Ruolo dei checkpoint inhibitors nelle neoplasie polmonari: le evidenze scientifiche e l’inserimento

dei checkpoint inhibitors nell’algoritmo decisionale del NSCLC

GRUPPO CCoordinatore: Diego Signorelli

Alessandro Inno

IRCCS Ospedale Sacro Cuore Don CalabriaNegrar, Verona

Immune Checkpoint Inhibitors for NSCLC:2nd line and beyond

Nivolumab Pembrolizumab Atezolizumab

StudyPhase

CheckMate-017 [1]

IIICheckMate-057 [2]

IIIKEYNOTE-010 [3]

II/IIIOAK [4]

III

n 135 vs 137 292 vs 290 345 vs 346 vs 343 425 vs 425+

Histology SQ (100%)Non-SQ (100%)

SQ (21%)Non-SQ (79%)

SQ (26%)Non-SQ (74%)

PD-L1 All comers All comers TPS≥1% All comers

IHC testtarget

28-8 DakoTC

28-8 DakoTC

22C3 DakoTC

SP 142 VentanaTC and IC

Schedule 3 mg/kgQ 14d

3 mg/kgQ 14d

2 mg/kg, 10 mg/kgQ 21d

1200 mgQ 21d

Control Arm Docetaxel 75 mg/m2

Q 21dDocetaxel 75 mg/m2

Q 21dDocetaxel 75 mg/m2

Q 21dDocetaxel 75 mg/m2

Q 21d

Line 100% 2nd 88% 2nd11% 3rd

69% 2nd20% 3rd

75% 2nd25% 3rd

mOS 9.2 vs 6.0HR 0.59, p<0.001

12.2 vs 9.4HR 0.73, p=0.002

10.4 vs 12.7 vs 8.5HR 0.71, p=0.0008*

13.8 vs 9.6HR 0.73, p=0.0003

1-yr survival 42% vs 24% 51% vs 39% 43.2% vs 52.3% vs 34.6% 55% vs 41%

mPFS 3.5 vs 2.8HR 0.62, p<0.001

2.3 vs 4.2 3.9 vs 4.0 vs 4.0 2.8 vs 4.0

RR 20% vs 9% 19% vs 12% 18% vs 18% vs 9% 14% vs 13%

TRAEs ≥ G3 7% vs 55% 10% vs 54% 13% vs 16% vs 35% 15% vs 43%

*pembrolizumab 2 mg/kg vs docetaxel; +primary analysis population

2nd line Checkpoint inhibitors for NSCLC: summary of evidence

1) Brahmer J, et al. N Engl J Med 2015;373(2):123-35. 2) Borghaei H, et al. N Engl J Med 2015;373(17):1627-39. 3) Herbst RS, et al. Lancet 2016;387(10027):1540-50. 4) Rittmeyer A, et al. Lancet 2017;389(10066):255-265.

2nd line Checkpoint inhibitors for NSCLC: a consistent benefit in OS

Vokes EE et al. Ann Oncol 2018;29(4):959-965. Herbst RS, et al. Lancet 2016;387(10027):1540-50.

Rittmeyer A, et al. Lancet 2017;389(10066):255-265.

2nd line Checkpoint inhibitors for NSCLC: PD-L1 expression

Checkmate 017[1]

Checkmate 057[2]

1) Brahmer J, et al. N Engl J Med 2015;373(2):123-35. 2) Borghaei H, et al. N Engl J Med 2015;373(17):1627-39. 3) Herbst RS, et al. Lancet 2016;387(10027):1540-50. 4) Rittmeyer A, et al. Lancet 2017;389(10066):255-265.

KEYNOTE 001[3]

OAK[4]

How long to treat?

• Continuous vs fixed duration• Treatment beyond progression

CheckMate 153: continuous vs 1-year fixed duration nivolumab

Spigel DR, et al. Ann Oncol 2017;28(Suppl5): Abstract 1297O.

CheckMate 153: continuous vs 1-year fixed duration nivolumab

Spigel DR, et al. Ann Oncol 2017;28(Suppl5): Abstract 1297O.

