Carcinoma escamoso: optimizacion de tratamiento

Noemi Reguart

Hospital Clínic Barcelona

National Cancer Database (US)

1998-1999 2000-2003 2004-2007 2008-2011

SCC 35% 28% 26% 27%

Non SCC 65% 72% 75% 72%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Incidence of SCC

27%

M. Behera WCLC 2015

An oncology outcomes database administered by the American College of Surgeons and the American Cancer Society

NSCLC Classification

X40

Courtesy of J.C. Soria

Imielinski, TCGA, Nature 2012

178 resected lung SqCC

The Cancer Genome Atlas (TCGA) initiative

Squamous NSCLC has a high somatic mutation burden and complex tumor genetic alterations

TCGA : Focal copy number alterations in SCC

Amplifications Deletions

MYCL MCL1

REL NFE2L2

SOX2 PDGFRA

EGFR FGFR1

CCND1

CRKL

ERBB2

MDM2

LRP1B ERBB4 FOXP1

CSMD1

CDKN2A

PTEN

RB1

The Cancer Genome Atlas (TCGA) initiative Imielinski, TCGA, Nature 2012

MINI13.05: Marc Ladanyi – Discussant

Cancer Discovery, April 30, 2015

• Comprehensive genomic profiling of 79 stage IV SQCLCs • 2 major SqCLC subtypes: FGFR1 amplified and PI3K aberrant. • PI3K-aberrant tumors had worse survival and more brain mets

PI3K and FGFR1 the 2 main pathways?

Paik P et al, Cancer Discovery 2015

Mountain, Chest 1997

Most common Driver mutations in lung cancer

Lung Cancer Consortium, ASCO 2011; Perez-Moreno et al. Clin Cancer Res 2012; Y. Shi , WCLC 2015

Squamous cell Adenocarcinoma

Gene Lung ADC Lung Squamous Cell

EGFR 14%, most at known sites Amplification (7%), rare non-canonical mutation (L861Q)

KRAS 31% mutation 1%, HRAS more common

BRAF 10%, 2% (V600/601) 4%, (no V600/601)

PIK3CA 7% mutation 16% mutation

ERBB2 5% mutation 3% non-canonical, rare amplification (<5%)

FGFRs 2% mutation 10% amplification, 12% mutation, fusions

DDRs 3% mutation 4% mutation

Schiller et al. N Engl J Med 2002

Study

arm

OS

(mo)

1 year

(%)

PCb 8.6 38

CV 8.1 36

Study arm

OS (mo)

1 year (%)

PC 7.8 31

GC 8.1 36

DC 7.4 31

PCb 8.1 34

Study

arm

OS

(mo)

1 year

(%)

PCb 9.9 43

GC 9.8 37

CV 9.5 37

Kelly et al. J Clin Oncol 2001 Scagliotti, et al. J Clin Oncol 2002

Pacli + carbo (PCb)

Cis + vin (CV)

Overa

ll surv

ival %

100

80

60

40

20

0

0

Months Months

Overa

ll surv

ival

30

Pacli + cis (PC)

Gem + cis (GC)

Doc + cis (DC)

Pacli + carbo (PCb)

5 10 15 20 25

Pacli + carbo (PCb)

Gem + cis (GC)

Cis + vin (CV)

Months

0

1.0

0.9

0.6

0.5

0.4

0.3

0.8

0.7

0.2

0.1

0

1.0

0.9

0.6

0.5

0.4

0.3

0.8

0.7

0.2

0.1

0

Overa

ll surv

ival

30 5 10 15 20 25 0 30 5 10 15 20 25

2002 2001 2002

First line Chemotherapy

N. Thatcher ELCC 2015

New chemo standards?............ Probably not

Nab-Paclitaxel WJOG5208L

Nab-Paclitax. Carboplatin

Paclitaxel CBDCA

Docetaxel Nedaplatin

Docetaxel CDDP

N 229 221 172 168

ORR (%) 41 24* 55.8 53

PFS (mo) 5.6 5.7 4.9 4.5*

OS (mo) 10.7 9.5 13.6 11.4*

G3-5 AE (%) 70 68 92 90

* Statistically significant

M. Socinski, Ann Oncol 2013 – Takehito Shukuya, Lancet Oncology 2015

♦ Primary objective: OS

♦ Patient selection not based on EGFR protein expression

♦ Mandatory tissue collection from archived tumor

Randomization stratified by: ECOG PS (0-1 vs. 2) and geographic region (North America, Europe, and Australia; vs. South America, South Africa, and India; vs. Eastern Asia)

