Coordinación científica:Dr. Fernando Rivera HerreroHospital Universitario Marqués de Valdecilla,

Santander

Organizado por: Fundación para el progreso

de la oncología en Cantabria

Tratamiento del paciente con CPNM con alteraciones distintas de

EGFR: reordenaciones ALK, ROS, NTRK, mut BRAF…Dra. Marga Majem

Hospital de la Santa Creu i Sant Pau, Barcelona

Jordan EJ, et al. Cancer Discov 2017

Molecular subtyping of pulmonary adenocarcinoma

• ALK

• ROS-1

• BRAF

• MET

• NTRK

• RET

• K-RAS

• Incidencia: 2–7% de los pacientes con

CPNM avanzado.

• Edad: 50-60 años.

• Fumador ocasional/No fumador.

• Metástasis cerebrales (> 50%)

durante el curso de la enfermedad

• Adenocarcinoma

como histología

predominante

• Pruebas:

IHQ/FISH/NGSALK = quinasa de linfoma anaplásicoCPNM = cáncer de pulmón no microcítico

De Castro, et al. Clin Transl Oncol 2011; Gridelli, et al. Cancer Treat Rev 2014 Shaw, et al. Cin Cancer Res 2011; Dearden, et al. Ann Oncol 2013

Hallberg, et al. Nat Rev Cancer 2013; Rikova, et al. Cell 2007; Soda, et al. Nature 2007

Unión al ligando

ALKinactiva

ALKactiva

Célula

normal

EML4-ALKconstitutivamente activa

Dominio de la

cinasa de ALK

Célula

tumoral

Dominio de

EML4

PI3K

Ras STAT3JAK

AKT MEK1/2

RAF

Disminución de

la apoptosis

mTOR ERK1/2

Crecimiento, proliferación, supervivencia, angiogénesis

0

50

1 2 3 ≥4

Pac

ien

tes

con

C

PN

M A

LK+

y m

etás

tasi

s en

el

SNC

(%

)

Número de metástasis cerebrales en el primer estudio …

ALK

• First generation: crizotinib (Also ROS, MET-TKI)

• Second generation:

– Ceritinib

– Alectinib

• Other second/third generation:

– Brigatinib (AP26113)

– Lorlatinib (PF-06463922)

– Entrectinib (RXDX-101)

ALK ALK-TKI inhibitors

ALK ALK-TKI vs CT in 1st Line

ALK ALK-TKI vs CRIZOTINIB in 1st Line

Alectinib vs Crizotinib in 1L

J-ALEX 300mg/12h

ALEX 600mg/12h

ALESIA 600mg/12h

Brigatinib vs Crizotinib in 1L

ALTA-1L

PENDING RESULTS

Lorlatinib vs Crizotinib in 1L

Ensartinib vs Crizotinib in 1L

ALK ALEX TRIAL: ALECTINIB in 1st Line

ALEX PFS ALEX OS

Shaw, et al. ASCO 2017; Peters, et al. N Engl J Med 2017; Camigde, et al. ASCO 2018

ALK ALTA 1L TRIAL: BRIGATINIB in 1st Line

Camidge et al, 2018

Brigatinib: NR (NR-NR)

Crizotinib: 9.2 m (7.4-12.9)

Response Rate in Brain Mets

Acumulate PD in CNSALK CNS ACTIVITY

ALEX TRIAL: ALECTINIB in 1st Line

ALK ALTA 1L TRIAL. BRIGATINIB in 1st Line, CNS ACTIVITY

ALK ALK-TKI in 2nd LINE and beyond

ALK Detection of acquired resistance to ALK inhibitors

ROS-1

• 1-2% NSCLC.

• Patient characteristics:

• Light smokers (<10 pack/year), never-

smokers, but also former/current smokers.

• Younger age (50 y)

• Adenocarcinoma.

• 60-75% female

• Brain M1 treatment-naïve: +/-36%

• The CNS is a common first site of PD in receiving

crizotinib (47%)

• Dx: Break apart FISH, IHQ, RT-PCR.

