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8 – 12 febrero
CANCER DE PULMÓN:Nuevo horizonte en la primera linea. Identificando mejores
perfiles de pacientes. Redefiniendo el tratamiento
Bartomeu Massutí MDHospital Universitario Alicante
ISABIAL
8 – 12 febrero
• Empleo: Consellería de Sanitat Generalitat Valenciana; Universidad Miguel Hernández
• Agencias Públicas: SAISE Hemato-Oncología Conselleria Sanitat GeneralitatValenciana
• Patentes/Acciones compañías farmacéuticas: No
• Financiación investigación: Convocatorias públicas
• Asesorías: Roche, BMS, MSD, Boehringer Ingelheim, Takeda, Abbvie
• Ponencias, Viajes: Roche, Pfizer, Merck Serono, Boehringer-Ingelheim, Astra-Zeneca
• Otros: Comité Dirección GECP
Conflictos de interés
8 – 12 febrero
NSCLC treatment “revolution”
Immunotherapy clinical trials in NSCLC
Immunotherapy limits
Prognostic and predictive factors
Real world clinical practice
8 – 12 febreroAnnals of Oncology 27 (Supplement 5): v1–v27, 2016 doi:10.1093/annonc/mdw326
Five years ago…
8 – 12 febrero
CT IO
8 – 12 febrero Updated version published 15 September 2020 by the ESMO Guidelines Committee
Dynamics algorithms changes
8 – 12 febrero
IO+IO+/-CT
CheckMate 227 MYSTIC NEPTUNE CheckMate 9LA
IO+CT
IMpower 150 KN 189KN 407
IMpower 131
IMpower 130
IMpower 132
IO Monotherapy
KN 024 KN 042 CheckMate 026 IMpower 110
Ph III CTs IT 1st line NSCLC
8 – 12 febrero
MetastaticSt IV NSCL
1st line therapy
Non-Squamous
No genomic target
PD-L1 < 1 %
IHC
PD-L1 1.49%
IHC
PD-L1 >50%
IHC
SquamousNo genomic target
PD-L1 < 1 %
IHC
PD-L1 1-49%
IHC
PD-L1 >50%
IHC
KEYNOTE 024
IMpower 110 IMpower 110
CHECKMATE 026 (PD-L1 > 5%)
KEYNOTE 042
MYSTIC
IMpower 131
KEYNOTE 407
CHECKMATE 227
MYSTIC
NEPTUNE
CHECKMATE 9LA
IO monotherapy
KEYNOTE 024
IMpower 110 IMPower 110
CHECKMATE 026 (PD-L1 > 5%)
KEYNOTE 042
MYSTIC
IO + CTIMpower 150 IMpower 130 IMpower 132
KEYNOTE 189
IO + IO+/-CT
CHECKMATE 227
MYSTIC
NEPTUNE
CHECKMATE 9LA
8 – 12 febrero
EGFR, ALK, ROS, BRAF NTRK, RET15-20 %
PD-L1 1-49% 40%
PD-L1 >50%30%
Platinum doubletsIO+CTIO+IO
Platinum doubletsIO monotherapy
IO+CTIO+IO
Platinum doubletsIO+CTIO+IO
8 – 12 febrero
EGFR, ALK, ROS, BRAF NTRK, RET15-20 %
PD-L1 1-49% 40%
PD-L1 >50%30%
Platinum doubletsIO+CTIO+IO
Platinum doubletsIO monotherapy
IO+CTIO+IO
Platinum doubletsIO+CTIO+IO
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8 – 12 febrero
•Efficacy •Safety
The outcomes data
•Age
•PS
•Smoking habit
•Comorbidities
•IT contraindications
•Patient´s preferences
The Patient
•Liver mets
•Brain mets
•Tumor burden
The disease
•Histology
•PD-L1 expression
•TMB
•Gene signatures
•Other biomarkers (LKB1, KEAP, ARIAD 1, KRAS…)
The tumor
8 – 12 febrero J Clin Oncol 37:1927-1934. © 2019
J Clin Oncol 36:2872-2878. © 2018
Steroids and IT?
8 – 12 febrero Cancers 2020, 12, 2827; doi:10.3390/cancers12102827
Steroids and IT metanalysis
8 – 12 febrero
Autoimmunes diseasesand IT?
J Clin Oncol 36:1905-1912. © 2018JAMA Network Open. 2020;3(12):e2029917.
AIDs 85/751 p → 11.3%Active AID →17%irAEs: 65.9 vs 39.9%No diff G3-4 AEs
The Oncologist 2019;24:e327–e337
- before initiation, nonselectiveimmunosuppressants could be replaced by specific selectiveimmunosuppressant drugsfollowing a short rotationphase- combining ICI with theselective immunosuppressantcould prevent exacerbation of the AD
https://doi.org/10.1016/j.annonc.2020.03.285
8 – 12 febrero
Viral infection and IT?
JAMA Oncol. 2020; 6(7):1063-1067.
DURVAST: Durvalumab in HIV+ →DCR 50%
Cohort Number AEs AEsG 3-4
ORR
HIV 21 5 24%
3 14%
528%
VHB/VHC 34 15 44%
10 29%
618%
Journal for ImmunoTherapy of Cancer (2019) 7:353
8 – 12 febrero
Lung Cancer 135 (2019) 188–195
P
F
S
< 65 y 0.64 (0.51-0.80) <0.001
> 65 y 0.76 (0.63-0.92) <0.001
< 75 y 0.70 (0.57-0.85) <0.001
> 75 y 0.91 (0.64-1.30) 0.597
O
S
< 65 y 0.71 (0.59-0.85) <0.001
> 65 y 0.81 (0.70-0.94) 0.005
< 75 y 0.77 (0.65-0.91) 0.003
> 75 y 1.03 (0.73-1.44) 0.88
Immunotherapy (2020) 12(8), 587–603
Age and IT?