Thatcher N. et al. Lancet Oncol 2015

PD

CRPRSD

PD

Neci + Gem-Cis q3w (N=545)

Necitumumab 800 mg D1, D8 Gemcitabine 1250 mg/m², D1, D8 Cisplatin 75 mg/m², D1

PD

Maximum of 6 cycles

First-line Stage IV Squamous-LC

ECOG PS 0-2

Neci q3w

800 mg D1, D8

Gem-Cis q3w (N=548)

Gemcitabine 1250 mg/m², D1, D8 Cisplatin 75 mg/m², D1

R

N=1093

.

• Necitumumab is a second-generation human IgG1 anti-EGFR monoclonal antibody

Time Since Randomization (Months)

Ove

rall

Su

rviv

al (%

)

16.5%

42.8%

Patients / events:

Neci + Gem-Cis: 545 / 418

Gem-Cis: 548 / 442

19.9%

47.7%

1yr OS

2yr OS

• 16% reduction risk of death, 1.6 month absolute improvement in OS • Similar RR 31% vs 29% (p ns)

Thatcher N. et al. Lancet Oncol 2015

SQUIRE Primary Outcome: Overall Survival (ITT)

GC+N

N=545

GC

N=548

Stratified HR (95% CI) 0.84 (0.74, 0.96)

Stratified p-value (log-rank) 0.01

Median, months (95% CI) 11.5 (10.4, 12.6) 9.9 (8.9, 11.1)

Thatcher et al. Lancet Oncol 2015; Paz-Ares Annals of Oncol 2016

EMA approved only in EGFR expressing tumours, IHC (DAKO PharmDx):

BUT only 5% tumors did not express EGFR (small sample size) OS H-Score >0 vs < 0: OS 11.7 vs 10 (HR 0.81)

SQUIRE Exploratory Analysis: EGFR H-Score

1. Fossella 2000; 2. Shepherd 2000; 3. Hanna 2004; 4. Shepherd 2005

< 9 months

Second Line………….very poor outcomes

5.7 5.6

7.5

4.6

8.37.9

6.7

4.7

0

1

2

3

4

5

6

7

8

9

Docetaxel Ifosfamide or vinorelbine

Docetaxel BSC Pemetrexed Docetaxel Erlotinib Placebo

TAX320 TAX317 JMEI BR.21

Med

ian

OS

(m

on

ths)

5.7 5.6

7.5

4.6

8.37.9

6.7

4.7

0

1

2

3

4

5

6

7

8

9

Docetaxel Ifosfamide or vinorelbine

Docetaxel BSC Pemetrexed Docetaxel Erlotinib Placebo

TAX320 TAX317 JMEI BR.21

Med

ian

OS

(m

on

ths)

Garon EB et al. Lancet 2014;384:665-73

• Primary endpoint: OS • Secondary: PFS, ORR, safety • Analysis by histology NOT preplanned

* Ramucirumab, a fully human monoclonal antibody that specifically binds VEGFR2

Squamous: 157 (25%)

Squamous: 171 (27%)

REVEL Primary Outcome: Overall Survival (ITT)

• 14% reduction risk of death, 1 month improvement in OS

Garon EB et al. Lancet 2014

REVEL: Overall Survival by Histology

Garon EB et al. Lancet 2014

* Subgroup analyses by histology in this study were not pre-planned

REVEL: AEs of interests by histology

Nonsquamous Squamous

Treatment Emergent Adverse Events Grade

Ramucirumab (N=465)

Placebo (N=441)

Ramucirumab (N=157)

Placebo (N=170)

Bleeding/ Haemorrhage*

Any 145 (31.2)† 60 (13.6) 36 (22.9) 33 (19.4)

3/4/5 11 (2.4) 8 (1.8) 4 (2.5) 5 (2.9)

Epistaxis Any 97 (20.9)† 30 (6.8) 19 (12.1)† 9 (5.3)

3/4/5 2 (0.4) 0 (0.0) 0 (0.0) 0 (0.0)

Gastrointestinal haemorrhage* Any 14 (3.0) 7 (1.6) 3 (1 .9) 3 (1.8)

