Puesta al da Inmunoterapia en cncer de pulmn

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Puesta al día: Inmunoterapia en cáncer de pulmón I Magnitud del beneficio clínico en

Puesta al día: Inmunoterapia en cáncer de pulmón I Magnitud del beneficio clínico en CPNM sin mutaciones driver. Guías clínicas Noemí Reguart, MD, Ph. D Hospital Clínic, IDIBAPS Barcelona, Spain

DISCLOSURE INFORMATION • Advisory Board/Consultancy/Speaker honoraria: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Guardant Health, Pfizer,

DISCLOSURE INFORMATION • Advisory Board/Consultancy/Speaker honoraria: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Guardant Health, Pfizer, Abbie, Ipsen, Novartis, Astra-Zeneca, Lilly, Takeda • Research Funding: Pfizer, Nano. String Technology, Novartis • Institutional financial interests: those related to clinical trials and patient recruitment

Disclaimer: de cara a dar una vision balanceada, completa y actualizada de la situación

Disclaimer: de cara a dar una vision balanceada, completa y actualizada de la situación del tratamiento del cancer de pulmón metastásico, se incluyen en algunas partes de esta presentación datos de ensayos clínicos de diferentes moléculas, en proceso de aprobación por la EMA.

Key milestones achieved in only 3 years!! EMA March 2019 Pembro+chemo SQ (1 L)

Key milestones achieved in only 3 years!! EMA March 2019 Pembro+chemo SQ (1 L) Pembro+chemo non-SQ (1 L) Atezo+chemo non-SQ (1 L) ≥ 50% 2019 * SQ, squamous; NSQ: non-squamous

IO (alone/combination) vs Chemo: we have a clear winner!! Martínez et al. Clin Cancer

IO (alone/combination) vs Chemo: we have a clear winner!! Martínez et al. Clin Cancer Res January 14 2019

Chemotherapy plus IO: How to decide? IO alone IO + Chemo IO +IO Martínez

Chemotherapy plus IO: How to decide? IO alone IO + Chemo IO +IO Martínez et al. Clin Cancer Res January 14 2019

Guidelines: ESMO Guidelines Levels of evidence and grades of recommendations included. Introduce a tool

Guidelines: ESMO Guidelines Levels of evidence and grades of recommendations included. Introduce a tool to assess the magnitude of clinical benefit (MCBS) Planchard D, et al. Ann Oncol. Oct 2018; Corrigendum 30 Jan 2019 Good methodologic background while their major limitation is ASCO Guidelines their slow updating Hanna N, et al. J Clin Oncol. 2017 NCCN Guidelines Real-time update. Weak methodology and poor comparative tols Ettinger DS et al. J Natl Compr Canc Netw. 2018 Version 4. 2019 — April 29, 2019 www. nccn. org SEOM Guidelines Recommendations by a group of experts on lung cancer based on literature. Levels of evidence and grades of recommendations included. No specific review intervals. Majem M, et al. CTO Nov 2018

Levels of Evidence & Grading System Lo. E I > III Go. R A

Levels of Evidence & Grading System Lo. E I > III Go. R A > E Infectious Diseases Society of America-US Public Health Service Grading System; Dykewicz et al, 2001

Levels of Evidence & Grading System Category, grade Definition Lo. E I > IV

Levels of Evidence & Grading System Category, grade Definition Lo. E I > IV Go. R A > E Adapted from the Infectious Diseases Society of America-US Public Health Service Grading System; Dykewicz et al, 2001

- Levels of Evidence & Grading System

- Levels of Evidence & Grading System

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1 V 1. 0 2015 Only

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1 V 1. 0 2015 Only graded after EMA approval V 1. 1 2017 Cherny, Ann Oncol 2015 and 2017

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1 Factors and Evaluations Forms (ESMO-MCBS)

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1 Factors and Evaluations Forms (ESMO-MCBS) Cherny, Ann Oncol 2015 and 2017

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1 Evaluation form 2 a: Primary

Magnitude of Clinical Benefit Scale (MCBS) V 1. 1 Evaluation form 2 a: Primary endpoint OS Evaluation form 2 b: Primary endpoint PFS

Magnitude of Clinical Benefit Scale changes rapidilly !!!

