squamous cell nsclc are we making progress?
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Squamous Cell NSCLC Are 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 - PowerPoint PPT PresentationTRANSCRIPT
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