Inmunoterapia: Nuevo paradigma de tratamiento en

primera línea de CPNCP avanzado

Delvys Rodríguez Abreu, MD

Medical Oncology Dept.

Hospital Universitario Insular de Gran Canaria. Spain

What we have in November 2017?

Monotherapy and Combinations.

• Monotherapy

Eberhardt – J Thorac Oncol 2015 Eberhardt – J Thorac Oncol 2015

Eberhardt – J Thorac Oncol 2015

Eberhardt – J Thorac Oncol 2015

Pembrolizumab and long-term survivors 1st line

8th TNM IASLC Classification, 3-y OS M1c: ~8%

PD-L1 > 50% (N=138) 3yOS: 29.7%

3-y

OS

ph

as

e I K

EY

NO

TE

00

1 T

ria

l

Leighl– ASCO 2017

Pembrolizumab up to PD

Leighl– ASCO 2017

PD-L1 >50%--58% N-27

3-y OS phase I KEYNOTE 001 Trial

Two „similar“ trials..

...but completely different outcomes! Carbone D et al, NEJM 2017; 376 (25): 2415-2426; Reck M et al, NEJM 2016; 375 (19):

1823-1833

KEYNOTE-024 Study Design (NCT02142738)

aOptional pemetrexed maintenance therapy for nonsquamous disease. bPermitted for nonsquamous disease only. cTPrior to the DMC recommendation and amendment 6, which permitted those in the chemotherapy arm to be offered pembrolizumab (based on interim analysis 2 data), patients were eligible for crossover when PD was confirmed by blinded, independent central radiology review.

Key Eligibility Criteria

• Untreated stage IV NSCLC

• PD-L1 TPS ≥50%

• ECOG PS 0–1

• No activating EGFR mutation or

ALK translocation

• No untreated brain metastases

• No active autoimmune disease

requiring systemic therapy

Pembrolizumab

200 mg IV Q3W (2 years)

R (1:1)

N = 305

Pembrolizumab

200 mg Q3W

for 2 years

Platinum-Doublet

Chemotherapya (4–6 cycles)

• Pemetrexed + carboplatinb

• Pemetrexed + cisplatinb

• Paclitaxel + carboplatin

• Gemcitabine + carboplatin

• Gemcitabine + cisplatin

End Points

Primary: PFS (RECIST v1.1, blinded

independent central review)

Key secondary: OS

Secondary: ORR, safety

Exploratory: DOR

PDc

Reck M, et al. NEJM 2016

Confirmed Objective Response Rate

Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, 2016.

0

10

20

30

40

50

60

Pembrolizumab Chemotherapy

OR

R, %

(95%

CI)

Δ17%

P = 0.0011

45%

28%

PR

CR

n = 6

n = 63

n = 41

n = 1

Reck M, et al. NEJM 2016

10,3 vs 6 months

Kaplan-Meier Estimate of OS: Updated Analysis

aNominal P value. NR, not reached. Data cutoff: July 10, 2017.

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%

2 ys OS 51.5% vs 34.5%

HR 0.63 62.3% Crossover

Brahmer et al. WCLC 2017

Efficacy of 2nd line chemo post IO?

10

mPFS2 on second-line therapy

21.5 (87.5% platinum-based)

versus 8.5 (94.4% IO)

Rina Hui et al, COSA 2017

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 sP

FS

2,

%

P e m b r o 1 5 4 1 3 4 1 1 7 1 0 8 9 6 8 0 7 3 6 4 3 8 1 2 3 0

C h e m o 1 5 1 1 2 2 1 0 0 6 4 5 7 4 2 3 5 2 5 1 3 7 2 0

N o . a t r is k

67.6% 41.8%

49.7% 19.0%

Events, n HR (95% CI)

Pembrolizumab 73 0.46 (0.34–0.62)

Chemotherapy 113

Median (95% CI) 21.5 mo (14.8 mo–NR) 8.5 mo (7.2–11.4 mo)

11

Phase 3 CheckMate 026 Study Design:

Nivolumab vs Chemotherapy in First-line NSCLC

Primary endpoint: PFS (≥5% PD-L1+)d

Secondary endpoints:

• PFS (≥1% PD-L1+)d

• OS

• ORRd

Nivolumab 3 mg/kg IV Q2W

n = 271

Randomize 1:1

Key eligibility criteria:

