Squamous Cell NSCLCAre we making progress?

Mark A. Socinski on behalf of Ramaswamy Govindan

Squamous Cell Lung Cancer: An Unmet Need

• Clinically challenging population – older, co-morbidities

• Platinum Doublets remain the standard of care – Gemcitabine- or Taxane-Based Regimens Commonly Used (? Role

of nab-paclitaxel)

• Antiangiogenic strategies are felt to be too toxic

• Pemetrexed no longer approved for use in this subset

• Cetuximab + cisplatin-vinorelbine (FLEX study): improved median OS (10.2 vs. 8.9 months) in SQLC – Not FDA-Approved

• New strategies are needed for this large group of patients

2

Lung Cancer Incidence by Histology1998-2002

Youlden DR et al. J Thorac Oncol 3:819-831, 2008

MALE FEMALE

LOCATION SQUAMOUS ADENOCARCINOMA SQUAMOUS ADENOCARCINOMA

Australia 27% 29% 17% 37%

Canada 30% 31% 18% 41%

France 41% 26% 20% 44%

Japan 33% 41% 11% 69%

Korea 46% 26% 17% 59%

Sweden 29% 30% 17% 40%

UK 40% 18% 28% 24%

USA 27% 31% 18% 38%

Lagging Outcomes for Squamous-Cell NSCLC

1-yr OS / 2-yr OSPeriod All (N=129,337) ADC (n=53,300) SQCC (n=22,944) HR*; P value

1990-1993 13.2 / 4.6 15.5 / 5.4 13.5 / 4.3 0.990; P=0.62

1994-1997 14.1 / 4.9 16.1 / 5.7 14.3 / 4.9 1.007; P=0.72

1998-2001 17.2 / 6.5 20.4 / 7.9 17.1 / 6.4 0.997; P=0.85

2002-2005 19.3 / 7.8 23.3 / 9.9 19.9 / 7.2 1.033; P=0.02

Epidemiological data show recent OS gains more pronounced for patients with adenocarcinoma histology, less for patients with squamous-cell tumors

Morgensztern D. J Thor Oncol 2009. vol 4 pp 1524ADC=AdenocarcinomaSQCC=Squamous Cell Carcinoma

* Comparison uses ADC data as reference

Most conspicuous outcome gap for squamous-cell NSCLC coincides with the introduction of

targeted therapies

1st Line Options

Chemo-naivePS 0-1

Stage IIIb/IV NSCLC

N = 1,050

Albumin-bound paclitaxel100 mg/m2 d1, 8, 15Carboplatin AUC 6 d121 Day Cycles

No Premedication

1:1

Paclitaxel 200 mg/m2 d1 Carboplatin AUC 6 d121 Day Cycles

With Premedication of Dexamethasone + Antihistamines

Phase III Study Design

Stratification factors:• Stage (IIIb vs IV)• Age (<70 vs >70)• Sex• Histology (squame vs nonsquame)• Geographic region

Primary Endpoint - ORR

Primary Endpoint ResultsObjective Responses – ITT

Response Ratio = 1.31(1.082 – 1.593)

P = 0.005Pe

rcen

t Res

pons

es 33%

25%

0%

10%

20%

30%

40%

IndependentRadiologic Review

nab-P/C

P/C

Renschler MF, Okamoto I, Hon JK, et al. Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line

therapy in patients with advanced non-small cell lung cancer [poster 110]. Poster presented at: Chicago Multidisciplinary Symposium in Thoracic

Oncology 2012; Sept 6-8; Chicago, IL.

ADENO, adenocarcinoma; CI, confidence interval; LC, large cell carcinoma; NOS, not otherwise specified; P/C, paclitaxel + carboplatin; sb, solvent-based; SCC, squamous cell carcinoma.

Independent Radiological Assessment of Overall Response Rate by Histology

a 95% CIs for response rate ratios are calculated according to the asymptotic 95% CI of the relative risk of nab-PC to sb-PC.

