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Saturday, February 11, 2012
Hollywood, Florida
Co-Chairs
Rogerio C Lilenbaum, MD
Co-Chair and Moderator
Neil Love, MD
Mark A Socinski, MD
Faculty
Chandra P Belani, MD
John Heymach, MD, PhD
Pasi A Jänne, MD, PhD
Thomas J Lynch Jr, MD
Heather Wakelee, MD
Clinical Challenges and Opportunities
in Squamous Cell Carcinoma
Mark A. Socinski, MD
Professor of Medicine and Thoracic Surgery
Director, Lung Cancer Section, Division of
Hematology/Oncology
University of Pittsburgh
Overview of NSCLC Histologies
NSCLC
adenocarcinoma
NSCLC large
cell carcinoma
NSCLC squamous
cell carcinoma
Adenocarcinoma is a
malignant epithelial tumor
with glandular differentiation
or mucin production,
showing acinar, papillary,
bronchoalveolar, or solid
with mucin growth patterns
or a mixture of these
patterns.
Large cell carcinoma is an
undifferentiated non-small
cell carcinoma that lacks the
cytologic and architectural
features of small cell
carcinoma and glandular or
squamous differentiation.
Squamous cell carcinoma is
a malignant epithelial tumor
showing keratinization
and/or intercellular bridges
that arise from bronchial
epithelium. These features
vary with degree of
differentiation, being
prominent in welldifferentiated tumors and
focal in poorly differentiated
tumors.
Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARCPress. 2004:26-30.
Retrospective Analysis of ECOG 1594 by Histology
Squamous
(n=224)
OS
(mo)
Large Cell
(n=74)
Other
(n=194)
Regimen
Median
95% C1
Median
95% C1
Median
95% C1
Median
95% C1
pvalue
CP
6.9
(5.3, 9.4)
9.1
(7.9, 10.9)
6.1
(2.9, inf)
6
(3.9, 9.1)
0.09
CG
9.4
(5.7, 15.5)
8.1
(6.8, 9.8)
9.7
(4.5, 17.1)
7.9
(6.3, 11.3)
0.63
CD
8.1
(5.5, 11.2)
7.7
(6.5, 9.4)
6.8
54.9, 11.7
8.2
(5.6, 12.4)
0.01
CbP
9.3
(7.3, 12.1)
7.6
(6.6, 9.8)
8.3
(3.6, 16.7)
6.9
(4.9, 11.6)
0.37
p-value
PFS
(mo)
Adenocarcinoma
(n=647)
0.18
0.39
0.37
0.82
CP
2.6
(1.7, 4.2)
3.7
(3.1, 4.3)
3.5
(1.4, inf)
2.8
(1.8, 4.0)
0.43
CG
4.1
(3.3, 6.6)
4.4
(3.8, 5.4)
4.5
(2.0, 11.5)
3.4
(2.8, 5.1)
0.43
CD
3.1
(2.4, 5.0)
3.7
(2.6, 4.6)
4.2
(2.0, 6.6)
3.6
(2.7, 5.6)
0.54
CbP
3.7
(3.0, 5.0)
3.5
(2.9, 4.2)
3.9
1.9, 7.8)
2.2
1.7, 3.9)
0.25
p-value
0.2
0.19
0.56
0.68
Histological subtypes did not influence overall survival and progression free survival in chemo-naïve
patients treated with platinum-based doublets involving paclitaxel, docetaxel or gemcitabine
Tien H et al. J Thorac Oncol 4:S493, 2009
Why did we start caring about
Squamous cell carcinoma?
Bleeding in a Randomized Phase II Trial
6 life-threatening PHs; 4 fatal
•Overall incidence: 9% (6/66)
•5 occurred with bevacizumab 7.5 mg/kg
Apparent risk factors
•Baseline hemoptysis
•Histology
- Squamous histology: 31% (4/13)
- Non-squamous histology: 4% (2/53)
Squamous histology patients subsequently excluded
from the pivotal phase III trial (ECOG 4599)
Johnson. J Clin Oncol. 2004;22:2184; Sandler. New Engl J Med 355:2542-50, 2006.
