirumabalternative to the SoCosimertinib?

NO new safety signals

EGFR

Reck M et al at ELCC, 104O

IMpower 150 EGFR subgroup

N= 10% of ITT populationPossibly good alternative in EGFRm NSCLC afterprogression to TKIs

Small number of patients

Exploratory subanalysis

NCT03991403 phase III trial in EGFR and ALK population willclear the doubts

ALK

Chow L et al at ESMO, 14780

ASCEND-7 Arm Brainmets

ALK

Barlesi F et al at ESMO, 3900

ASCEND-7 Arm LM

ALK

Camidge D et al at ESMO, 1487PD

LORLATINIB post2nd G

ALK

Wolf J et al at WCLC, A02.07

ALUR updated Final Analysis

ALK

Gadgeel SM et al at ESMO, LBA81_PR

BFAST ALK cohort

ROS1

Barlesi et al at ELCC, Abs 1090

ENTRECTINIBIntegrated analysis

ROS1

Paz-Ares L et al at WCLC, MA14.02

ENTRECTINIBROS1/NTRK solid

tumors with CNS Mets

ROS1

Drilon A et al at ESMO, 444PD

REPROTECTINIBTRIDENT-1 Study

Phase I/II

KRAS G12C

Lanman BA et al at AACR, Abs 4455; Fakih M et al at ASCO, Abs 3003; Govindan R et al at ESMO, 446PD

AMG 510

RET

Drilon A et al at WCLC

LIBRETO-001(LOXO-292)

ORR 68% ORR 85%

RET

Gainor et al at ASCO,

ARROW(BLU-667)

CNMP SINmutaciones

driver

QT + ANTIANGIOGÉNICOS

Mantenimiento Pemetrexed + Bevacizumab

Seto T et al at ASCO, Abs 9003

Ramalingam SS et al at ASCO, Abs 9902

INMUNOTERAPIA 2L

Garon EB et al at ASCO, LBA9015

KeyNote-001 5-Y-OS

IO 2LActualizaciones

NIVOLUMAB

CheckMate-003: 6-Y-OS

CheckMate-017/057: 5-Y-OS

Gettinger S et al at WCLC, OA14.04Antonia SJ et al, Lancet Oncol 2019

IO 2L

Bazhenova L et al at WCLC, OA04.01

S1400I (Lung-MAP)

IO 2L

Arrieta O et al at WCLC, MA11.04

Pembro + Docetaxel

Pneumonitis grade 1-2: 22,5% vs 5,3%; p=0,029

INMUNOTERAPIA 1L

Spigel et al at ESMO, LBA78

Impower 110

IO 1L

Peters S et al at ESMO, LBA4_PR

CheckMate-227 Part 1 Final analysis

IO 1LCheckMate-227 Part 1

Final analysis

Peters S et al at ESMO, LBA4_PR

IO 1L

Peters S et al at ESMO, LBA4_PR

CheckMate-227 Part 1 Final analysis

IO 1L

Peters S et al at ESMO, LBA4_PR

CheckMate-227 Part 1 Final analysis

IO 1L

Borghaei et al at WCLC

Pembro PD-L1 < 1%

IO 1L

Mok T et al at ELCC, 102O

ActualizacionesPEMBROLIZUMAB

Reck M et al at WCLC

KeyNote-024 3-Y-OS

KeyNote-042 Final Analysis

IO 1L

Gadgeel SM et al at ASCO; Abs 9013

ActualizacionesPEMBROLIZUMABKeyNote-189: 18,7m follow

up and PFS2

IO 1LActualizacionesPEMBROLIZUMAB

KeyNote-407: Final analysis and PFS2

Paz-Ares L et al at ESMO, LBA82

TAKE-HOME MESSAGES

• Ratificación de osimertinib como SoC en EGFR+ mutaciones comunes (↑OS, ↑actividad intracraneal, ↓toxicidad)

• EGFR+ QT + Gefitinib: ↑OS llamativo pero ↑ toxicidad

• EGFR+ Erlotinib + beva/ramucirumab: ↑PFS alternativas 1L

• Nueva diana molecular accionable KRAS G12C con datos prometedores del AMG 510

• No demostrado ↑OS con doble mantenimiento beva/pemetrexed en nsNSCLC, monoterapia sigue siendo el estándar

• Ratificación de colas de largos supervivientes a 5ª con nivo y pembro– En PD-L1<1% 5-y-OS de 8,9% vs 2% frente a Docetaxel

• Atezolizumab ↑OS en TC3 o IC3WT: nueva opción terapéutica para altos expresores de PD-L1

• Nivo + Ipi: ↑OS frente a QT– Mayor beneficio: PD-L1 >=50% y <1%