Conclusions nab-P/C improves ORR (primary endpoint) vs P/C (P=0.005),

particularly in patients with squamous histology (P<0.001) Secondary endpoints:

No significant difference in PFS or OS between treatment arms, with HRs trending in favor of nab-P/C

Strongest trends in favor of nab-P/C elderly patients and in squamous cell histology

Safety: increased rate of grade 3/4 anemia, reduced rates of grade 3/4 neurotoxicity and myalgias with nab-P/C

FLEX Phase III Trial: Cisplatin/Vinorelbine ± Cetuximab in EGFR+ Advanced NSCLC

Primary endpoint: OSSecondary endpoints: 1- and 2-year survival rates,

6-month and 12-month PFS rates, response rate, safety, quality of life

Pirker R et al. Lancet 373: 1525-31, 2009

Stage IIIB or IVEGFR-expressing

chemotherapy-naïve NSCLC

RANDOMIZE

Cisplatin/Vinorelbine+

CetuximabN=550

Cisplatin/VinorelbineN=550

Overall Survival Time: ITT

CT + Erbitux(n=557)

CT(n=568)

No. of events 421 447

Median OS, months[95% CI]

11.3[9.4–12.4]

10.1[9.1–10.9]

HR[95% CI]

0.871[0.762–0.996]

p-value 0.0441-year survival, % 47 42

MonthsAt risk

CTCT/Erbitux

568 383 225 134 48 0 0557 383 251 155 53 3 0

0 6 12 18 24 30 36

Ove

rall

Sur

viva

l (%

)

11.310.10

25

50

75

100

OS by Subgroups: Ethnic Origin and Histology (ITT)

 

Median OS (months)

CT + Erbitux CT HR [95% CI] p-value

All (n=1125) 11.3 10.1 0.871 [0.762–0.996]

0.044

Caucasian (n=946)

Adenoca. (n=413) SCC (n=347)

10.5 9.1 0.803[0.694–0.928]

0.003

12.0 10.3 0.815[0.649–1.023]

0.077

10.2 8.9 0.794[0.626–1.007]

0.057

Asian (n=121) 17.6 20.4 1.179[0.730–1.905]

0.499

FLEX survival: high EGFR expressionSquamous cell carcinoma (N=144)

Number of patients at risk

CT 69 42 2 017 7CT + cetuximab 75 52 10 032 19

Ove

rall

surv

ival

(%)

Months

0

10

20

30

40

50

60

70

80

90

100

180 6 12 24 30

Survival

Median 1-year

▬ CT + cetuximab 11.2 mo 44%

▬ CT 8.9 mo 25%

HR=0.62 [95% CI 0.43–0.88]

Necitumumab (IMC-11F8)• Fully human IgG1 monoclonal antibody to EGFR

• Increases antitumor activity when combined with gemcitabine/cisplatin or pemetrexed/cisplatin in NSCLC xenografts

• First in human study: DLT grade 3 headache associated with nausea, vomiting, and fever (2 pts) RP2D 800 mg weekly or every 2 weeks PR-2 pts; SD-16 pts

Kuenen B et al. Clin Cancer Res 15:1915-1923, 2010

RANDOMIZE

IMC-11F8

Arm B: CIS + GEM Cisplatin 75 mg/m2 (30-60 min IV), D1Gemcitabine 1250 mg/m2 (30 min IV), D1, 8

Arm A: IMC-11F8 + CIS + GEM IMC-11F8 800 mg (50-min IV), D1, 8Cisplatin 75 mg/m2 (30-60 min IV), D1Gemcitabine 1250 mg m2 (30 min IV), D1, 8

SQUIRE: phase III, 1st line NSCLC, squamous

947 patients Stage 4 NSCLC Squamous ECOG PS 0-2

PRCRSD

PD1

1

ECLIPSE Study Overview

16

R

Gemcitabine + Carboplatin

+ iniparib

Gemcitabine + CarboplatinPatient Population:• Advanced squamous cell

carcinoma

N= 825

Endpoints:Primary: OSSecondary: PFS, TTP, ORR, safety/tolerability, QoL

First Patient Enrolled: March 5, 2010

International, Open-label

Doses: Gemcitabine 1000 mg/m2 D 1 & 8 q3wk Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk

• Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks)

• Patients may remain on study regimen after 6 cycles if there is no evidence of PD or the presence of DLTs1:

1

Maintenance

Pemetrexed - Overall Survival by Histology

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pemetrexed 15.5 mos Pemetrexed 9.9 mos

Placebo 10.3 mos

Placebo 10.8 mos

Non-squamous (n=481) Squamous (n=182)

HR=0.70 (95% CI: 0.56-0.88) P =0.002

HR=1.07 (95% CI: 0.49–1.73) P =0.678

Surv

ival

Pro

babi

lity

Time (months) Time (months)

SATURN study design

Stratification factors:• EGFR IHC (positive vs negative vs indeterminate)• Stage (IIIB vs IV)• ECOG PS (0 vs 1)• CT regimen (cis/gem vs carbo/doc vs others)• Smoking history (current vs former vs never)• Region

