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

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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

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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

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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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•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

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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

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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%

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Antibiotics, microbiome and IT?

J Thorac Oncol 2020;15:1147-1159Science 359, 91–97 (2018)

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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

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Biomarkers Predictive Factors

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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

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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

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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