Shaw N Engl J Med 2014; Gainor JCO Precis Oncol 2018, Tejas Patil, JTO 2018.

Summary of Critotinib trials

Shaw- NEJM 2014 * Shaw – ESMO 2016 (1206PD) * Wu – JCO 2018 * Mazières – JCO 2015 * Moro-Sibilot – WCLC 2018 * Vassal – ASCO 2018 * Michels – JTO 2019 * Landi – JTO 2017

ROS-1

TKI-naïve Study N ORR

PFS

(months)

Patients with CNS metastases

N ORR PFS

Crizotinib Profile 1001 et al1-5 phase 1-2,

retrospective

32-127 69-80% 9.1-19.2 232 73.9% 10.2

Ceritinib A Korean study6 phase 2 30 63% 19.3 8 25% 6.0

Brigatinib NCT014494617 phase 1/2 1 1/1 21.6 N/A N/A N/A

Cabozantinib NCT016395088 phase 2 Ongoing

Entrectinib ALKA-372-

001+STARTRK-

1+STARTRK-211

phase 1/2 53 77.4% 19.0 23 73.9% 13.6

Lorlatinib NCT019708659,

Ph2(CohortEXP-6)12

phase 1-2 7-13 57-61.5% 21.012 612 66.7% N/A

Repotrectinib TRIDENT-113 phase 1 10 80% N/A 3 3/3 N/A

1. Shaw AT et al N Engl J Med 2014 Nov 20;371(21):1963-71. 2. Wu YL et al. J Clin Oncol 2018;36:1405-11. 3. Michels S et al. J Thor Oncol 2017;12:S379-80.4. Morosibilot D et al. J Thor Oncol 2015;10(2_suppl):S65.

5. Mazières J et al. J Clin Oncol 2015;33:992-9. 6. Lim SM et al. J Clin Oncol 2017;35:2613-18. 7.Gettinger SN et al Lancet Oncol. 2016 Dec;17(12):1683-1696. 8.Drilon A et al Cancer Discov. 2017 Apr;7(4):400-409.

9.Shaw AT et al. Lancet Oncol 2017;18:1590–9.10.Nosaki K et al J Thorac Oncol 2017;12:S1069. 11.Doebele RC et al. 2018 WCLC OA02.0112.Ou SI et al. 2018 WCLC OA02.03.13.Lin JJ et al. 2018 WCLC OA02.02.

First line therapeutic strategies for ROS1 NSCLCROS-1

Gainor JCO Precis Oncol 2018.

Mechanism of resistance in ROS1 to crizotinib

ROS1 resistance mutations (mostly G2032R) is the most common resistance mechanisms to crizotinib.

ROS-1

Therapeutic strategies for pretreated ROS1 NSCLC

• Ceritinib: ALK & ROS1 TKI

• Brigatinib: ALK, ROS & EGFR TKI

• Lorlatinib: ALK & ROS1 TKI

• Entrectinib: ROS1, NTRK & ALK TKI

• Repotrectinib: ROS1, NTRK & ALK inhibitor

BRAF V600E

1Planchard D et al. Lancet Oncol 2016;17:642-6502Planchard D et al. Lancet Oncol 2016;17:984-9933Planchard D et al. Lancet Oncol 2017;18:1307-1316

BRAF 2% Non-SCC NSCLC

BRF113928 TRIAL

BRF113928 Cohort A→ Dabrafenib in BRAF mut NSCLC pretreated pts

Planchard D et al. Lancet Oncol 2016;17:642-650

BRAF

BRF113928 Cohort B → Dabrafenib + Trametinib in BRAF mut NSCLC pretreated pts

Planchard D et al. Lancet Oncol 2016;17:984-993

BRAF

BRF113928 Cohort C: Dabrafenib + Trametinib in 1st line BRAF mut NSCLC

Planchard D et al. Lancet Oncol 2017;18:1307-1316

BRAF

Median DoR (IRC Assessed): 15.2 (7.8-23.5)

