La Inmunoterapia en el tratamiento del CPNM avanzado...

La Inmunoterapia en el tratamiento del CPNM

avanzado.

¿Cuál, cómo, cuándo y a quiénes?

Rosario García Campelo

Medical Oncology Unit.

University Hospital A Coruña

FIRST LINE THERAPY… A TSUNAMI KEYNOTE 024…IO mono > 50%

IMPOWER 150…IO+CT+BEV all comers KEYNOTE 189…IO+CT all comers CHECKMATE 227…IO+IO (TMB)

KEYNOTE 042…IO mono PD-L1 positive KEYNOTE 407 IO+CT SCC

IMPOWER 131…IO+CT SCC

To treat or not to treat…

The sooner we can identify who will

benefit or better, who won´t the best…

Rationale of prescribing

Who will benefit?

PD-L1 as a biomarker in NSCLC

Khunger – JCO Precision Oncology 2017 Meta-analysis. N=6664 from phase I-III trials

KEYNOTE-024:

Study Design

KEY STUDY END POINTS

Primary: PFS (RECIST v1.1, per blinded independent central review)

Secondary: OS, ORR, safety

Exploratory (prespecified): DOR, patient-reported outcomes

Key Eligibility Criteria

• Untreated stage IV NSCLC

• PD-L1 TPS ≥50%

• No activating EGFR mutation or ALK

translocation

• No untreated brain metastases

• No active autoimmune disease

requiring systemic therapy

R (1:1)

N = 305

Pembrolizumab

200 mg IV Q3W

(2 years)

Platinum-doublet

chemotherapy

(4-6 cycles)

Pembrolizumab

200 mg IV Q3W

(2 years)

PDa

aTo be eligible for crossover, progressive disease (PD) had to be confirmed by

blinded, independent central radiology review, and all safety criteria had to be met.

KEYNOTE 024 1st line setting: PD-L1 selected NSCLC Overall Survival Updated Analysis

Events, n HR (95% CI)

Pembrolizumab 73 0.63

(0.47–0.86)

P = 0.002a Chemotherapy 96

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0

C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0

N o . a t r is k

Median (95% CI) 30.0 mo (18.3 mo–NR) 14.2 mo (9.8 mo–19.0 mo)

70.3% 54.8% 51.5%

34.5%

Crossover to

Pembrolizumab

N = 82

Brahmer et al. WCLC 2017

14% 6%

2%

30%

46%

2% EGFR mut

EML4-ALK

Ros-1

PD-L1+

CT

BRAF

30%

70%

0 0 0

PD-L1+

Chemotherapy

In 2018, before AACR…the certainties…

AFTER SUCH AN AMAZING AACR 2018…

and SO many good tweets…

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0

C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0

N o . a t r is k

70.3% 54.8% Median (95% CI)

30.0 mo (18.3 mo–NR) 14.2 mo (9.8 mo–19.0 mo)

KN 024 vs KN 189

Brahmer J et al. WCLC 2017. Gandhi L, et al. NEJM 2018

INDIVIDUALIZE

THERAPEUTIC DECISION

Pembrolizumab + pemetrexed/ platinum can be considered a new standard of

care for unpreviosuly treated advanced non-squamous NSCLC, independently of

PD-L1 status

OUTSTANDING RESULTS: despite the “low results” in control arm, more than

expected (at least for me) survival benefit

Median OS: NR vs 11.3 meses

Reduccion of risk of death by 51%

For those PD-L1 > 50% pembro monotherapy and pembro+platinum doublet are

valid treatment options: personalize decision

PD-L1 testing is still valid…and this is my personal opinion

My main thouhgts…

KEYNOTE-042: study design

Randomized, Open-label, Phase III Study Comparing Pembrolizumab Monotherapy vs a Platinum-Based Doublet in First Line, TPS ≥1% Stage IV

NSCLC

* Positive defined as proportion score (PS) of >1%, where weakly positive is 1–49% and strongly positive is ≥50%.

