Papel de la quimioterapia en la era de la inmunoterapia

Dr. Oscar Juan VidalHospital Universitari i Politècnic La Fe, Valencia

Chemotherapy for NSCLC:A plateau has been reached

OS by treatment groupstage IV NSCLC

Schiller et al. NEJM 2001

Histological classification for decision making:Cisplatin vs carboplatin meta-analysis

Ardizzoni et al. JCNI 2007

Histological classification for decision making:Benefit of bevacizumab in Non-Squamous

Sandler et al. NEJM 2006

Carboplatin – Paclitaxel (OS)

Cisplatin – Gemcitabine (PFS)

Reck et al. JCO 2009

Histological classification for decision making:Differential effect of pemetrexed in Non-squamous vs squamous

Scagliotti et al. JCO 2008

Overall no difference in PFS or OS

Cis/Pem better than Cis/gem in non-Sq

Cis/pem inferior than cis/gem in non-Sq

Histological classification for decision making:Maintenance pemetrexed in Non-squamous

Paz Ares et al. JCO 2013

Pemetrexed maintenance offers superior OS in non-squamous

NSCLC

PARAMOUNT trial

Molecular profiling of lung adenocarcinomaTargeted therapy demonstrated superior efficacy than chemotherapy

Jordan et al. Cancer Discovery 2017

Immunotherapy in pretreated patients

Nivolumab – CheckMate 017 (PIII)1

2nd Line, squamous, PD-L1 All-ComerNivolumab – CheckMate 057 (PIII)2

2nd Line, non-squamous, PD-L1 All-Comer

Pembrolizumab - Keynote 010 (PII/III)3

2nd+ Line, PD-L1 TPS ≥1%Atezolizumab – OAK (PIII)4

2nd+ Line, PD-L1 All-Comer

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

Immunotherapy in pretreated patients

PDL1 ≥ 50%: 14.9 vs. 17.3 vs. 8.2

HR 0.54, HR 0.50

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

Response according to PD-L1 positivity in LC

Checkmate 017: Nivolumab vs. Docetaxel

Spigel, ASCO 2015

Checkmate 057: Nivolumab vs. Docetaxel

Horn, ESMO 2015

Keynote 01: pembrolizumab OAK: atezolizumab

Gainor, AACR 2015 Barlesi, ESMO 2016

Molecular profiling of lung adenocarcinomaPembrolizumab in 1st line stage IV NSCLC with PD-L1 ≥50%

Reck et al. NEJM 2016

NewtreatmentparadigminNSCLC

PDL1statusMolecular

PD-L1≥50%PD-L1<50%

EGFR ALK ROS1BRAFV600E HER2 NTRK MET

1STLINEPembrolizumab*,#

Platinumbased-CT+/-bevacizumab*#,

Andmaintenance;CBDCA/Pem/Pembr*

Platinumbased-CT+/-necitumumab*,#

Crizotinib*,#Ceritinib@

Entrectinib@

2NDLINE• Nivolumab*#• Atezolizumab*#• Pembrolizumab*#IfPD-L1+• Docetaxel+Ramucirumab*,#

Platinumbased-CT

• Nivolumab*#• Atezolizumab*#• Pembrolizumab*#IfPD-L1+• Docetaxel+Nintedanib#/Ramu*,#

T790M+à Osimertinib*#(ifnotreceivedas1stLine)

T790M–or1stLineOsimertinibà Pem/Platinum

Ceritinib*#Alectinib#*Brigatinib*Lorlatinib*

Afatinib*,#Erlotinib*,#+/-BVZ#

Gefitinib*,#Dacomitinib@Osimertinib@

Crizotinib*,#Ceritinib*#Alectinib#

Dabrafenib+

Trametinib*#

2018:Entrectinib*,#LOXO101*

Trastuzumab@TDM1@…

Crizotinib@

Platinumbased-CT

Squamous Non-Squamous

*FDAapproved#EMAapproved

@Notyetapproved

PD-L1Oncogeneaddiction

50%

Courtesy Jordi Remon. SEOM 2017

New treatment paradigm in NSCLC

Role of chemotherapy in 1st line treatment of advanced NSCLC

2/3 of patients received chemotherapy in first line

Clasificación de los tumores según la infiltración de linfocitos (TILs) y la expresión de PDL1

Teng et al. Cancer Res 2015

Generalidades de Estrategias de combinaciones con inhibidores de checkpoint

Harris SJ et al. Cancer Biol Med 2016

Benefit of anti-PDL1 combined with chemotherapy in mouse models

Randomized phase-2 study of carboplatin and pemetrexed with or without pembrolizumab as 1st line therapy: Keynote-21 Cohort G

Progression Free Survival

Response rate

Borghaei et al. ESMO 2017

KEYNOTE-189: Phase III study of pembrolizumab or placebo plus pemetrexed and platinum as 1st line therapy

Gandhi et la. AACR 2018

KEYNOTE 407: Phase III study of carboplatin-paclitaxel/Nab-paclitaxel with or without pembrolizumab for Squamous NSCLC

Paz-Ares et al. ASCO 2018

IMpower150: OS of Atezolizumab + CT ± Bevacizumab vs CT + Bevacizumab in 1L Non-squamous NSCLC

Socinski et al. ASCO 2018

Impower131: PFS of Atezolizumab + Carboplatin+ Paclitaxel or Nab-paclitaxel vs Carboplatin + Nab-Paclitaxel as 1L Squamous NSCLC

Jotte et al. ASCO 2018

Immunological effects of cancer therapy

Galluzzi et al. Cancer Immunol Res 2016

Chemotherapy modulates tumor immunity by different mechanisms

Emmens et al. Cancer Immunt Res 2015

Chemotherapy and Immunological responses

Chemotherapy

Enhance immune response Reduce immune response

Immune-based mechanism of chemotherapy

Bracci et al. Cancer Death and Diffent 2014

Chemotherapy after immunotherapy

OR = 0.30

Grigg ASCO 2017, Leger ASCO 2017, Schvartsmana Lung Cancer 2017

ORR to 39%. PFS 4.7 months OS 9.0 months

Progression after the next line of therapy (PFS2) in the KEYNOTE 024

Bramer at al. ASCO 2017

Trials combining immune agents with chemotherapy

Tang et al. Ann Oncol 2018

Stage IV NSCLC

Solange Peters ASCO 2018

juan_osc@gva.es