Progression-free survival

Planchard D et al. Lancet Oncol 2017;18:1307-1316

Overall survival

BRAF BRF113928 PFS &OS with Dabrafenib + Trametinib 1st line

• Incidence•8-30% of sarcomatoid lung carcinomas (SLC)

•ADC-SCC: 5-8%

•3-4% ADC

•SCC: 0-2%

• Clinicopathologic features• older patients ( median 65-75 yr )

• ↓ proportion of never smokers

• mutually exclusive with other drivers

• 15-20% with concurrent MET amplification

• No associated with tumor stage.

MET exon 143-4% NSCLC

DX: DNA-based NGS, RNA seq

Median DoR 9.1 m ( 6.4, 12.7)

Median PFS estimate: 7.3 m (5.4, 9.1)

Drilon A. WCLC 2018

PR0FILE 1001 Crizotinib

MET exon 14

Wolf ASCO 2019

Capmatinib: MET inhibitor.

Wolf ASCO 2019

MET exon 14 Tepotinib: MET-TKI inhibitor.

MET exon 14 Tepotinib: MET-TKI inhibitor.

Drug Administered MET alteration Putative resistance mechanism Notes

Crizotinib

8 mo of disease control1MET D1010H MET D1228N

(acquired second site mutation on tumor rebiopsy)

high total MET and phospho-MET IHC+ on

post-PD biopsy

Crizotinib

13 mo of disease control2MET D1010H

(MET Y1230C)

MET Y1230C(detected in ctDNA on PD)

Crizotinib

8 mo of disease control3MET c.3028delG MET Y1230H

(acquired in tumor, MET amp + MET D1228N, Y1230H,

Y1230S, and G1163R in plasma)

thereafter responded to Glesatinib

Gefitinib + Crizotinib 8.8 mo of disease control4 MET amplification (+EGFR L858R) MET Y1248H, D1246N, EGFR T790M, MET

amplification, EGFR L858R

NIH3T3 cells harboring either mutation

respond to type II MET-TKIs,

Gefitinib+ Capmatinib 7.2 mo of disease control4 MET amplification (+EGFR Del19) MET D1246N,

Savolitinib + Osimertinib

9 mo of disease control5MET amplification(+EGFR ex19 del)

MET D1228V(acquired second site mutation on tumor rebiopsy)

thereafter responded to Cabozantinib +

Erlotinib

1. Heist R et al, J Thoracic Oncol, 2016; 2. Ou et al, J Thoracic Oncol, 2017; 3. Engstrom et al, Clinical Cancer Res 2017; 4. Li A, et al. Clin Cancer Res 2017; 5 Bachall et al, Cancer Discov, 2016; 6. Qi et al,

Cancer Res, 2011; 7. Tiedt et al, Cancer Res 2011; Bahcall M, Awad MM, et al, Clin Cancer Res. 2018; Awad MM, Bahcall M, et al. ASCO 2018

Mechanisms of acquired resistance to MET TKIs

NTRK

Click to edit Master subtitle style

>20 known NTRK gene fusion variants with intact TRK kinase domain

ESMO proposed NRTK gene fusion detection algorithm

NTRK is tumor agnostic. TRK fusions found in diverse cancer histologiesNSCLC: 11 pts

Farago JCO Precis Oncol 2018

PazAres ELCC 19, Doeble AACR 2019

NTRK Entrectinib Integrated analysis

(phase 1 ALKA-372-001 & STARTRK-1 and phase 2 STARTRK-2)

• Selective TRK, ROS1, ALK-TKI

• CNS-active

PazAres ELCC 19, Doeble AACR 2019

NTRK Entrectinib Integrated analysis

(phase 1 ALKA-372-001 & STARTRK-1 and phase 2 STARTRK-

2)

PazAres ELCC 19, Doeble AACR 2019

NTRK Entrectinib Integrated analysis

(phase 1 ALKA-372-001 & STARTRK-1 and phase 2 STARTRK-

2)