Magnitude of Clinical Benefit Scale changes rapidilly !!!

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver alterations (EFGR/ALK): A. Any positive PD-L 1 B. Regardless of PD-L 1 2) 2 L CPNM without driver alterations (EFGR/ALK)

Key factors used in First Line Treatment with IO: * Only ESMO Guideines Courtesy

Key factors used in First Line Treatment with IO: * Only ESMO Guideines Courtesy A. Calles

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver alterations (EFGR/ALK): A. Any positive PD-L 1 B. Regardless of PD-L 1 2) 2 L CPNM without driver alterations (EFGR/ALK)

1 L CPNM without driver alterations EFGR/ALK, monotherapy KEYNOTE 024: PD-L 1 ≥ 50%

1 L CPNM without driver alterations EFGR/ALK, monotherapy KEYNOTE 024: PD-L 1 ≥ 50% Reck, NEJM 2016; Brahmer , ASCO 2017, WCLC 2017 KEYNOTE 042: PD-L 1 ≥ 1% Mok, Lancet 2018, ELCC 2019

Clinical Practice Guidelines: 1 L CPNM without driver alterations EFGR/ALK, monotherapy, PDL 1 positive

Clinical Practice Guidelines: 1 L CPNM without driver alterations EFGR/ALK, monotherapy, PDL 1 positive Trial Absolute OS gain OS HR (95% CI) Qo. L/toxicity KN-024 (PD-L 1 50%) OS gain: 15. 8 months. 2 -year survival gain 17% 0. 63 (0. 47– 0. 86) KN-042 (PD-L 1 1%) OS gain: 4. 6 months. 2 -year survival gain 11. 3% PD-L 1 1%: 0. 81 (0. 71 Improved toxicity profile – 0. 93) PD-L 1 20%: 0. 77 (0. 64– 0. 92) PD-L 1 50%: 0. 69 (0. 56– 0. 85) Improved toxicity profile & Qo. L * KN 042 (pembro+quimio all comers) not EMA approved yet ESMO-MCBS SEOM IA MCBS 5 (Form 2 a) IA - -

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver alterations (EFGR/ALK): A. Any positive PD-L 1 B. Regardless of PD-L 1 2) 2 L CPNM without driver alterations (EFGR/ALK)

1 L CPNM without driver alterations EFGR/ALK, combinations non-squamous Gandhi KN 189, NEJM 2018;

1 L CPNM without driver alterations EFGR/ALK, combinations non-squamous Gandhi KN 189, NEJM 2018; Socinsky, Impower 150, NEJM 2018; Papadimitrakopoulou, IMpower 132, WCLC 2018; Cappuzzo, IMPOWER 130, ESMO 2018 Paz-Ares LG, KN 407, NEJM 2018; Jotte RM , IMPower 131, ASCO 2018

Clinical Practice Guidelines: 1 L CPNM without driver alterations EFGR/ALK, monotherapy, regardless of PD-L

Clinical Practice Guidelines: 1 L CPNM without driver alterations EFGR/ALK, monotherapy, regardless of PD-L 1 Trial KN-189 Qo. L/toxicity ESMO-MCBS OS gain: NA (>3 months; NR at 0. 49 (0. 38 -0. 64) 21 months). 2 -year survival gain: NA yet OS gain: 4. 5 months. 0. 78 (0. 64 -0. 96) 2 -year survival gain: NR Similar toxicity profile. Better Qo. L. IA MCBS 4 (Form 2 a) Slightly worse toxicity profile. IA Qo. L not reported MCBS NA yet IA IMPower 132 OS gain: 4. 5 months. 2 -year survival gain: NR 0. 81 (0. 64 -1. 03) Slightly worse toxicity profile. IB Qo. L not reported MCBS NA yet IB KN-407 OS gain: 4. 6 months. 2 -year survival gain: NA yet OS gain: 0. 1 months. 2 -year survival gain: 7. 8% In PD-L 1 <1%: PFS gain: 0. 9 months 0. 64 (0. 49 -0. 85) Similar toxicity profile. Qo. L not reported Slightly worse toxicity profile. Qo. L not reported Increased toxicity. No Qo. L reported. Improved PROs IA IMPower 150 IMPower 131 CM 227 Absolute OS gain In TMB high: PFS gain: 1. 8 months OS HR (95% CI) 0. 96 (0. 78 -1. 18) In PD-L 1 <1%: HR for progression 0. 74 (0. 58– 0. 94) In TMB high: HR for progression 0. 58 (0. 41– 0. 81) IA MCBS NA yet IB MCBS NA yet In PD-L 1 <1%: 1 (Form 2 b) In TMB high: IA MCBS NA yet (Form 2 b) SEOM IA IB -