Primary Endpoint: OS in TPS ≥50% Secondary Endpoints: PFS (RECIST 1.1) PS ≥50%, OS and PFS (PS ≥1%), safety

Patients:

• Advanced/Metastatic NSCLC

• Measurable disease

• ECOG PS 0–1

• PD-L1 IHC positive*

(Stratification: TPS ≥50% vs

TPS 1–49%)

• ALK translocation negative

• No EGFR-sensitizing mutation

• No untreated CNS metastases

Off Study

R A N D O M I S E D

1:1 N=1240

PD

PD

Platinum Doublet Q3W, 4–6 cycles Paclitaxel/Carboplatin

or Pemetrexed/Carboplatin

(nonsquamous Hx, +/– pemetrexed maintenance)

Pembrolizumab 200 mg Q3W

Up to 2 years*

ClinicalTrials.gov identifier: NCT02220894

CNS: central nervous system; ECOG: Eastern Cooperative Oncology Group performance status; NSCLC: non-small-cell lung cancer; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PD: progressive disease; PD-L1: programmed cell death ligand 1; Q3W: every 3 weeks.

Reck M, et al. IMpower150 PFS analysis.

20

a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w.

IMpower150 study design

Arm A

Atezolizumabb +

Carboplatinc + Paclitaxeld

4 or 6 cycles

Atezolizumabb

Arm C (control)


+ Bevacizumabe

4 or 6 cycles

Bevacizumabe

Su

rviv

al

follo

w-u

p

Stage IV or

recurrent metastatic non-

squamous NSCLC

Chemotherapy-naivea

Tumour tissue available

for biomarker testing

Any PD-L1 IHC status

Stratification factors:

• Sex

• PD-L1 IHC expression

• Liver metastases

N = 1202

R

1:1:1

Arm B

Atezolizumabb +


+ Bevacizumabe

4 or 6 cycles

Atezolizumabb

+

Bevacizumabe

Maintenance therapy

(no crossover permitted)

Treated with

atezolizumab

until PD by

RECIST v1.1

or loss of

clinical benefit

AND/OR

Treated with

bevacizumab

until PD by

RECIST v1.1

The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical

benefit


INV-assessed PFS in ITT-WT (Arm B vs Arm C)

2

1

INV, investigator. Data cutoff: September 15, 2017

6.8 mo (95% CI: 6.0, 7.1)

8.3 mo (95% CI: 7.7, 9.8)

HR, 0.617 (95% CI: 0.517, 0.737)

P < 0.0001 Minimum follow-up: 9.5 mo

Median follow-up: ~15 mo

1st L IO+CT: Again PD-L1 matters…

IMPOWER 150

Reck – ESMO IO 2017


Promising preliminary OS benefit for Arm B vs Arm C was observed; next OS interim data are anticipated in 1H 2018

23

Data cutoff: September 15, 2017

Preliminary OS in ITT-WT (Arm B vs Arm C)

HR, 0.775 (95% CI: 0.619,

0.970)

P = 0.0262 Minimum follow-up: 9.5 mo

14.4 mo

(95% CI: 12.8, 17.1)

19.2 mo

(95% CI: 16.8, 26.1)

Arm B: atezo + bev + CP

Arm C: bev + CP

ASCO 2018, Abst 9002 mOS 19.2 vs 14.7 HR 0.78

THE PD-L1> 50%

Study PDL-1 Prevalence

KN024 PEMBRO MONO (>50%) 30%

KN189 PEMBRO (>50%) ≈33%

Imp150 TC/IC 3

17%

mPFS 10.3m (HR 0.5) 9.4 (HR 0.36) 12.6m (HR 0.39)

mOS 30m (HR 0.63) NR (0.42) NA

THE < 50%


KN189 1-50% ≈31%

Imp150 TC/IC 1,2,3

51%

mPFS 9m (HR 0.55) 11m (HR 0.5)

mOS NR (HR 0.55) 22.5 (HR 0.77)★

THE NEGATIVES <1%


KN189 <1%

31%

Imp150 TC0/IC0

48%

mPFS 6.1 (HR 0.75) 7.1m (HR 0.77)

mOS 15.2 (HR 0.59) 17.1 (HR 0.82)★

ASCO 2018 Abstr 9001: Nivo + QT vs QT in NSCLC with <1% tumor PD-L1 expression: Results from CheckMate 227. PFS HR 0.74 favoring Nivo+ QT

Second-Line IO: Does PD-L1 worth?