Efficacy in NSCLC

PazAres ELCC 19, Doeble AACR 2019

NTRK Entrectinib Integrated analysis

(phase 1 ALKA-372-001 & STARTRK-1 and phase 2 STARTRK-

2)

Efficacy in Brain Mets

FEBRUARY 19 2019 Entrectinib Granted Priority Review by FDA

for NTRK+ Tumors and ROS1+ NSCLC

NTRK Larotrectinib (LOXO-101) Integrated dataset

(adult phase 1, SCOUT, NAVIGATE)

Lassen, ESMO 2018

• Highly selective TRK inhibitor, Limited activity of other kinase

• Activity in CNS disease

NTRK Larotrectinib (LOXO-101) Integrated dataset

(adult phase 1, SCOUT, NAVIGATE)

Lassen, ESMO 2018

Larotrectinib in TRK fusion NSCLC

8 NTRK1

3 NTRK3

EMA

Orphan drug for salivary gland cancer, papillary thyroid

carcinoma & glioma.

FDA

Adult and pediatric tumors with NTRK fusion (Nov18)

NTRK NEXT GEN TRK-TKI

Potent 2nd gen TRK TKIActivity against AR TRK-TKI

LOXO-195: PHASE 1 & EAP

RR: 34% (10/29)

Hyman, AACR 2019

Drilon et al. Nat Rev Clin Oncol 2018;15:151–67; Kato et al. Clin Cancer Res 2017; 23:1988–97; Pietrantonio et al. Ann Oncol 2018;Mar 10; Su et al. PLoS One 2016;11(11)

RET Rearranged during transfection

• 1-2% NSCLC

• Younger age (< 60y)

• Never-smoker

• Signet ring cells in > 10%

• Papillary or leipidic

• Smaller tumors (< 3 cm) with LN mets

• Poorly differentiated tumors

• Fusion partners: KIF5B, CCDC6.

• RET-rearrangements detected by

NGS, multiplex RNA seq, FISH. IHC

not ready.

RET Multi-TKI, activity data

RET testing n ORR % PFS, mo OS, mo

Cabozantinib

(Drilon, ASCO 2016)

FISH/NGS 26 28 5.5 9.9

Cabozantinib

(Gautschi, ASCO 2016)

FISH/NGC/RT-PCR 21 37 3.6 4.9

Vandetanib

(Sato, ASCO 2016)

FISH/RT-PCR 19 53 4.7 47% 1-year

Vandetanib

(Lee, Ann Oncol 2017)

FISH confirmed 17 18 4.5 11.6

Vandetanib

(Gautschi, ASCO 2016)

FISH/NGC/RT-PCR 11 18 2.9 10.2

Sunitinib

(Gautschi, ASCO 2016)

FISH/NGC/RT-PCR 10 22 2.2 6.8

Any RET inhibitor

(Gautschi, ASCO 2016)

FISH/NGC/RT-PCR 41 23 2.9 6.8

Lenvatinib

(Velcheti, ESMO 2016)

NGS 25 16 7.3 NE

RET EVOLUTION OF RET+ NSCLC THERAPY

• High CNS activity

Highly selective RET inhibitor (RET fusions & mutations)

• BLU-667

• LOXO-292

Drillon ASCO 2018, Oxnard WLCC 2018, Subbiah Cancer Discov. 2018

RET Next generation RET TKI in NSCLC

K-RAS

K-RAS25% ADK

No targeted therapy

MET ex14 RET NTRK K-RAS OTHER

Coordinación científica:Dr. Fernando Rivera HerreroHospital Universitario Marqués de Valdecilla,

Santander

Organizado por: Fundación para el progreso

de la oncología en Cantabria

Tratamiento del paciente con CPNM con alteraciones distintas de

EGFR: reordenaciones ALK, ROS, NTRK, mut BRAF…Dra. Marga Majem

Hospital de la Santa Creu i Sant Pau, Barcelona