1:1Chemonaïve

advanced NSCLCn=1,949

Non-PDn=889

4 cycles of 1st-line platinum-based doublet*

Placebo PD

Erlotinib150mg/day PD

Mandatory tumour sampling

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxelEGFR = epidermal growth factor receptor; IHC = immunohistochemistry

Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours

Secondary endpoints: Overall survival (OS) in all patients and those with EGFR

IHC+ tumours; OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL)

OS*: all patients (ITT)

0 3 6 9 12 15 18 21 24 27 30 33 36Time (months)

OS

prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=438) Placebo (n=451)

11.0 12.0

*OS is measured from time of randomisation into the maintenance phase;ITT = intent-to-treat population

HR=0.81 (0.70–0.95)Log-rank p=0.0088

1.00.4

Subgroup analysis of PFS

All

MaleFemale

CaucasianAsian

Adenocarcinoma Squamous-cell

Never smokerFormer smokerCurrent smoker

HR (95% CI) n0.71 (0.62–0.82) 884

0.78 (0.66–0.92) 6540.56 (0.42–0.76) 230

0.75 (0.64–0.88) 7440.58 (0.38–0.87) 128

0.60 (0.48–0.75) 4010.76 (0.60–0.95) 359

0.56 (0.38–0.81) 1520.66 (0.50–0.88) 2420.80 (0.67–0.97) 490

0.6 0.8 1.2Favourserlotinib

Favoursplacebo

HR

SATURN: OS in patients with SD on first-line chemotherapy according to histology

Squamous-cell 1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36Time (months)

10.6 13.7

HR=0.76 (0.59–1.00)Log-rank p=0.0457

Erlotinib (n=155) Placebo (n=142)

Non-squamous

HR=0.67 (0.48–0.92)Log-rank p=0.0116

Erlotinib (n=97) Placebo (n=93)

OS

prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36Time (months)

8.3 11.3

Measured from time of randomisation into the maintenance phase

Squamous NSCLC

• Standard remains platinum plus either a taxane or gemcitabine

• nab-paclitaxel may be more active• Maintenance options a bit more limited• Avoid bevacizumab and pemetrexed • Cetuximab could be a consideration in

selected patients – stay tuned for neci…

New Avenues for theTreatment for Squamous Cell NSCLC

ImmunotherapyNovel molecular targets

CANCER AND IMMUNE SYSTEM IMMUNOEDITING

T cell

TCR

CTLA-4

APC

MHC CD80/CD86

CD28

T-cell activation

T-cell inhibition

CTLA-4

CD80/CD86

T cell

TCR

APC

MHC

CD28

T cell

TCR

CTLA-4

APC

MHC CD80/CD86

T-cell activationand proliferation

ipilimumabblocksCTLA-4

Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010.

Mechanism of Action of Ipilimumab

26

Note: Steroids were given as premedication for chemotherapy*Phased : 2 doses of paclitaxel /carboplatin given prior to start of ipilimumab

ConcurrentIPI + Pac/Carbo

PhasedIPI + Pac/Carbo

Controlp + Pac/Carbo

Treatment Phase Maintenance Phase

Follow-upphase

C C C C C C

C C C C C C

C C C C C C

p p

p p p p p p

IPI IPI

IPI IPI

p p

q3w q12w

Follow-upphase

Follow-upphase

C: chemotherapy doublet (Pac 175mg/m2)/Carbo (AUC=6); IPI: Ipilimumab (10 mg IV); p: Placebo

p p IPI IPI IPI IPI

IPI IPI IPI IPIRANDOMIZE

1:1:1

n=130

First-line Stage IIIb/IV NSCLC (n=204)

ED-SCLC (n=130)

CA184-041: Study Schema

27

Summary Efficacy Results CA184041

End-point NSCLC SCLCConcurrent Phased Concurrent Phased

irPFSHR versus control (95%CI)

0.806(0.553, 1.174)

0.724 *(0.495, 1.059)

0.751(0.475, 1.188)

0.640 *(0.403, 1.016)

mWHO PFS HR versus control (95%CI)

0.882 (0.612, 1.271) ,

0.691 *(0.478, 0.999)

0.933 (0.588, 1.481)

0.927 (0.591, 1.453)

OSHR versus control (95%CI)

0.988(0.669, 1.460)

0.866(0.587, 1.278)

0.947 (0.585, 1.536)

0.753 (0.461, 1.232)

*statistically significant

Results favouring phased ipilimumab schedule across multiple end-points in both NSCLC and SCLC cohorts

Reck M, et al. Presented at the 2011 World Congress of Lung Cancer; July 3-7; Amsterdam, Netherlands. Abstract 1365.Lynch T, et al. Presented at: ESMO Congress, Milan, Italy; October 8-12, 2010; Poster and abstract 375PD.

