Take home message

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Roma, 28 Marzo 2017

Take home message

Emilio Bria

Oncologia, Dipart. di Medicina,

Università di Verona, Az. Osp. Univ. Int., Verona

emilio.bria@univr.it

Immunoterapia nel tumore del polmone

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• Advisory Boards/Honoraria/Speakers’

fee/Consultant for:

– MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, Roche

• Research Support / Grants from:

– A.I.R.C. (Associazione Italiana Ricerca sul Cancro)

– I.A.S.L.C. (International Association for the Study of Lung Cancer)

– L.I.L.T. (Lega Italiana per la Lotta contro i Tumori) – Fondazione Cariverona

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Deriving ‘Take-Home Messagges’

………for

First Line

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IHC [PD-L1 Assay]

Clinical Indication #2

‘Evidence-Based’ Algorythm

‘Suspect’

NSCLC Morphology

Non-Squamous Squamous

EGFR wt

ALK/ROS1 non-rearr.

Clinical Indication #1

IHC [TTF-1, p63]

EGFR mut

ALK/ROS1 rearr.

Pathology Report

TKIs

(5)

Clinical Indicati on

‘Suspect’

NSCLC Morphology

Non-Squamous Squamous

IHC [TTF-1, p63]

IHC [ab-ALK D5F3] Ventana IHC [ab-PD-L1 22C3] Dako

Pathology Report

What if……….

ALK+

EGFR wt

ROS1 non-rearr.

EGFR mut

ROS1 rearr.

TKIs TPS>50% TPS<50%

PEMBRO Chemo

(6)

Molecular analysis – positive samples*

17,8%

31,9%

*AT ANY TIME, during the history of the disease

N° 1787 926 482 63 241 269 15 89

15,8%

3,7% 4%

20%

3,3%

Patients

Characteristics % (N)

Median age 68 years

(24 - 94)

< 45 years-old 3% (51)

Females 36% (642)

Males 64% (1145)

Current smokers 31% (551)

Former smokers 47% (848)

Never smokers 22% (388)

Adenocarcinoma 75.3% (1345)

Squamous 15.7% (280)

NSCLC NOS 3.9% (69)

1787 patients included

Predictive feature EGFR test EGFR mut ALK test ALK trans

Predictive histology (n=1448) 88% (1273) 24% (310) 61% (885) 9% (80)

Younger than 45 years (n= 51) 80% (41) 31.7% (13) 65% (33) 24% (8)

Never smokers (n= 386) 89% (345) 48.6% (168) 57% (220) 16.8% (37)

Females (n= 642) 86.6% (556) 35.4% (197) 56% (362) 11.3% (41)

Gobbini E et al, AIOM 2016

Molecular Testing in the ‘Real World’

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NSCLC: Molecular Portrait

mEGFR

15% re-ALK 5%

re-ROS1 1%

PD-L1 TPS>50%

20%

PD-L1 TPS 0-49%

59%

mEGFR re-ALK re-ROS1

PD-L1 TPS>50% PD-L1 TPS 0-49%

Time-to-report: 3-4 weeks?

(8)

Scagliotti G et al, JCO 2008

HISTOLOGY allows to improve survival ………..1.5-2 months

How much HISTOLOGY assessment does

contribute to Survival Improvement?

(9)

Scagliotti G et al, Lung Cancer 2014

How much MAINTAINANCE does contribute to Survival Improvement?

MAINTAINANCE allows to improve survival ………..

2.5-3 months

(10)

Zhou C et al, ASCO 2012 – Ann Oncol 2015

MOLECULAR PATHOLOGY allows to globally improve survival ………..over 3 yrs!

How much MOLECULAR PATHOLOGY does

contribute to Survival Improvement?

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Reck M et al, ESMO 2016 &

NEJM 2016

TOO EARLY TO ESTABLISH for:

• High Patients’ Attrition (Eligible 20-30%)

• Missing OS data considering cross-over

• High censoring rate

If Target HR for PFS reached, tested for OS superiority

How much targeting PD-L1-ADDICTION does

contribute to Survival Improvement?

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Remon J et al, BMC Cancer 2017

Upcoming First-line Strategies for I-O

?

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Deriving ‘Take-Home Messagges’

………for ≧ Second

Line

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NSCLC: Molecular Portrait

mEGFR

15% re-ALK 5%

re-ROS1 1%

PD-L1 TPS>50%

20%

PD-L1 TPS 0-49%

59%

mEGFR re-ALK re-ROS1

PD-L1 TPS>50% PD-L1 TPS 0-49%

• How much will be the relative benefit of I-O

for these (pre-treated) patients?