Brahmer –NEJM 2015 * Borghaei – NEJM 2015 * Felip -ESMO 2017 * Herbst – Lancet Oncol 2016 * Herbst – ESMO 2016 * Herbst – ASCO 2017 * Rittmeyer – Lancet 2017

TC3/IC3: 20.5 vs. 8.9 PDL1 ≥ 50%:

14.9 vs. 17.3 vs. 8.2 HR 0.54, HR 0.50

Pembro - PD-L1 ≥1%

Nivo - All comers Nivo - All comers

Atezo - All comers

2nd line IO: THE SAME SIGNAL, PD-L1 MATTERS

Nivolumab vs Docetaxel

CheckMate 017 Phase III

Nivolumab vs Docetaxel

CheckMate 057 Phase III

Pembrolizumb vs Docetaxel

KeyNote 010 Phase III

Atezolizumab vs Docetaxel

Poplar

Phase II

Atezoliuzmab vs Docetaxel

OAK Phase III

Line of T 2nd 100% 2nd line 100% 2nd line 65%, 3rd line 35% 2nd 70% 3rd 20%m > 3 10% 2nd l75% 3rd 25%

ORR 20% vs 9% 19% vs 12% 18% vs 18% 15% vs 15% 14 vs 13%

PFS m 3.5 vs 2.8 2.3 vs 4.2 3.9 vs 4 vs 4 2.7 vs 3 2.8 vs 4

OS m 9.2 vs 6 12.2 vs 9.4m

10.4-12.7 vs 8.5

12.7 vs 9.7

10.1 vs 8.6 (SCC) 13.8 vs 9.6

HR OS

HR PDL1-

HR PDL1+

0.59

0.70

0.50

0.73

0.87

0.40

0.71-0.61

NA

0.54-0.50

0.73

1.09

0.49

0.73

0.75

0.41

MY VIEW FOR THE SECOND LINE

THERAPY …today

Zehir et al. Nat Med 2017

Mutational landscape of metastatic cancer from

10,000 patients

CheckMate 227 Part 1 Study Design

Database lock: January 24, 2018; minimum follow-up: 11.2 months

N = 1189

<1% PD-L1 expression

N = 550

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 396

Histology-based chemotherapyb

n = 397

Nivolumab 240 mg Q2W n = 396

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 187

Histology-based chemotherapyb

n = 186

Nivolumab 360 mg Q3W + histology-based chemotherapyb

n = 177

R 1:1:1

Key Eligibility Criteria • Stage IV or recurrent NSCLC • No prior systemic therapy • No known sensitizing EGFR/ALK

alterations • ECOG PS 0–1

Stratified by SQ vs NSQ

R 1:1:1

aNCT02477826 bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cThe TMB co-primary analysis was conducted in the subset of patients randomized to nivolumab + ipilimumab or chemotherapy who had evaluable TMB ≥10 mut/Mb

≥1% PD-L1 expression

Nivolumab + ipilimumab n = 396

Chemotherapyb

n = 397

Patients for PD-L1 co-primary analysis

Co-primary endpoints: Nivolumab +

ipilimumab vs chemotherapy

• OS in PD-L1–selected populations

• PFS in TMB-selected populations

Nivolumab + ipilimumab n = 139

Chemotherapyb n = 160

Patients for TMB co-primary analysisc

TMB and Tumor PD-L1 Expression Identify Distinct and

Independent Populations of NSCLC

Tumor PD-L1 expression

aSymbols (dots) in the scatterplot may represent multiple data points, especially for patients with <1% tumor PD-L1 expression. The black line shows the relationship between TMB and PD-L1

expression as described by a linear regression model; bAmong patients in the nivolumab +ipilimumab and chemotherapy arms; TMB ≥10 mut/Mb, n = 299; TMB <10 mut/Mb, n = 380

TMB and tumor PD-L1 expressiona

PD-L1 expression (%)

TM

B (

nu

mb

er

of

mu

tati

on

s/M

b)

0

20

40

60

80

100

160

120

140

0 20 40 60 80 100

TMB ≥10 mut/Mbb

TMB <10 mut/Mbb

<1%

29% ≥1%

71%

<1%

29% ≥1%

71%

<1%

29% ≥1%

71%

<1%

29% ≥1%

71%

Co-primary Endpoint: PFS With Nivolumab + Ipilimumab

vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)a

Nivo + ipi 139 85 66 55 36 24 11 3 0

Chemo 160 103 51 17 7 6 4 0 0

Nivo + ipi (n = 139)

Chemo (n = 160)