Pemetrexed in Squamous Carcinoma
First line: Median survival
• CP: 9.4 months; 95% CI 8.4, 10.2
• CG: 10.8 months; 95% CI 9.5, 12.1
– Adjusted HR; 95% CI: 1.23; 1.00, 1.51
Maintenance
• Pemetrexed, 9.9 months
• Placebo, 10.8 months
– HR = 1.07 (95% CI: 0.49-1.73)
– p = 0.678
Scagliotti, G. V. et al. J Clin Oncol; 26:3543-3551 2008
Ciuleanu T et al. Lancet 374:1432-1440, 2009
Heterogeneity of mRNA Expression Levels in
NSCLC: AC versus SCCA
NSCLC
Total
NSCLC
Squamous
NSCLC
Adenocarcinoma
SCCA vs AC
N = 1,802
(SCCA) N = 392
(AC) N = 920
p-value
N
1,014
264
500
Median
2.92
4.31
2.5
Range
0.14-60.58
0.14-59.16
0.39-30.33
Biomarker
TS
* Mann-Whitney test
Gandara D et al. ASCO 2010
(Reference <2.33
for pemetrexed)
% Below
Reference
Level
NSCLC-Total
41.3%
NSCLC-Adenoca
45.7%
NSCLC-SCCA
25.9%
<0.001*
New Cytotoxics in Squamous
Cell Carcinoma
Phase III nab-P/C vs P/C Study Design
Socinski MA et al. ASCO 2010, LBA# 7511
Chemo-naive
PS 0-1
Stage IIIb/IV
NSCLC
N = 1,050
nab-Paclitaxel 100 mg/m2 d1, 8, 15
Carboplatin AUC 6 d1
No Premedication
n = 525
1:1
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
With Premedication of
Stratification factors:
Dexamethasone + Antihistamines
 Stage (IIIb vs IV)
n = 525
 Age (<70 vs >70)
 Sex
 Histology (squamous vs nonsquamous)
 Geographic region
Results: Baseline Demographics
nab-P/C
(n = 521)
P/C
(n = 531)
All Patients
(N = 1052)
60 (28, 81)
448 (86)
73 (14)
60 (24, 84)
449 (85)
82 (15)
60 (24, 84)
897 (85)
155 (15)
Female, n (%)
129 (25)
134 (25)
263 (25)
ECOG, n (%)
0
1
Histology of Primary Diagnosis, n (%)*
133 (26)
385 (74)
113 (21)
416 (78)
246 (23)
801 (76)
254 (49)
228 (44)
264 (50)
221 (42)
518 (49)
449 (43)
Large Cell Carcinoma
9 (2)
13 (2)
22 (2)
Other
29 (6)
33 (6)
62 (6)
Stage III
99 (19)
107 (20)
206 (20)
Stage IV
421 (81)
424 (80)
845 (80)
12 (2)
8 (2)
20 (2)
513
521
1034
Never Smoked
138 (27)
144 (28)
282 (27)
Smoked and Quit
165 (32)
146 (28)
311 (30)
Smoked and Still Smokes
210 (41)
231 (44)
441 (43)
Age, median (range) years
<70 years, n (%)
≥70 years, n (%)
Adenocarcinoma
Squamous Cell Carcinoma
Stage at Current Diagnosis, n (%)*
Prior Chemotherapy, n (%)
Smoking Status, n (%)
*Data was missing for 1 pt at the time of this analysis
Primary Endpoint Results (ITT Population)
Objective Response Rates – All Histologies
Percent Responses
50%
Response Ratio = 1.31
Response Ratio = 1.26
(1.082 – 1.593)
(1.060 – 1.496)
P = 0.005
P = 0.008
nab-P/C (n = 521)
P/C (n = 531)
40%
30%
20%
37%
33%
30%
25%
10%
0%
Independent Radiologic
Review
Investigator Assessment
Objective Responses by Histology
Squamous
P < 0.001
Nonsquamous
P = 0.060
P = 0.808
P = 0.069
Percent Responses
50%
40%
nab-P/C
P/C
41%
37%
37%
30%
29%
20%
24%
30%
26%
25%
10%
0%
Independent
Radiologic
Review
n = 228
Investigator
Assessment
n = 221
Socinski MA et al. ASCO 2010 #7511
Independent
Radiologic
Review
n = 292
Investigator
Assessment
n = 310
Secondary Endpoints: PFS and OS
Carboplatin/
paclitaxel
Carboplatin/
nab paclitaxel
Hazard ratio
p-value
Median PFS — all
patients
(n = 531, 521)
5.8 months
6.3 months
0.902
0.214
Median OS — all
patients
(n = 531, 521)
11.2 months
12.1 months
0.922
0.271
Exploratory Overall Survival Analysis in Selected Strata
Carboplatin/
paclitaxel
Carboplatin/
nab paclitaxel
Hazard ratio
p-value
9.5 months
10.7 months
0.890
0.284*