3/4/5 3 (0.6) 1 (0.2) 1 (0.6) 1 (0.6)

Pulmonary haemorrhage* Any 34 (7.3) 25 (5.7) 15 (9.6) 21 (12.4)

3/4/5 5 (1.1) 4 (0.9) 3 (1.9) 4 (2.4)

Haemoptysis Any 25 (5.4) 16 (3.6) 11 (7.0) 16 (9.4)

3/4/5 3 (0.6) 2 (0.5) 1 (0.6) 2 (1.2)

Hypertension* Any 54 (11.6)† 23 (5.2) 14 (8.9) 6 (3.5)

3/4/5 27 (5.8)† 13 (2.9) 8 (5.1)† 0 (0.0)

Infusion-related reaction* Any 18 (3.9) 20 (4.5) 5 (3.2) 8 (4.7)

3/4/5 4 (0.9) 3 (0.7) 1 (0.6) 1 (0.6)

Proteinuria Any 15 (3.2)† 5 (1.1) 6 (3.8)† 0 (0.0)

3/4/5 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)

†P value <0.05 between treatment groups, comparison based on Fisher’s exact tests *Consolidated AE category comprising synonymous MedDRA preferred terms.

Garon EB et al. Lancet 2014

• *Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted †Dose reduction to 100 or 50 mg permitted

• ‡Tumor assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter

Key secondary endpoint

Overall survival

Other secondary endpoints: ORR, DCR,

tumor shrinkage, PRO, safety

1:1

Stratified by east Asian vs non-east Asian

Afatinib 40 mg* QD

Erlotinib 150 mg† QD

SCC of the lung (Stage IIIB/IV)1

Progressed after ≥4 cycles of a

first-line platinum-doublet

ECOG PS 0–1

Adequate organ function

Primary endpoint

PFS by

independent review‡

Soria, Lancet Oncol 2015

N=795

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

EstimatedPFSprobability

Timeofprogression-freesurvival(months)

0 3 6 9 12 15 18 21 24 27

Afatinib

n=398

Erlotinib

n=397

Median, months

(95% CI)

2.6

(2.0–2.9)1.9

(1.9–2.1)

HR (95% CI) 0.81 (0.69–0.96)

p value 0.0103

Afatinib

n=398

Erlotinib

n=397

Median, months

(95% CI)

7.9

(7.2–8.7)6.8

(5.9–7.8)

HR (95% CI) 0.81 (0.69–0.95)

p value 0.0077

3 6 9 12 15 3018 21 24 27

Timeofoverallsurvival(months)

0.2

0.4

0.6

0.8

1.0

0

EstimatedOSprobability

0

36.4%

28.2%22.0%

14.4%

LUX-Lung 8: Primary endpoint PFS

Soria, Lancet Oncol 2015

OS PFS

• 19% reduction risk of death, <1 month improvement in OS • Similar RR 6% vs 3% (p ns)

Subgroup Aberration present (%) HR (95% CI)†

LL8

LL8 subset* (n=238)

0.82 (0.71–0.96)‡

0.73 (0.56–0.96)

EGFR No (94.1)

Yes (5.9)

0.72 (0.54–0.95)

1.04 (0.33–3.25)

TP53 No (12.2)

Yes (87.8)

0.54 (0.24–1.24)

0.74 (0.55–0.99)

LRP1B No (60.5)

Yes (39.5)

0.74 (0.52–1.05)

0.73 (0.47–1.13)

MLL2 No (67.2)

Yes (32.8)

0.68 (0.49–0.96)

0.83 (0.52–1.32)

CDKN2A No (71.4)

Yes (28.6)

0.75 (0.54–1.03)

0.68 (0.40–1.14)

FAT3 No (72.3)

Yes (27.7)

0.69 (0.50–0.96)

0.75 (0.44–1.27)

EGFR No (93.7)

Yes (6.3)

0.76 (0.57–1.01)

0.42 (0.12–1.43)

SOX2 No (56.3)

Yes (43.7)

0.78 (0.54–1.11)

0.70 (0.46–1.07)

KLHL6 No (59.7)

Yes (40.3)

0.76 (0.54–1.08)

0.72 (0.46–1.12)

PIK3CA No (63.0)

Yes (37.0)

0.72 (0.51–1.02)

0.78 (0.50–1.23)