8 – 12 febreroAlessi ASCO 2020 #9568334
PS and IT?
8 – 12 febreroJ Thorac Oncol. 2019;14:1244–1254.
Brain mets and IT?
Lancet Oncol 2020 Published Online April 3, 2020
Pembrolizumab 10 mg/kg43 p → 37 with PD-L1 >1%Brain response 11/37 (29.7%)Median OS: 9.9 m1 y survival→ 40%
8 – 12 febrero
Antibiotics, microbiome and IT?
J Thorac Oncol 2020;15:1147-1159Science 359, 91–97 (2018)
8 – 12 febrero
Median PFS always < 9 m
IO monotherapy IO + CT IO + IO
8 – 12 febreroJ Immunother Cancer 2020;8:e000500
Ann Oncol 28: 2707–2714, 2017
Early tumor shrinkage and Depth of Response and survival
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Complexity of immunotherapy interactions
8 – 12 febrero
Biomarkers Predictive Factors
8 – 12 febrero
Only PD-L1 is approved as biomarker but…Logistic and technical limitations, heterogenity, spatial and temporal dynamics PD-L1
Hong ASCO 2019JAMA Oncol. 2016;2(1):46-54.
Tissue: quality and quantity / Time archivedEpitope stabilityDiff Ab, Platforms, MetodologiesInter-observer reliability
8 – 12 febrero
PFS: 8.3 vs 5.4 m HR 0.78OS: 22.8 vs 16.4 m HR 0.75
PD-L1 continuous variable: ICIs outcome in PD-L1 >90% vs 50-89%
Shah ASCO 2020 #307323Annals of Oncology 30: 1653–1659, 2019
8 – 12 febrero
PD-L1 and TMB: Predictive factors for …PFS or OS?
JAMA Network Open. 2019;2(7):e196879.doi:10.1001/jamanetworkopen.2019.6879
8 – 12 febreroRizvi ASCO 2019
Gene mutation and PD-L1 expression
8 – 12 febreroGenome Medicine 2018 DOI: 10.1186/s13073-018-0605-7.
Genomics mechanisms sensitivity/resistance to IT
• IFNGR1
• JAK1
• JAK2
• JAK3
• ALPNR
• SOCS1
• MSH2
• MSH6
• PMS2
• POLE
• BRCA2
• KRAS
• STK11
• TP53
• PTEN
• ARID1A
• PBRM1
• SMARCA4
• EZH2
• B2M
8 – 12 febrero
Molecular abnormalities for a positive or negative selection for IT
STK11WT;KEAP1WT and PDL1 TPS ≥1%
STK11MUT and/or KEAP1MUT and PDL1 TPS ≥1%
Skoulidis WCLC 2019 Rizvi WCLC 2019
8 – 12 febrero
Moving beyond PD-L1: complexity and dynamics of cancer immune response
Cristescu et al., Science 362, eaar3593 (2018) 12 October 2018
8 – 12 febreroJAMA Network Open. 2020;3(6):e207205.doi:10.1001/jamanetworkopen.2020.7205
PD-L1 and clinical practice in USA
8 – 12 febrero
Opening direct comparison IT regimens?
Boyer WCLC 2020
8 – 12 febrero
Carcinoma no escamoso Carcinoma escamoso
PD-L1 > 50% PD-L1 > 1% PD-L1 < 1%
PD-L1 > 50% PD-L1 < 50%
Combinación Platino Combinación Platino-Pemetrexed
Combinación Platino-Paclitaxel-Bevacizumab
Pembrolizumab Pembrolizumab
Platino-Pemetrexed-Pembrolizumab
Platino-Pemetrexed-Pembrolizumab
Carboplatino-Paclitaxel-Bevacizumab-Atezolizumab
Carboplatino-Paclitaxel-Bevacizumab-Atezolizumab
Nivolumab+Ipilimumab + Quimioterapia
Nivolumab+Ipilimumab + Quimioterapia
PD-L1 > 50% PD-L1 < 50%
Combinación Platino Combinación Platino
Pembrolizumab Pembrolizumab
Carboplatino-Paclitaxel-Pembrolizumab
Carboplatino-Paclitaxel-Pembrolizumab
Nivolumab+Ipilimumab + Quimioterapia
Nivolumab+Ipilimumab + Quimioterapia
El largo camino desde EMA hasta el SNS español
8 – 12 febrero
• IT have changed metastatic NSCLC landscape and outcomes
• Currently therapeutic decisions and drug labels driven by histology and IHC PD-L1
BUT….
• Most of patients with progression before 9 months
• Histology: prognostic factor; could define only chemotherapy associated to IT
• Patients and disease characteristics should modulate treatment choice
• PD-L1: predictive factor mainly for response and PFS
AND
• Academic research in dose and treatment duration fields is needed
• Multi-parameter decision tools are coming
Take home messages
8 – 12 febrero
“ If you ar not confused, you are not payingattention…”
Tom Peters: Thriving on chaos: Handbook for a management revolution
bmassutisbmassutis@seom.orgtomeumassutis@gmail.com
8 – 12 febrero
Gracias
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