First-line Stage IIIb/IV NSCLC (n=204)

ED-SCLC (n=130)

28

Activity by Baseline Histology (CA184041, NSCLC)

Non-Squamous

Response Patient group

Phased-Ipivs Control

Concurrent-Ipivs Control

SquamousOS

All

SquamousNon-SquamousmWHO-PFS

All

SquamousNon-SquamousirPFS

All

Phased Control

HR and 95% CI HR and 95% CI0.5 1 1.5 0.5 1 1.5

Favors Favors Control Concurrent

Lynch T, et al. Presented at the 2011 World Congress of Lung Cancer; July 3-7, 2011; Amsterdam, Netherlands. Abstract 701.

29

PD or AE leading to DC

MaintenanceP P P…

ToxicityProgressionFollow-upRandomize

Overall Survival

PD or AE leading to DC

InductionC C C C C C + + + + I I I I

InductionC C C C C C + + + + P P P P

Arm A

Arm B

I = ipilimumab P = placebo C = chemotherapy

CRPRSD

CRPRSD

ScreeningMaintenance

I I I…

N=920

90% power for HR = 1 during chemotherapy alone period and 0.75 post chemotherapy alone period.

Stage IV sqNSCLCPS ≤1No brain mets

Approximately 250sites, 36 countries, 920 subjects treated

CA184104 – Study Design in Stage IV Squamous NSCLC

30

Ribas A. N Engl J Med 2012;366:2517-2519.

PD-1 DIRECTED IMMUNOTHERAPY

Clinical Activity of BMS-936558 in NSCLC Patients

• ORR was assessed using modified RECIST v1.0• 3 NSCLC patients had a persistent reduction in baseline target lesions in the

presence of new lesions but were not classified as responders for the ORR calculation

Pop Dose(mg/kg)

Ptsn

ORRn (%)

Duration of Response

(mo)

SD 24 wkn (%)

PFSR at 24 wk

(%)

ALL NSCLC 1-10 76 14 (18) 1.9+ to 30.8+ 5 (7) 26

NSCLC

1 18 1 (6) 9.2+ 1 (6) 16

3 19 6 (32) 1.9+ to 30.8+ 2 (11) 41

10 39 7 (18) 3.7 to 14.8+ 2 (5) 24

Clinical Activity by Histology, Efficacy Population

ParameterBMS-936558 Dose, mg/kg

1 3 10ORR, No. patients* (%)

Squamous 0

n=53 (50)n=6

3 (43)n=7

Non-squamous0

n=123 (23)n=13

4 (13)n=31

SD 24 wk, No. patients (%) Squamous 0 0 0 Non-squamous 1 (8) 2 (15) 2 (6)PFSR at 24 wk, (%) Squamous 0 50 43

Non-squamous 14 37 21

*1 patient of unknown histology who received 1mg/kg had an OR.

Phase 3 Study of Anti-PD-1 Compared to Docetaxel in 2nd-Line Advanced/Metastatic Squamous Cell NSCLC

(CA209-017/NCT01642004)

Start Date: September 2012Estimated Study Completion Date: August 2014Estimated Primary Completion Date: August 2014Status: RecruitingStudy Director: BMS

Primary Endpoints• ORR• OS

Secondary Endpoints• PFS• ORR and OS in PD-L1+ vs PD-L1– subgroups• Duration of OR• Time to OR• Proportion of patients exhibiting disease-related

symptom progression per Lung Cancer Symptom Scale

Key Eligibility Criteria• ≥ 18 years of age• Stage IIIB/IV squamous cell NSCLC or recurrent disease

following RT or surgical resection• Prior Pt-containing chemotherapy• ECOG PS ≤ 1• Formalin fixed, paraffin-embedded (FFPE) tumor tissue

block or unstained slides of tumor sample (archival or recent) must be available for biomarker evaluation

Phase 3 TrialStage IIIB/IV or recurrent

squamous cell NSCLC N=264

Docetaxel75 mg/m2 IV

Q3W

Anti-PD-13 mg/kg IV

Q2W

Treat until progression or unacceptable toxicity or withdrawal of consent

Co-Primary Objective Response Rate (ORR) & Overall Survival (OS)