MAP3K13 No (67.2)

Yes (32.8)

0.80 (0.57–1.11)

0.66 (0.40–1.08)

BCL6 No (68.9)

Yes (31.1)

0.74 (0.54–1.03)

0.79 (0.47–1.32)

FGF12 No (71.4)

Yes (28.6)

0.76 (0.55–1.04)

0.77 (0.45–1.32)

ERBB No (71.0)

Yes (29.0)

0.74 (0.54–1.03)

0.70 (0.42–1.16)

FGF No (41.2)

Yes (58.8)

0.69 (0.45–1.06)

0.76 (0.53–1.08)

LUX-Lung 8: Predictive analysis by OS

0.5 0 1.5 2.0 1.0 2.5

Favors afatinib Favors erlotinib

SVs

Predefined

families:

any aberration

CNAs

J.C. Soria WCLC 2015

• NONE Genetic Abnormality is predictive of benefit to afatinib treatment compared with erlotinib

• DO NOT not appear to be associated with longer PFS/OS

Jan 2016 June 2016 June 2017

Case report by N.Reguart, N. Vilariño

Squamous, male, heavy smoker…I can’t believe it!

Lawrence et al. Nature 2014

Lung adenoc 8.9 and SCC 8.1 mut/MB estimated from exome sequencing

Squamous cell lung cancer has a very high rate of somatic mutations

Squamous

LC

TMB is higher in patients with smoking history

Govindan et al. Cell 2012

Smoking history

Ock et al. Clin Cancer Res 2016

TME immuno type I common in lung tumors TILs+

PD-L1+

Type I

TILs-

PD-L1-

Type II

PD-L1-

TILs+

Type IV

PD-L1+

TILs-

Type III

EGFRmutantNSCLCALKrearrangedNSCLC

KRASNSCLCMELANOMA

PDL-1 TPS and histology

Aggarwal C, ASCO 2017

* Data from KEYNOTE-001, -010, and -024

PD-L1 TPS ≥1%_67%

PD-L1 TPS ≥50%_ 28%

CheckMate 017 - Study Design

• One pre-planned interim analysis for OS

• At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)

• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03

Patients stratified by region

and prior paclitaxel use

Nivolumab

3 mg/kg IV Q2W

until PD or

unacceptable toxicity

n = 135

Docetaxel

75 mg/m2 IV Q3W

until PD or

unacceptable toxicity

n = 137

Ra

nd

om

ize

1:1

• Primary Endpoint:

– OS

• Additional Endpoints:

Investigator-assessed ORR

Investigator-assessed PFS

Correlation between PD-L1

expression and efficacy

Safety

Quality of life (LCSS)

• Stage IIIb/IV SQ NSCLC

• 1 prior platinum doublet-based

chemotherapy

• ECOG PS 0–1

• Pre-treatment (archival or

fresh) tumor samples required

for PD-L1 analysis

N = 272

LCSS = Lung cancer symptom scale

100% SqCC

J. Brahmer, et al. N Engl J Med. 2015

CheckMate 017 in SCC: Primary endpoint OS

Based on August 2015 DBL. Symbols refer to censored observations.

1. J. Brahmer, et al. N Engl J Med. 2015; 2. Borghaei H et al. Poster presentation at ASCO 2016

Updated OS 2 years follow-up2

Nivolumab

Docetaxel

CheckMate 017: Squamous

Median OS Nivo = 9.2 months

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 24 30 332721

OS

(%

)

18-mo OS rate = 13%

Time (months)

18-mo OS rate = 28%

Overall Survival1

OS(%)

100

80

60

40

0

20

332724211815129630 30

Docetaxel

2-yrOS=23%

2-yrOS=8%Nivolumab

Time(months)

Nivolumab (n = 135)

Docetaxel (n = 137)

mOS mo, (95% CI)

9.2 (7.3–13.3)

6.0 (5.1–7.3)

# deaths 86 113

HR = 0.59 (95% CI: 0.44–0.79); P < 0.001

CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

Non-squamous (n = 74)

74 28 14 10 9 8 0 0 0

Years

1 y OS, 42%

2 y OS, 24%

3 y OS, 17% 5 y OS, 15% 20

40

60

80

100

0 0 1 2 3 4 5 6 7 8

Squamous (n = 54)

No. at Risk

54 20 12 10 8 8 3 0 1

OS

(%)

Years

1 y OS, 41%

2 y OS, 24%

3 y OS, 20% 5 y OS, 16%

20

40

60

80

100

0 0 1 2 3 4 5 6 7 8

Julie Brahmer, AACR 2017

1. Brahmer J, et al. New Engl J Med. 2015;373:123–135. 2. Spigel DR, et al. Presented at ASCO 2015, Abstract 8009. 3. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109.