10.4 months
19.9 months
0.583
0.009*
Squamous
(n = 221, 229)
Age ≥70 years
(n = 82, 74)
* Subgroup analyses exploratory in nature
Nab Paclitaxel Phase II Trial In Advanced
Squamous Carcinoma of the Lung
Gemcitabine
Carboplatin
R
Primary
Endpoints:
ORR
N=120
Nab-paclitaxel
Carboplatin
NCT01236716 Chinese Society of Lung Cancer
Trial Outcome with Targeted Agents in
Squamous Cell CA
Agent
Bevacizumab
Sorafenib
Motesanib
Cediranib
Figitumumab
Cetuximab
Trial
Phase II
Phase III
ESCAPE
Phase III
MONET
Phase II
BR24
Phase III
ADVIGO (2)
Phase III
FLEX
Results
Associated with increased risk of
severe pulmonary hemorrhage
(4/13 pts)
Increased risk of death
Increased risk of hemoptysis
No increased toxicity or efficacy
No histology specific findings but
increased toxicity and no benefit
No histology specific findings
FLEX Overall Survival Time: ITT
No. of events
Median OS, months [95% CI]
CT + Cetuximab
(n = 557)
CT
(n = 568)
421
447
11.3
[9.4–12.4]
10.1
[9.1–10.9]
HR [95% CI]
0.871
[0.762–0.996]
p-value
1-year survival, %
0.044
47
42
OS by Subgroups: Ethnic Origin and Histology (ITT)
Median OS (months)
CT + Cetuximab
CT
HR [95% CI]
p-value
All (n=1125)
11.3
10.1
0.871
[0.762–0.996]
0.044
Caucasian (n=946)
10.5
9.1
0.803
[0.694–0.928]
0.003
Adenoca. (n=413)
12.0
10.3
0.815
[0.649–1.023]
0.077
SCC (n=347)
10.2
8.9
0.794
[0.626–1.007]
0.057
17.6
20.4
1.179
[0.730–1.905]
0.499
Asian (n=121)
High and low EGFR expression
High EGFR expression
• IHC score ≥200
Low EGFR expression
• IHC score <200
O’Byrne et al. J Thorac Oncol 2010
FLEX survival: High EGFR expression
Squamous cell carcinoma (N = 144)
Survival
Median
1-year
CT + cetuximab
11.2 mo
44%
CT
8.9 mo
25%
HR = 0.62 [95% CI 0.43–0.88]
Ongoing Trials in Squamous NSCLC
Iniparib in Untreated Stage IV
Squamous NSCLC
DNA replication
DNA DSB
DNA SSB
Chemo
PARP
Base excision repair
Iniparib
ATM/ATR
wt p53/
mt p53
γ-H2AX
BRCA1
Rad50
MRE11
NBS1
RAD51
BRCA2
Rad52/4
RPA
ERCC1
Adapted from N.J. Curtin, 2006
Homologous Recombination Repair (HR)
Target Cancers = defective in HR
BRCA1/2 mutant (breast, ovarian),
ERCC1 abnormalities (colon, NSCLC),
p53 mutant tumors.
ECLIPSE Study Overview
N= 825
International, Open-label
Gemcitabine + Carboplatin
Patient Population:
• Advanced squamous cell
carcinoma
R
Endpoints:
Primary: OS
Secondary: PFS, TTP, ORR,
safety/tolerability, QoL
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
1:1
• 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 DLTs
Gemcitabine + Carboplatin
+ Iniparib
First Patient Enrolled: March 5, 2010
Necitumumab
• 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
SQUIRE: Phase III, 1st line
NSCLC, squamous
947 patients
Stage 4
NSCLC
Squamous
ECOG PS 0-2
R
A
N 1
D
O
M
I
Z
E 1
Arm A: IMC-11F8 + CIS + GEM
IMC-11F8 800 mg (50-min IV), D1, 8
Cisplatin 75 mg/m2 (30-60 min IV), D1
Gemcitabine 1250 mg m2 (30 min IV), D1, 8
Arm B: CIS + GEM
Cisplatin 75 mg/m2 (30-60 min IV), D1
Gemcitabine 1250 mg/m2 (30 min IV), D1, 8
PR
CR
IMC-11F8
SD
PD
Squamous Cell Lung Cancer:
An Unmet Need
• 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
Saturday, February 11, 2012
Hollywood, Florida
Co-Chairs
Rogerio C Lilenbaum, MD
Co-Chair and Moderator
Neil Love, MD
Mark A Socinski, MD
Faculty
Chandra P Belani, MD
John Heymach, MD, PhD
Pasi A Jänne, MD, PhD
Thomas J Lynch Jr, MD
Heather Wakelee, MD