ECOG PS, Eastern Cooperative Oncology Group Performance Status; OR, objective response; PFS, progression-free survival; Pt, platinum; RT, radiotherapy

Phase 2 Study of Anti-PD-1 in Subjects With Advanced/ Metastatic Squamous Cell NSCLC Who Have Received At Least Two Prior

Systemic Regimens (CA209-063/NCT01721759)Phase 2 Trial

Stage IIIB/IV Squamous cell NSCLC N=100

Anti-PD-13 mg/kg IV

Q2W

Treat until progression or unacceptable toxicity or withdrawal of consent

Objective Response Rate (ORR)

Start Date: November 2012Estimated Study Completion Date: February 2014Estimated Primary Completion Date: February 2014Status: RecruitingStudy Director: BMS

Primary Endpoints• ORR (investigator assessed)

Secondary Endpoints• ORR (by independent radiology review committee)

Key Eligibility Criteria• ≥ 18 years of age• Stage IIIB/IV squamous cell NSCLC • ECOG PS ≤ 1• Progression or recurrence after both 1st-line

Pt-doublet chemotherapy and ≥1 approved subsequent line of systemic therapy

• No active CNS metastases, carcinomatous meningitis, active or suspected autoimmune disease or interstitial lung disease

• No prior treatment on either arm of Study CA209-017 or CA184-104

• No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 or other antibody targeting T-cell co-stimulation or checkpoint pathways

ECOG PS, Eastern Cooperative Oncology Group Performance Status; ORR, Objective response rate; PFS, Progression-free survival; Pt, Platinum

Structural variants• Translocations• Fusions• Inversion

Copy number alterations

• Amplifications• Deletions• LOH

Point mutations & indels

• Missense• Nonsense• Splice site• Frameshift

Gene expression• Outlier expression• Isoform usage• Pathways & signatures

Wild type AGTGA

Mutant AGAGA

Adapted from: Roychowdhury et al. Sci Transl Med; 20122

37

Therapeutic targets in squamous cell lung carcinoma

Nature. 2012 Sep 27;489(7417):519-25

38

Gene Event Type Frequency

CDKN2A

Deletion/Mutation/Methylation

72%

PI3KCA Mutation 16%PTEN Mutation/

Deletion15%

FGFR1 Amplification 15%EGFR Amplification 9%PDGFRA Amplification/

Mutation9%

CCND1 Amplification 8%DDR2 Mutation 4%BRAF Mutation 4%ERBB2 Amplification 4%FGFR2 Mutation 3%

Therapeutic targets in squamous cell lung carcinoma

Nature. 2012 Sep 27;489(7417):519-25

39

Therapeutic targets in squamous cell lung carcinomas, defined by TCGA

Nature. 2012 Sep 27;489(7417):519-25

40

CDKN2A: Loss of Function Through Multiple Mechanisms

Tumor samples

Three most common mechanisms

Homozygous deletion 30%Methylation 21%Mutation 17%

Open clinical trials with targeted agents in SCC- Lung

Trial ID Sponsor Phase Targeted agent Target class

NCT01491633 Dana-Farber Cancer Institute II

Dasatinib BCR/ABL, SRCNCT01514864 Bristol-Myers Squibb II

NCT01041781Cancer and Leukemia Group B III Celecoxib COX

NCT01702714 Hoffmann-La Roche I RO5083945

EGFR

NCT01485809 Seoul Veterans Hospital II Gefitinib

NCT01523587Boehringer Ingelheim Pharmaceuticals III Afatinib/Erlotinib

NCT01561456 Axelar AB II AXL1717 IGF-1R

NCT01642004 Bristol-Myers Squibb IIIBMS-936558 (anti-PD1)

Immune basedNCT01285609 Bristol-Myers Squibb III Ipilimumab

NCT01519804 Genentech II Onartuzumab MET

NCT01346540 Boehringer Ingelheim I/IIBIBF-1120 (Nintedanib) VEGFR

NCT00998192 Oncolytics Biotech II Reolysin (Reovirus) Virus

Chemo-biological Treatment for Squamous Cell NSCLC

• Platinum based doublet therapy for early stage and locally advanced squamous NSCLC

• nab-PCb option for advanced disease• Role of maintenance chemotherapy

limited but erlotinib and docetaxel remain options

• Immunotherapy holds promise• Several novel targets identified