PD-L1 expression

OS

≥1%

<1%

≥5%

<5%

≥10%

<10%

NQa

PFS

≥1%

<1%

≥5%

<5%

≥10%

<10%

NQa

Squamous NSCLC (CheckMate 017)1,2

NOT PREDICTIVE

Unstratified HR

Interaction P-value

0.69 0.56

0.58

0.53 0.47

0.70

0.50 0.41

0.70

0.39

0.67 0.70

0.66

0.54 0.16

0.75

0.58 0.35

0.70

0.45

Non-squamous NSCLC (CheckMate 057)3

PREDICTIVE

PD-L1-positive expression NQ PD-L1-negative expression

0.25 1.0 2.0

Nivolumab Docetaxel

0.5 0.125 1.0 0.5 2.0 0.25

Nivolumab Docetaxel

Unstratified HR

Interaction P-value

0.59 0.0646

0.90

0.43 0.0004

1.01

0.40 0.0002

1.00

0.91

0.70 0.0227

1.19

0.54 <0.0001

1.31

0.52 0.0002

1.24

1.06

CheckMate 017: Nivolumab benefit by PD-L1

KEYNOTE 010- Study Design

Herbst R, Lancet 16

N = 1034

22% SqCC

•Coprimary Endpoints:

–OS and PFS

* No staification by histology

OS, PD-L1 TPS ≥1% (total population)

0 5 10 15 20 25 0

10

20

30

40

50

60

70

80

90

100

Time, months

O v e r a

l l S

u r v

i v a l , %

344 346 343

259 255 212

115 124 79

49 56 33

12 6 1

0 0 0

Treatment Arm Median

(95% CI), mo Rate at

1 y HRa

(95% CI)

P

Pembro 2 mg/kg 10.4 (9.4-11.9) 43.2% 0.71 (0.58-0.88) 0.0008

Pembro 10 mg/kg 12.7 (10.0-17.3) 52.3% 0.61 (0.49-0.75) <0.0001

Docetaxel 8.5 (7.5-9.8) 34.6% — —

Pembro 2 vs 10 mg/kg: HR 1.17, 95% CI 0.94-1.45

KEYNOTE-010: OS in ITT by PDL-1 expression

Herbst R, Lancet 16

0 5 10 15 20 25 0

10

20

30

40

50

60

70

80

90

100

Time, months

O v e

r a l l

S u

r v i v

a l , %

139

151

152

110

115

90

51

60

38

20

25

19

3

1

1

0

0

0

Treatment Arm Median

(95% CI), mo HRa

(95% CI)

P

Pembro 2 mg/kg 14.9 (10.4-NR) 0.54 (0.38-0.77) 0.0002

Pembro 10 mg/kg 17.3 (11.8-NR) 0.50 (0.36-0.70) <0.0001

Docetaxel 8.2 (6.4-10.7) — —

OS, PD-L1 TPS ≥50% stratum

Pembro 2 vs 10 mg/kg: HR 1.12, 95% CI 0.77-1.62

KEYNOTE-010: 3 years OS

29.5%

22.1%

12.3%

Herbst RS, ASCO 2017

0.1 1 10

Overall Sex

Male Female

ECOG performance status 0 1

Histology Squamous Adenoc

521/1033

332/634 189/399

149/348 367/678

128/222 333/708

0.67 (0.56-0.80)

0.65 (0.52-0.81) 0.69 (0.51-0.94)

0.73 (0.52-1.02) 0.63 (0.51-0.78)

0.74 (0.50-1.09) 0.63 (0.50-0.79)

Subgroups No. of Events/

No. of Patients Hazard Ratio (95% CI)

Favors Pembrolizumab Favors Docetaxel

PD-L1 tumor proportion score 50% 1%–49%

204/442 317/591

0.53 (0.40-0.70) 0.76 (0.60-0.96)

Age <65 years 65 years

317/604 204/429

0.63 (0.50-0.79) 0.76 (0.57-1.02)

Tumor sample Archival New

266/455 255/578

0.70 (0.54-0.89) 0.64 (0.50-0.83)

EGFR status Mutant Wild type

46/86 447/875

0.88 (0.45-1.70) 0.66 (0.55-0.80)

Roy S. Herbst, ESMO ASIA 2015; Lancet 2015 Analysis cut-off date: September 30, 2015.