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2° line Nivolumab: no restrictions according to histology or PD-L1…………EVEN IF………

Borghaei H et al, NEJM 2015 Reckamp KL et al, WCLC 2015

Squamous Non-Squamous

Boundary p<0.03

Boundary <0.0408

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aKaplan–Meier estimates, with error bars indicating 95% Cls

bFor the comparison of the full Kaplan–Meier survival curves for each treatment group

Marginal benefit Relevant benefit

Borghaei H et al ASCO 2016

2° line Nivolumab (CM 057): Clinical (Prognostic)

Benefit According to PD-L1

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 The majority of patients with no PD- L1 expression are alive at month 3

 OS HR and separation of curves favoring NIVO are observed in the landmark analysis

Randomized Pts with PD-L1 <1%

Randomized Pts with PD-L1 <1% Alive at Month 3

Peters S et al WCLC 2016

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0 3 6 9 12 15 18 21 24 27

Overall Survival (Months)

Probability of Survival

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0 3 6 9 12 15 18 21 24 27

Overall Survival (Months)

Probability of Survival Nivolumab

Docetaxel

Nivo vs. DOC: OS in PD-L1 <1%

Death Rate (0 to 3 months)

NIVO (292 pts) DOC (N = 290 pts) 59 (20.2%) 44 (15.2%)

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0 10 20 30 40 50 60 70 80 90 100

Patients with factor in OS subgroup (%) 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 expression^a ECOG

PS

• Post-hoc, exploratory multivariate analysis suggested that nivolumab-treated

patients with poorer prognostic features and/or aggressive disease when combined with lower or no tumor PD-L1 expression may be at higher risk of death within the first 3 months

– These included the following known prognostic factors: <3 months since last treatment, PD as best response to prior treatment, and ECOG PS = 1

Nivo vs. DOC: OS in PD-L1 <1%

Peters S et al WCLC 2016

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Barlesi F et al, ESMO 2016

2° line Atezolizumab: no restrictions according to histology or PD-L1 …………EVEN IF………

OAK [Ph. III]

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Herbst R et al, Lancet 2016

2° line Pembrolizumab: PD-L1 will matter

Garon P et al, AACR 2015

TPS ≥1% TPS ≥50%

HR 0.54 (p=0.0002) HR 0.50 (p<0.0001)

HR 0.71 (p=0.0008) HR 0.61 (p<0.0001) Target HR 0.60

HR 0.71 (p=0.0008) HR 0.61 (p<0.0001).

(21)

Baas P et al, ASCO 2016

TPS 0/1-49%: how much is the benefit?

TPS 1-24% TPS 25-49%

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Efficacy of I-O in EGFR-Mutant patients [RCTs]

Phase III RCTs, I-O vs. DOC

PFS OS

KN010

CM057

OAK

Herbst R et al, Lancet 2016 Borghaei et al, NEJM 2015 Barlesi F et al, ESMO 2016

• High probability of differential effect of I-O

vs. Chemo according to EGFR mutation.

• High risk of qualitative (and quantitative)

interaction

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General Population

(n = 1585)

EGFR + (n=101) BORR n (%)

CR PR SD Mixed PD

Not determ.

284 10 (<1) 274 (17) 398 (25) 18 (1) 664 (42) 221 (14)

8 0 8 (8) 19 (19)

2 (2) 52 (51) 20 (20)

EGFR-Mutant - Median OS: 8.3 months (3.2-

13.4)

Median F.U.: 6.2 months (max 18.8 months)

Overall - Median OS:

12.1 months (10.6-13.6)

0 2 4 6 8 10 12 14 16 18 20

18%

[95% CI 16.0-19.8%]

8%

[95% CI 2.6-13.1%]

Overall EGFR+

ORR OS EAP NIVO ≧2nd line NSCLC

Efficacy of I-O in EGFR-Mutant patients [EAP]

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• As for EGFR, ALK (and ROS1), PD-L1 assay is going to identify a subset of patients whereas I-O might represent a

‘game-changer’.

• Pathologists must be supported (with resources and

technologies) to find the more cost-effective strategy to integrate multiple IHC platforms for disease

characterization and subsequent treatment optimization.

• 2

^nd

-line data support I-O for all patients, although many (serious) concerns are emerging:

– In the near future, patients candidate to receive 2^nd-line I-O will be those with PD-L1 expression of 1-49% or undetermined.

– Thus, if we target not simply ‘a survival advantage’ but ‘a clinically relevant benefit’, PD-L1, as well as clinical (i.e. prognostic features) and molecular parameters (EGFR mutation) should be considered

Conclusions

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