Clinical Practice Guidelines: Summary MCBS with IO First Line i) IO mono NSCLC ii)

Clinical Practice Guidelines: Summary MCBS with IO First Line i) IO mono NSCLC ii) Chemo-IO No-squamous Squamous iii) IO-IO Trials Lo. E/Go. R MCBS Score KN-024* IA 5 KN-042 ? KN-189* IA 4 IMPower 150* IA ? IMPower 132 IB ? KN-407* IA ? IMPower 131 IB ? CM-227 TMB high IA ? PD-L 1 1%, 20%, 50% ? EMA approvals from January 2016 to 20 September 2018; ESMO-MCBS version 1. 1 ; Cherny NI, Ann Oncol 2017; Planchard, Ann Oncol 2018

NCCN Guidelines v. 3: Stage IV NSCLC (no DRIVERS)

NCCN Guidelines v. 3: Stage IV NSCLC (no DRIVERS)

NCCN Guidelines v. 4: Stage IV NSCLC (no DRIVERS)

NCCN Guidelines v. 4: Stage IV NSCLC (no DRIVERS)

ESMO 2018 Guidelines: Stage IV Non-Squamous (no DRIVERS) Planchard D, et al. Ann Oncol.

ESMO 2018 Guidelines: Stage IV Non-Squamous (no DRIVERS) Planchard D, et al. Ann Oncol. 2018

ESMO 2018 Guidelines: Stage IV Squamous Planchard D, et al. Ann Oncol. 2018

ESMO 2018 Guidelines: Stage IV Squamous Planchard D, et al. Ann Oncol. 2018

SEOM 2018 Guidelines: Stage IV NSCLC (no DRIVERS) PS 0 -1 SCC non-SCC Platinum

SEOM 2018 Guidelines: Stage IV NSCLC (no DRIVERS) PS 0 -1 SCC non-SCC Platinum based-CT (I, A) Platinum+Taxane+Pembrolizumab#(I, A) Platinum+Taxane+Atezolizumab#(I, B) Platinum+Pemetrexed (II, A) Taxol+CBDCA+Bevacizumab (I, A) Paclitaxel+CBDCA+Bev+Atezolizumab# (I, A) Platinum+Pemetrexed+Pembrolizumab(I, A) Platinum+Pemetrexed+Atezolizumab#(I, b) 2 nd line If no prior IO: • Nivolumab (IA) • Atezolizumab (IA) • Pembrolizumab (PD-L 1 + >1%) (IA) Docetaxel (IB) 3 rd line Docetaxel (if not previously given) CT, chemotherapy; SCC, squamous; BSC, best supportive care (*) combination of immunotherapy + CT may be considered# # Not EMA approved PS 3 -4 PD-L 1≥ 50% SCC and non-SCC PD-L 1< 50% 1 st line PS 2 If no prior IO: • Nivolumab (IA) • Atezolizumab (IA) • Pembrolizumab (PD-L 1 + >1%) (IA) Docetaxel (IB)+/- Nintedanib (II, B) Pemetrexed(I, B) (if not previously given) Docetaxel +/- Nintedanib Pemetrexed (if not previously given) Single agent CT (I, B) Carboplatin-based CT (II, A) Pembrolizumab (I, A)(*) Platinum based-CT Docetaxel + Nintedanib (non-SCC) Pemetrexed (non-SCC) Docetaxel Majem, CTO 2018 BSC (II, B)

