tratamiento del paciente con cpnm con alteraciones distintas de … · 2019-07-03 · shaw n engl j...
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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