KEYNOTE-010: OS by Subgroups

KEYNOTE-010: Adjusted HR for OS (PD-L1 TPS ≥1%)

Herbst RS, ASCO 2017

Exploratory, post hoc, multivariate analyses

Analysis of all 550 patients of antitumor activity of Pembrolizumab in advanced NSCLC enrolled in KEYNOTE-001

Hellmann – WCLC 2015

KEYNOTE-010: Subgroup analysis by PDL-1

OAK- Study Design

Atezolizumab 1,200mg IV q3w Loss of clinical benefit

Docetaxel 75mg/m2 q3w

Locally advanced or metastatic previously

treated NSCLC

Locally advanced/metastatic

NSCLC

Tumour specimen available (FFPE)

1–2 prior lines of chemo including 1 line of platinum chemo

All PD-L1 status allowed

PD

R

1:1

Stratification factors Primary endpoints (first 850 enrolled patients)

Secondary endpoints

• PD-L1 IC expression (0 vs 1 vs 2 vs 3)

• Histology (squamous vs non-squamous)

• Prior chemotherapy regimens (1 vs 2)

• OS in ITT population

• OS in patients with ≥1% PD-L1 expression (TC1/2/3 or IC1/2/3)

• ORR, PFS, and DoR

• Safety

No crossover

Rittemeyer Lancet 17

26% SqCC

(N=850 enrolled)

Rittemeyer Lancet 17

aStratified HR

Atezolizumab Docetaxel

55%

40%

41%

27%

18-mo OS

12-mo OS

Median 13.8 vs 9.6 mo HR, 0.73a (95% CI, 0.62, 0.87) P = .0003

Minimum follow-up = 19 months

Ove

rall

Surv

ival

, %

Months

OAK study: OS ITT (N = 850)

Atezolizumab Docetaxel

Minimum follow-up 19 months

Landmark OS – 12 month 59% 46%

Landmark OS – 18 month 44% 31%

Median OS, mo (95% CI) 15.6 (13.3, 17.6) 11.2 (9.3, 12.6)

HR (95% CI) 0.73 (0.60, 0.89); P=0.0015

Atezolizumab Docetaxel

Minimum follow-up 19 months

Landmark OS – 12 month 42% 29%

Landmark OS – 18 month 30% 16%

Median OS, mo (95% CI) 8.9 (7.4, 12.8) 7.7 (6.3, 8.9)

HR (95% CI) 0.73 (0.54, 0.98); P=0.0383

Ove

rall s

urv

iva

l (%

)

Time(months)

Median 11.2 mo

(95% CI, 9.3, 12.6)

Median 15.6 mo

(95% CI, 13.3, 17.6)

Atezolizumab

Docetaxel

Atezolizumab

Docetaxel

Ove

rall s

urv

iva

l (%

)

Time(months)

Median 7.7 mo

(95% CI, 6.3, 8.9)

Median 8.9 mo

(95% CI, 7.4, 12.8)

non-squamous ITT (n=628) squamous ITT (n=222)

Rittmeyer, et al. Lancet 2016; Barlesi, et al. ESMO 2016 (abstr LBA44); Roche data on file

OAK: OS by histology

OAK: OS HR by histology and PD-L1

Gadgeel, et al. WCLC 2016 (abstr PL04a.02)

0.35

n (%) Subgroup

96 (15%)

Non-squamous

Median OS, mo Atezolizumab Docetaxel

22.5 8.7

HR

TC3 or IC3

TC2/3 or IC2/3

TC1/2/3 or IC1/2/3

TC0 and IC0

All non-squamous

Squamous

TC3 or IC3

TC2/3 or IC2/3

TC1/2/3 or IC1/2/3

TC0 and IC0

All squamous

ITT

628 (100%)

188 (30%)

333 (53%)

290 (46%)

41 (18%)

222 (100%)

77 (35%)

130 (59%)

89 (40%)