• Stage IV or recurrent NSCLC

• No prior systemic therapy for

advanced disease

• No EGFR/ALK mutations sensitive to

available targeted inhibitor therapy

• ≥1% PD-L1 expressiona

• CNS metastases permitted if

adequately treated at least 2 weeks

prior to randomization

Chemotherapy (histology dependent)b

Maximum of 6 cycles

n = 270

Disease progression or

unacceptable toxicity

Disease

progression

Crossover

nivolumabc

(optional)

Tumor scans Q6W until

wk 48 then Q12W

aDako 28-8 validated; archival tumor samples obtained ≤6 months before enrollment were permitted; PD-L1 testing was centralized

bSquamous: gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2; gemcitabine 1000 mg/m2 + carboplatin AUC 5; paclitaxel 200 mg/m2 + carboplatin AUC 6;

Non-squamous: pemetrexed 500 mg/m2 + cisplatin 75 mg/m2; pemetrexed 500 mg/m2 + carboplatin AUC 6; option for pemetrexed maintenance therapy cPermitted if crossover eligibility criteria met, including progression confirmed by independent radiology review dTumor response assessment for PFS and ORR per RECIST v1.1 as determined by independent central review

Stratification factors at randomization:

• PD-L1 expression (<5% vs ≥5%)a

• Histology (squamous vs non-squamous)

ESMO 2016 Socinski et al ESMO 2016

CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC

12

PFS and OS (≥5% PD-L1+)

Median OS,

months

14.4

Nivo

13.2

Chemo

Median PFS 4.2

Nivo

5.9

Chemo

Months

OS

(%

)

24 21 18 15 12 9 6 3 30

100

80

60

40

0

20

0 27

Nivolu

mab

Chemothe

rapy

HR = 1.02

Nivolumab is not better than chemotherapy in 1st line treatment of patients with PDL1 >/= 5%

Also not better among those with PDL1 >/= 50%

Socinski et al ESMO 2016

13

ORR by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

111 94 47 60 n =

47

2328

33

0

10

20

30

40

50

60

70

80

90

100

High Low/medium

ORR

(%)

TMB Subgroup

Nivolumab

Chemotherapy

Nivolumab Chemotherapy

47 30 26 21 16 12 4 1 60 42 22 15 9 7 4 1

111 54 30 15 9 7 2 1 1 94 65 37 23 15 12 5 0 0

Nivolumab n = 47 n = 60

9.7 (5.5, NA)

5.8 (4.4, 9.1)

Chemotherapy

Median PFS, months (95% CI)

High TMB

PF

S (

%)

3 6 9 12 15 18 21

No. at Risk by Time Months

100

90

80

70

60

50

40

30

20

10

0

0

Nivolumab

Chemotherapy

0 3 6 9 12

Months

15 18 21 24

Nivolumab

Chemotherapy

100

90

80

70

60

50

40

30

20

10

0

n = 111 n = 94

4.1 (2.8, 5.4)

6.9 (5.6, 8.8)

HR = 1.82 (95% CI: 1.30, 2.55)

Nivolumab Chemotherapy

(95% CI) Median PFS, months

Low/Medium TMB

HR = 0.62 (95% CI: 0.38, 1.00)

Carbone et al. NEJM 2017

Mutational burden will be a predictive factor

• Atezolizumab was dosed at 1200 mg IV q3w in all cohorts

• Primary endpoint: Independent review facility (IRF)-assessed objective response rate (ORR) per RECIST v1.1

• Secondary endpoints:

• IRF-assessed progression-free survival (PFS) and

duration of response (DOR) per RECIST v1.1

• Investigator (INV)-assessed ORR, PFS and DOR

per RECIST v1.1 and modified RECIST

• Overall survival (OS)

• Safety

BIRCH: Phase II Trial of Atezolizumab Monotherapy

in PD-L1–Selected Advanced NSCLC1

a PD-L1 expression evaluated by IHC using the VENTANA SP142 assay.

IHC, immunohistochemistry; PD, progressive disease.

1. Peters S, et al. J Clin Oncol. 2017. Carcereny et al., BIRCH. WCLC 2017 16

Cohort 1 (1L) No prior chemo

n = 138

Cohort 2 (2L) 1 prior platinum chemo

n = 271

Cohort 3 (3L+) ≥ 2 prior chemos (including 1 platinum)

n = 254

PD

Until loss of clinical benefit

• Locally advanced or

metastatic NSCLC

• Tumor PD-L1

expression by IHCa

(TC2/3 and/or IC2/3)

• ECOG PS 0 or 1

• No brain metastases

N = 667

• Baseline PD-L1 expression was scored by IHC

in tumor cells (TC) as percentage of PD-L1

expressing TC and in tumor-infiltrating immune

cells (IC) as percentage of tumor area

• TC2/3 or IC2/3 = TC or IC ≥ 5%

Response Rates and Drug Exposure

CR, complete response; PR, partial response; SD, stable disease.

TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing cells, respectively;

TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells; TC2 or IC2 = TC2/3 or IC2/3 excluding TC3 or IC3.

Investigator assessment. Error bars correspond to 95% CIs.

Data cutoff date: August 7, 2017. Carcereny et al., BIRCH. WCLC 2017 17

Atezolizumab

Exposure Mean (SD)

Treatment duration, mo 9.8 (10.8)

Dose intensity, % 98.5 (7.0)

No. of doses 14.6 (15.1) 0

20

40

60

80

100

CR/PR SD

TC2/3 or IC2/3

TC3 or IC3

TC2 or IC2

Fre

qu

en

cy,

%

n = 23 n = 36 n = 13 n = 21 n = 57 n = 36

32% 35%

26%

41%

18%

49%

• Durable survival was observed in all PD-L1 subgroups

Overall Survival – PD-L1 Subgroups

Carcereny et al., BIRCH. WCLC 2017 18

Median duration of survival follow-up = 34.3 months

Phase I/II study of Durvalumab in advanced NSCLC

Durvalumab 0.1–10 mg/kg q2w

15 mg/kg q3w x 1 year

Dose escalation

Dose expansion* 10 mg/kg q2w x 1 year

Squamous NSCLC

First line (n=29)

Second line (n=33)

Second line (n=56)

Third line + (n=75)

Non-squamous NSCLC

First line (n=30)

Third line + (n=81)

•Tumour assessments were conducted at weeks 6, 12, 16, then every 8 weeks during the treatment period.

•After 1 year of treatment, patients entered follow-up.

•Treatment beyond disease progression was permitted in the absence of clinical deterioration and if the investigator considered that the patient would continue to receive benefit.

•Upon progression during the follow-up period, retreatment was offered for up to an additional 12 months.

Antonia et al ASCO 2017

Tumor response rate by PDL1 expression only

n/N (%)

95% CI

High PD-L1

expression*

(n=154)

Low PD-L1

expression*

(n=116) Total

(n=287)†

RECIST response (ORR)‡ 39/154 (25.3%)

18.7–33.0

7/115 (6.1%)

2.5–12.1

50/285 (17.5%)

13.3–22.5

Treatment setting

First line 14/49 (28.6%)

16.6–43.3

1/9 (11.1%)

0.3–48.2

16/59 (27.1%)

16.4–40.3

Second line 12/46 (26.1%)

14.3–41.1

1/24 (4.2%)

0.1–21.1

15/80 (18.8%)

10.9–29.0

≥Third line 13/59 (22.0%)

12.3–34.7

5/82 (6.1%)

2.0–13.7

19/146 (13.0%)

8.0–19.6 Pembrolizumab

RR 45% in PDL1

expression >50%

Antonia et al ASCO 2017

More trials to come...

NCCN guidelines 1st line- version 9. 2017

• Combinations

Stromal PD-L1 modulation of T

cells

Immune cell modulation

of T cells

PD-L1/PD-1-mediated

inhibition of

tumor cell killing

IFNg-mediated

upregulation of tumor

PD-L1

Priming and activation

of T cells

PD-L2-mediated inhibition of

TH2 T cells

receptor

B7.1

Chen DS, Irving BA, Hodi FS.

Clin Cancer Res. 2012;18:6580.

As Good as Immunotherapy is… it only works this well for about 20-30%

of patients: So what about the other 80% of patients?

Multiple Factors Determine Sensitivity and Resistance in the Immune Microenvironment

Potential for benefit in all

cancers!

Unmet medical need remains: combination therapies are likely to be requiro improve patient outcomes

Targeted therapy

Immune checkpoint

monotherapy

Chemotherapy

Hypothetical KM curve

Time

Perc

en

t su

rviv

al

Combinations with

immunotherapy

Combinations

IO-IO IO-CT

Combined inhibition of tumor angiogenesis and the immune checkpoint

Manegold C, et al. JTO 12: 194, 2016 27

Hossein Borghaei, et al. WCLC 2017

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

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T i m e , m o n t h s

Pr

og

re

ss

io

n-

Fr

ee

S

ur

viv

al, %

60 51 43 32 24 22 17 9 1 0 63 42 35 25 18 13 8 5 1 0

N o . a t r i s k

Median (95% CI)