Median PFS,b mo 7.2 5.4

HRc 97.5% CI

0.58 0.41, 0.81

P = 0.0002

Months

0

20

40

60

80

100

0 6 12 18 3 9 15 21 24

PF

S (

%)

Chemotherapy

Nivolumab + ipilimumab

1-y PFS = 43%

1-y PFS = 13%

aPer blinded independent central review (BICR); median (range) of follow-up in the co-primary analysis population was 13.6 mo (0.4, 25.1) for nivo + ipi and 13.2 mo (0.2, 26.0) for chemo; b95% CI: nivo + ipi (5.5, 13.2 mo), chemo (4.4, 5.8 mo); c95% CI: 0.43, 0.77 mo; dThe P-value for the treatment interaction was 0.0018

No. at risk

• In patients with TMB <10 mut/Mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35)d

Some reflections from Checkmate 227…and

TMB

Introduces nivolumab + ipilimumab as a new option for first-line NSCLC

with TMB ≥10 mut/Mb

Durable benefit while sparing first-line chemotherapy and preserving

effective second-line options

Do we need OS data…don´t forget in CM 026 PFS by TMB did not

correlate with OS

Access to TMB determination, turnaround time, analytical validation,

standarization…

Does TMB need prospective validation?

A BIG CHALLENGE

LIPI 0 (Good) = no factor, LIPI 1 (intermediate) = elevated LDH (ULN) or dNLR (>3) , LIPI 2 (Poor)= elevated LDH and dNLR dNLR= neutrophiles / (leucocytes-neutrophiles)

LIPI: Lung Immune Prognosis Index

Mezquita L, et al. JAMA Oncol 2018

16.5 vs. 10.0 vs. 4.8

6.3 vs. 3.7 vs. 2.0

PEMBROLIZUMAB

All histologies

PD-L1> 50%

CHEMOTHERAPY

Platinum doublet

DOCETAXEL +/- NINTEDANIB

AFATINIB

PEMETREXED (non-SCC)

IO Combos?

Pembro + CT

Atezo+ CT+Avastin

Non-squamous

PD-L1<50%

NIVO-IPI

All histologies

TMB > 10 (PD-L1 independent)

CHEMOTHERAPY

DOCETAXEL +/- NINTEDANIB

AFATINIB

PEMETREXED (non-SCC)

OTHER IMMUNOTHERAPIES

Adapted from Brahmer J, et al. ASCO 2017

NSCLC: Who, When, Which?

Just looking at the curves…

Borghaei H, et al. N Engl J Med. 2015;373(17):1627-1639.

CHECKMATE-057

Deleterious effect in a subgroup of patients?

Early deaths (<3 mo.): characteristics

Single Baseline Characteristics by OS With Nivolumab CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

Pa

tien

ts w

ith

fac

tor

in

OS

su

bg

rou

p (

%)

OS ≤3 months OS >3 months

<3 mo from

last TX

PD best resp.

No maint.

TX

>5 sites with

lesions

Bone mets

Liver mets

Never Current/ former

0 1 <1% ≥1% ≥5% ≥10%

EGFR mut.-pos.

Prior therapy

Smoking status

Baseline disease site

PD-L1 expressiona

ECOG PS

Rapid PD

High Tumor Burden

Poor PS

Peters – WCLC 2016

Hyperprogressive disease

Ferrara et al. WCLC 2017

N = 242

14% HPD with IO vs. 5% with CT Associated factors: > 2 metastatic sites poor outcome

Where is PS 2 in all these Phase

III clinical trials?

NOWHERE…

And Elderly >75y

7-11%

Checkmate 153: Overall Survival

Patients, n (%)

OS <70 years (n = 830)

≥70 years (n = 544)

ECOG PS 0−1 (n =

1,230)

ECOG PS 2

(n = 123)

Median OS, months (95% CI)

9.4 (8.3, 10.9)

10.3 (8.3, 11.6)

10.5 (9.3, 11.4)

3.9 (3.1, 6.3)

6-month OS rate, % (95% CI)

63 (59, 66)

63 (59, 67)

65 (62, 68)

42 (33, 51)

1-year OS rate, % (95% CI)

43 (39, 47)

45 (40, 50)

46 (43, 49)

23 (16, 32)

Spigel D, et al. WCLC 2016

All patients

(N = 809) ≥70 years (n = 279)

ECOG PS 2 (n = 98)

Median OS, months (95% CI)

9.9 (8.7, 13.1)

11.2 (7.6, NA)

5.4 (3.9, 8.3)


81 (78, 83) 78 (73, 83) 65 (54, 74)


67 (63, 70) 66 (59, 71) 46 (34, 57)

Checkmate 171: Overall Survival

Popat S, et al. ESMO 2017

PS 2…should we treat those pts with IO?