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver

Clinical Practice Guidelines for IO in NSCLC: Outlook 1) 1 L CPNM without driver alterations (EFGR/ALK): A. Any positive PD-L 1 B. Regardless of PD-L 1 2) 2 L CPNM without driver alterations (EFGR/ALK)

Immunotherapy a game-changer: cure? Phase I Long Follow up 4 y OS phase I

Immunotherapy a game-changer: cure? Phase I Long Follow up 4 y OS phase I KEYNOTE 001, Pembro 5 y OS phase 1 CA 209 -003, Nivo Median OS (95% CI), mo Overall (N = 129) 9. 9 (7. 8, 12. 4) 3 y OS 20% Pembrolizumab up to PD 4 y OS, 16% 2 years Nivolumab Previously treated cohort Felip E, ASCO 2018 Brahmer, AACR 2018

Second Line NSCLC (phase 3 trials) Brahmer, NEJM 2015 ; Borghaei, NEJM 2015 ;

Second Line NSCLC (phase 3 trials) Brahmer, NEJM 2015 ; Borghaei, NEJM 2015 ; Felip, ESMO 2017; Herbst, Lancet Oncol 2016; Herbst, ESMO 2016; Herbst, ASCO 2017; Rittmeyer, Lancet 2017

Clinical Practice Guidelines: 2 L CPNM without driver alterations EFGR/ALK, monotherapy Trial Absolute OS

Clinical Practice Guidelines: 2 L CPNM without driver alterations EFGR/ALK, monotherapy Trial Absolute OS gain OS HR (95% CI) Qo. L/toxicity ESMO-MCBS SEOM NCCN Check. Mate 017 OS gain: 3. 2 months 2 -year survival gain: 15% 0. 59 (0. 44 -0. 79) Improved toxicity profile. IA Qo. L not reported MCBS 5 (Form 2 a) IA Category 1 Check. Mate 057 OS gain: 2. 8 months. 2 -year survival gain: 13% 0. 73 (0. 59 -0. 89) Improved toxicity profile. IA MCBS 5 (Form 2 a) IA Category 1 KN-010 2 -year survival gain: 15. 6% 0. 71 (0. 58 -0. 88) Improved toxicity profile. IA MCBS 5 (Form 2 a) IA Category 1 OAK OS gain: 4. 2 months 0. 73 (0. 62 -0. 87) Improved toxicity profile. IA MCBS 5 (Form 2 a) IA Category 1

Clinical Practice Guidelines: Summary MCBS with IO Second Line IO mono Trial Squamous Non-squamous

Clinical Practice Guidelines: Summary MCBS with IO Second Line IO mono Trial Squamous Non-squamous NSCLC Lo. E/Go. R MCBS Score IA 5 KN-010 (≥ 1%) IA 5 OAK IA 5 Check. Mate 017 Check. Mate 057

Clinical Practice Guidelines: Fragile Patients PS ≥ 2 Elderly * Check. Mate 153; Check.

Clinical Practice Guidelines: Fragile Patients PS ≥ 2 Elderly * Check. Mate 153; Check. Mate 171 ** KN 024; Check. Mate 026 NCCN ESMO SEOM Chemotherapy Cat 2 A IA IB, IIA IO - IIIB* - NCCN ESMO SEOM Chemotherapy - IA (doublet) IB (single agent) IB IO - IIIA** IB

Take Home Messages • Immunotherapy (alone or in combination) is a new So. C

Take Home Messages • Immunotherapy (alone or in combination) is a new So. C in First Line treatment • IO monotherapy, less toxic than chemo, reserved for PD-L 1 ≥ 50% and in second line if not previously given. Not enough evidence in PD-L 1 1 -49%. • ¿When do we associate chemotherapy? • If PD-L 1 UK or <50% (agressive biology ? higher ORR) • Which chemo? Are they equal? Used schedules as in trials • ¿When do we associate another IO? • TMB high (≥ 10 mut/Mb)? CM-227 final analysis awaited • ¿When do we spare IO? • Contraindications (severe autoinmunes diseases, esteroids/IS) • ECOG ≥ 2? • PD-L 1 <1% + TMB low?

Thank you for your attention!!! nreguart@clinic. cat

Thank you for your attention!!! nreguart@clinic. cat