19.0 (8.5–NR)

8.9 (6.2–11.8)

57%

37%

52%

29%

Events,

n/N

HR (95%

CI)

Pembro + PC 26/60 0.54

(0.33–0.88)

P = 0.0067a PC alone 40/63

Δ24.8%

(95% CI, 7.2%‒40.9%)

P = 0.0029a

Progression-Free Survival

0 3 6 9 12 15 18 21 24 270

10

20

30

40

50

60

70

80

90

100

Time, months

Ove

rall S

urv

ival, %

60 57 55 51 46 44 36 22 7 1 63 58 57 51 43 39 29 18 9 0

No. at risk

Overall Survival Data Cut-Off: May 31, 2017

•a24 additional deaths since primary analysis (pembro + PC, n = 7; PC alone, n = 17). bP value is descriptive (one-sided P < 0.025).

Median Follow-Up: 18.7 mo

Events,

n/N

HR (95%

CI)

Pembro + PC 20/60a 0.59

(0.34–1.05)

P = 0.03b PC alone 31/63a

77%

69%

Median (95% CI)

NR (22.8–NR)

20.9 (14.9–NR)

70%

56%

Hossein Borghaei, et al. WCLC 2017

Crossover ~ 75%

IO-IO Combinations (Phase I) (Nivolumab/Ipilimumab – Durvalumab/Tremelimumab)

• Response: 23-43%

• Substantial Toxicity

• Conflicting Impact of PD-L1 expression:

23% 22%

29%

40%

0%

10%

20%

30%

40%

50%

60%

70%

All PDL-L1+ (>25%) PD-L1- (<25%) PD-L1- (0%)

Objective Response Rate (D10-20 q4/2w T1)

Durva + Treme

Goldmann J, ASCO 2017, abstract 9093 Goldmann J, ASCO 2017, abstract 9093

Goldmann J, ASCO 2017, abstract 9093; Antonia et al. Lancet Oncol. 2016;17(3):299-308

43

21

57

92

2313

28

50

0

20

40

60

80

100

… … … …

Nivo 3 + ipi 1 Q6/12W Nivo 3

Overall <1% ≥1% ≥50%

PD-L1

expression

• Response: 33 – 68%

• PFS: 5.5 – 8.4 m

• OS / 1 year OS: 11.6 – 19.2 m / 50 – 86%

• Grade 3/4 AEs: 25 – 72%

• No Impact of PD-L1 Expression

Rizvi N et al, J Clin Oncol 2016; Liu S et al, ASCO 2017; abstract

9092

Phase I Nivolumab + CT,

Atezolizumab + CT

CheckMate 012: First-Line Nivolumab + Chemotherapy in NSCLC

3-Year KM Estimates of OS Rates

• 3-year KM estimates of OS rates by chemotherapy regimen: nivolumab + pemetrexed–cisplatin (non-SQ only), 27%; nivolumab + paclitaxel–carboplatin (any histology), 32%; nivolumab + gemcitabine–cisplatin (SQ only), 8%

33

No. of patients at risk

56 54 40 30 20 16 13 9 4 1 0

1-year OS: 71%

2-year OS: 37%

3-year OS: 25%a

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48 54 57

OS

(%

)

Time since first dose (months)

aBetween 2 and 3 years, there were 6 deaths due to disease and 1 patient was censored due to loss to follow-up; KM = Kaplan–Meier

Selected phase 3 combination studies with immune checkpoint inhibitors in 1st-line advanced NSCLC

Pembrolizumab

Durvalumab

SOC=standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed September 2017.

Atezolizumab

An

ti-P

D-1

/PD

-L1

KEYNOTE-407 Pembrolizumab+Carbo+Paclitaxel (or nab)

Placebo+Carbo+Paclitaxel (or nab) Primary endpoint: OS, PFS

Stage IV Squamous NSCLC

N=560

Nivolumab Primary endpoints:

OS, PFS

CheckMate 227

Part 1

Nivolumab + ipilimumab

Nivolumab

Platinum-based chemotherapy Stage IV o recurrent NSCLC

N=2220

KEYNOTE-189 Pembrolizumab+Platinum+ Pemetrexed

Placebo+Platinum+ Pemetrexed Primary endpoint: PFS

Stage IV Non squamous NSCLC

N=570

IMpower 150

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint: PFS, OS Atezolizumab + bevacizumab + paclitaxel + carboplatin Stage IV non-squamous NSCLC