PFS from randomization

Response status PFS HR (95% CI)

CR/PR 0.45 (0.24-0.85)

SD 0.44 (0.17-1.09)

OS from randomization

OAK: OS post-PD in the atezolizumab arm by post-PD treatment

Gandara R, et al. ASCO 2017. Abstract #9001

Immune Checkpoint Inhibitors:1st line

KEYNOTE-024: study design

Reck M, et al. N Engl J Med 2016;375(19):1823-1833.

KEYNOTE-024: PFS and RR

Reck M, et al. N Engl J Med 2016;375(19):1823-1833.

KEYNOTE-024: Updated OS results(median follow-up 19.1 months)

Kaplan-Meier Estimate of OS: <br />Updated Analysis

Presented By Julie Brahmer at 2017 ASCO Annual Meeting

NSCLC avanzato: algoritmo decisionale in Italia nel 2018

Non-Squamous NSCLC Squamous NSCLC

EGFR/ALK/ROS1+

TKIs

EGFR/ALK/ROS1-PDL1 <50%

Platinum doublet +/-BevacizumabMaintenance

EGFR/ALK/ROS1-

PDL1 ≥50%PDL1 ≥50% PDL1<50%

Platinum doubletPembrolizumab

Platinum doublet +/-BevacizumabMaintenance

Platinum doublet

Nivolumab/AtezolizumabPembrolizumab if PDL1>1%

1st line

Docetaxel +/-nintedanib

2nd line

Nivolumab/AtezolizumabPembrolizumab if PDL1>1%

Docetaxel

The (next) future:

• 1st-line ICI for PDL1 <50%?

• Biomarkers (TMB)

• Combinations• ICI + Chemo• ICI + Chemo + anti-VEGF• ICI + ICI

KEYNOTE-042: study design

Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

KEYNOTE-042: OS

Lopes G, ASCO 2018.

OS TPS ≥ 50%

OS TPS ≥ 20%

OS TPS ≥ 1%

KEYNOTE-042: OS

Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

KEYNOTE-189 & KEYNOTE-407: study designsKEYNOTE-189

Primary Endpoints:- PSF- OS

KEYNOTE-407

Gandhi L, et al. N Engl J Med 2018;378(22):2078-2092.

Paz-Ares LG, et al. ASCO 2018

KEYNOTE-189 & KEYNOTE-407: OS data

Gandhi L, et al. N Engl J Med 2018;378(22):2078-2092.

Paz-Ares LG, et al. ASCO 2018

KEYNOTE-189

KEYNOTE-407

Jotte R, ASCO 2018

IMpower131

IMpower131: Atezolizumab+CnP vs CnP in SQ-NSCLC

Jotte R, et al. ASCO 2018

IMpower150: study design

Socinski MA, et al. N Engl J Med 2018;378(24):2288-2301.

IMpower150: OS in ITT-WT and Key subgroups

Socinski MA, et al. N Engl J Med 2018;378(24):2288-2301.

CheckMate 227

Hellmann MD, et al. N Engl J Med 2018;378(22):2093-2104.

Co-primary End Points for Nivolumab plus Ipilimumab vs. Chemotherapy:• Progression-free survival in populations selected on the basis of TMB• Overall survival in populations selected on the basis of PD-L1 expression

CheckMate 227: PFS in patients with high TMB

Hellmann MD, et al. N Engl J Med 2018;378(22):2093-2104.

PFS: Nivolumab + Chemotherapy and Nivolumab + Ipilimumab <br />By TMB

Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

CheckMate 227: exploratory analysis in PDL1 <1%

1st line Checkpoint inhibitors for NSCLC: summary of evidence

Immune Checkpoint Inhibitors:Stage III

PACIFIC trial: study design

Antonia SJ, et al. N Engl J Med 2017;377(20):1919-1929.

PACIFIC trial: PFS by BIRC

Antonia SJ, et al. N Engl J Med 2017;377(20):1919-1929.

PACIFIC trial: safety

Antonia SJ, et al. N Engl J Med 2017;377(20):1919-1929.

Aknowledgments

alessandro.inno@sacrocuore.it