0.61

0.72

0.75

0.73

0.57

0.76

0.71

0.82

0.73

18.7 11.3

17.6 11.3

14.0 11.2

15.6 11.2

17.5

10.4

11.6

9.9

9.7

7.6

8.7

8.9

7.1

7.7

13.8 9.6 0.73 850

0.2 20.2 1 2

In favour of docetaxel Hazard Ratio In favour of atezolizumab

KEYNOTE-024: First Line Pembrolizumab

A Phase III, randomized, open-label study of pembrolizumab vs platinum-doublet chemotherapy as first-line therapy in patients with advanced or metastatic NSCLC that expresses PD-L1 in ≥50% of tumor cells

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

• Secondary endpoints: ORR, OS, safety, and tolerability

• Exploratory endpoint: DOR

Key Inclusion Criteria

• Advanced, previously untreated NSCLC

• PD-L1+ tumor expression ≥50%

• No EGFR sensitizing mutation or ALK translocation

• ECOG PS ≤ 1

Pembrolizumab 200 mg Q3W

(2 years)

R

1:1

Investigator choice of platinum-based chemotherapy

For 4–6 cycles

Optional crossover after disease progression

N=305

Reck M et al. N Engl J Med. 2016

50%

19% SqCC

Time (months)

62%

50%

0 3 6 9 12 15 18

0

20

40

60

80

100

PF

S,

%

48%

15%

80%

72%

0 3 6 9 12 15 18 21

0

20

40

60

80

100

Time (months)

OS

, %

70%

54%

KEYNOTE-024: PFS and OS (PD-L1 ≥50%)

Events,

n

Median,

mo

HR

(95% CI)

P

Pembro 73 10.3 0.50

(0.37-0.68) <0.001

Chemo 116 6.0

Events,

n

Median,

mo

HR

(95% CI)

P

Pembro 44 NR 0.60

(0.41-0.89) 0.005

Chemo 64 NR

Reck M et al. N Engl J Med. 2016

KEYNOTE-024: PFS in Subgroups

Reck M et al. N Engl J Med. 2016

New strategies for SqCC-NSCLC

Trial Eligibility N /EP Bio-marker Study Arms

Roche

IMpower-131

Stage IIIB/IV Squamous,

1200 PFS

All corners 1. Atezo+ Carbo/taxol_ Atezo man 2. Atezo+ Carbo/ Nab-paclitaxel_ Atezo

man 3. Carbo/ Nab-paclitaxel

MSD KN-407 Stage IV, Squamous

560 PFS/OS

All corners 1. Pembro + Carboplatin/ Nab-paclitaxel/taxol

2. Carboplatin/ Nab-paclitaxel/taxol

Roche IMpower-1103

Stage IIIB/IV, Chemonaïve SCC/non-SCC

570 PFS/OS

PD-L1 expression (TC or IC ≥ 1% [TC1/2/3 or IC1/2/3])

1. Atezo 2. Chemo

AZ MYSTIC Stage IIIB/IV SCC/non-SCC

675 PFS

Collected, not defined for eligibility

1. Durva + Treme 2. Durva 3. Chemo

AZ NEPTUNE Stage IIIB/IV SCC/non-SCC

800 OS

Collected, not defined for eligibility

1. Durva + Treme 2. Chemo

BMS CM-227 Stage IIIB/IV, SCC/non-SCC

1980 PFS/OS

PDL1 positive 1. Nivo 2. Nivo + Ipi 3. Nivo + Chemo 4. Chemo

NCT02451030 Phase I

Safety 1. Pembro + Necitumumab 48

ESMO Guidelines for Advanced Stage IV SCC

Silvia Novello, ESMO Guidelines, Annals of Oncol 2016

ESMO Guidelines for Advanced Stage IV SCC

Silvia Novello, ESMO Guidelines, Annals of Oncol 2016

* Nectimumumab and afatinib not recommended in updated NCCN

New Algorism for SqCC Lung Cancer Treatment

Yi-Chen Zhang, ESMO open 2016

OS HR 0.35

HR 0.88

OS HR 0.59, 0.74, 0.73

Necitumumab???

OS HR 0.84

Afatinib???

OS HR 0.81

OS HR 0.35

HR 0.88

OS HR 0.59, 0.74, 0.73

THANK YOU!!! nreguart@clinic.cat