N=1202

IMpower 130 Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel Primary endpoint: PFS, OS

Stage IV non-squamous NSCLC

N=724

IMpower 131

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint: PFS, OS Atezolizumab + carboplatin + paclitaxel Stage IV squamous NSCLC

N=1021

Primary endpoint: PFS, OS MYSTIC

Durvalumab

Durvalumab + tremelimumab

SOC chemotherapy

Stage IV NSCLC

N=1118

Nivolumab + ipilimumab

Nivolumab + chemotherapy

Platinum-based chemotherapy

IMpower 132 Atezolizumab + platinum+ pemetrexed

Platinum + pemetrexed Primary endpoint: PFS, OS

Stage IV non-squamous NSCLC

N=568

NEPTUNE Durvalumab + tremelimumabl

SOC chemotherapy Primary endpoint: OS

Stage IV NSCLC

N=960

Primary endpoint: PFS POSEIDON

Durvalumab + SOC chemotherapy

Durvalumab + tremelimumab + SOC chemotherapy

SOC chemotherapy

Stage IV NSCLC

N=801

CheckMate 227

Part 2

Nivolumab + chemotherapy

Chemotherapy Primary endpoint: PFS, OS

Stage IV or recurrent NSCLC

N=480

PD-L1≥1%

PD-L1<1%

MYSTIC Study Design

• Phase 3, randomized, open-label, multicenter, global study (>175 sites across Asia, Australia, Europe, and North America)1-3

FPCD: 3Q2015 LPCD: 2Q2016

Data anticipated: mid-2017

Primary endpoint 1. PFS in all patients and in PD-L1(+) patients 2. OS in all patients

Secondary endpoints • ORR, DoR, PFS,e OSf

• Safety/tolerability, QoL • PK, immunogenicity

Follow-up for OS

Subsequent treatments Arm 1

Durvalumab iv 20 mg/kg q4w for 4 doses +

Tremelimumab iv 1 mg/kg q4w for 4 doses

Durvalumab iv 20 mg/kg q4w starting on Week 16, for 9 doses (n=364)

Arm 2 Durvalumab iv 20 mg/kg q4w for 13 doses,

for up to 12 months (n=364)

Arm 3 SoCb (n=364)

PD R

1:1:1

n=1118 Patients with locally

advanced or metastatic NSCLC (EGFR and

ALKwt,a Stage IV), 1L (N=1850)

Stratification

1. PD-L1 status (positive vs negative)

2. Histology (squamous vs nonsquamous)

IMpower150 (GO29436) All-Comer NSQ Phase III Trial

NSQ = non-squamous

A: Atezolizumab +

Carboplatin + Paclitaxel

C: Carboplatin + Paclitaxel +

Bevacizumab

B: Atezolizumab +

Carboplatin + Paclitaxel +

Bevacizumab

R

1:1

Su

rviv

al F

/U

PD or loss of clinical benefit

PD

Atezolizumab

Maintenance (No crossover permitted)

Atezolizumab +

Bevacizumab

Bevacizumab

PD or loss of clinical benefit

Stage IV Non-Squamous

NSCLC

Chemo naive

Stratification factors:

• Sex

• PD-L1 IHC expression

• Liver mets

N=1200

Secondary endpoints

• Investigator-assessed ORR, DOR, TTD, TIR

• IRF-assessed PFS; safety

Co-Primary endpoints

• Investigator-assessed PFS

• OS

PD-L1 stratification = TC3 and any IC vs T0/1/2 and IC2/3 vs TC0/1/2 and IC0/1

Borghaei et al. WCLC 2017, Reck et al. NEJM 2016, Leighl et al JCO 2017, Sandler et al. NEJM 2006, Schiller et al. NEJM 2002

PD1 2nd line

Chemotherapy

Anti-VEGFAnti-VEGF

How much improve in NSCLC?

Pro

po

rtio

n S

urv

ivin

g

PD1 1st line 51.5% at 2ys

IO-CT1st line 70% at 18 months

Some take home messages

• Monotherapy is the standard today in PD-L1>50%.

• Combinations must be better than monotherapy but not for all.

• Multiple remaining questions—?

• We need betters biomarkers.

• Different toxicities and more toxic in combo!!.

• Several phase 3 IO-CT and IO-IO now ongoing but close.

Thanks!!

Dr. Delvys Rodríguez Abreu

Servicio Oncología Médica

Hospital Universitario Insular de Gran Canaria

drodabr@gobiernodecanarias.org