Immunotherapy in elderly patients OAK

KEYNOTE 010

CHECKMATE 057

CHECKMATE 017

Immunotherapy in brain mts

CHECKMATE 057

CHECKMATE 017

OAK

Lack of benefit of PD1 blocade vs docetaxel <br />in EGFR-mutant NSCLC (PFS)

EGFR mutant

OAK

KEYNOTE 010

Kowanetz M, et al. AACR 2018

ASCO 2018, Abst 9002 mOS EGFR mut HR 0.54

Baseline autoimmune disorders in NSCLC

In a SEER database, from 14% to 25% of NSCLC patients have ≥ 1 autoimmune diseases

Patients’ Characteristics with autoimmune disease

Most common Autoimmune diseases

Khan et al. JAMA Oncol., 2016. Khan et al. Lung Cancer, 2018 Courtesy Dr. Remón

%

In lung cancer patients, AD not associated higher mortality

UNDERLYING AUTO-

IMMUNE DISEASES

[VALOR]% [VALOR]%

[VALOR]% [VALOR]% [VALOR]%

[VALOR]%

0 0 0

20

40

60

80

100

1. Menzies AM, et al. Ann Oncol. 2017

Autoimmune disorder (AD) flare during anti-PD-1 treatment in patients with

advanced melanoma and pre-existing ADs (N=52)1

Overall AD flare requiring immuno-

suppression (N=52)

Polymyalgia rheumatica

(N=3)

Sjogren's syndrome

(N=2)

Psoriasis (N=8)

GI disorders (N=6)

Neurological disorders

(N=5)

Pre-existing AD

2 / 52 patients (4%) discontinued anti-PD-1 due to AD flare

15 / 52 patients (29%) had other imAEs, 4 of whom permanently discontinued

ORR was 33% (17 / 52 patients)

Pro

po

rtio

n o

f p

atie

nts

wit

h f

lare

, %

Immune thrombocytopaenic

purpura (N=2)

Rheumatoid arthritis (N=13)

AD, autoimmune disease; GI, gastrointestinal; ORR, objective response rate; PD-1, programmed cell death 1.

Leonardi G, et al. J Clin Oncol 2018

13p (23%) AID flare Gr 1-2: 87% Gr 3-4: 13% 2p discontinue IO 21 (38%) irAE Gr 1-2: 17p (74%) Gr 3-4: 6p (26%) 8p discontinue IO RR 22%

General health and performance status are important when considering whether an individual

patient would tolerate one of the higher grade irAEs.

At present there is no test to predict likelihood of

toxicity with immunotherapy.

1L Immunotherapy plus CT…

toxicities issues

Gandhi et al. NEJM 2018. Reck M, et al IO 2017. Reck M, et al., NEJM 2016

Arm B: atezo +

bev + CP (n = 393)

Arm C (control): bev + CP (n = 394)

All cause AE, n (%)

Grade 3-4

Grade 5

385 (98%)

242 (62%)

23 (6%)

390 (99%)

230 (58%)

21 (5%)

Treatment-related AE, n (%)

Grade 3-4

Grade 5a

371 (94%)

219 (56%)

11 (3%)

376 (95%)

188 (48%)

9 (2%)

Serious AE, n (%)

Treatment-related serious AE

165 (42%)

100 (25%)

134 (34%)

76 (19%)

AEs of special interest, n (%)b

Grade 3-4

Grade 5

199 (51%)

45 (11%)

0

108 (27%)

13 (3%)

0

Some notes to conclude…

BIOMARKERS FOR IO PD-L1, the first one, the imperfect one… still matters

TMB expensive and immature...

LIPI, why not?

Patient characteristics (PS 2, autoinmune diseases, EGFRmut, ALK….): IO is not the best option

Toxicity matters…overall with combinations

La Inmunoterapia en el tratamiento del CPNM avanzado...

Documents

Transcript of La Inmunoterapia en el tratamiento del CPNM avanzado...