Transcript Emerging Targets for Squamous Cell NSCLC

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
– 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 FDAApproved
• New strategies are needed for this large group of
patients
2
Lung Cancer Incidence by Histology
1998-2002
LOCATION
MALE
FEMALE
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%
Youlden DR et al. J Thorac Oncol 3:819-831, 2008
Lagging Outcomes for Squamous-Cell NSCLC
Epidemiological data show recent OS gains more pronounced for patients with
adenocarcinoma histology, less for patients with squamous-cell tumors
1-yr OS / 2-yr OS
Period
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
* Comparison uses ADC data as reference
Most conspicuous outcome gap for squamouscell NSCLC coincides with the introduction of
targeted therapies
ADC=Adenocarcinoma
SQCC=Squamous Cell Carcinoma
Morgensztern D. J Thor Oncol 2009. vol 4 pp 1524
1st Line Options
Phase III Study Design
Chemo-naive
PS 0-1
Stage IIIb/IV
NSCLC
N = 1,050
Albumin-bound paclitaxel
100 mg/m2 d1, 8, 15
Carboplatin AUC 6 d1
21 Day Cycles
No Premedication
1:1
Stratification factors:
• Stage (IIIb vs IV)
• Age (<70 vs >70)
• Sex
• Histology (squame vs nonsquame)
• Geographic region
Primary Endpoint - ORR
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
21 Day Cycles
With Premedication of
Dexamethasone + Antihistamines
Primary Endpoint Results
Objective Responses – ITT
Response Ratio = 1.31
(1.082 – 1.593)
P = 0.005
Percent Responses
40%
30%
nab-P/C
P/C
33%
25%
20%
10%
0%
Independent
Radiologic Review
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.
ADENO, adenocarcinoma; CI, confidence interval; LC, large cell
carcinoma; NOS, not otherwise specified; P/C, paclitaxel + carboplatin; sb,
solvent-based; SCC, squamous cell carcinoma.
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.
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
Stage IIIB or IV
EGFR-expressing
chemotherapy-naïve
NSCLC
R
A
N
D
O
M
I
Z
E
Cisplatin/Vinorelbine
+
Cetuximab
N=550
Cisplatin/Vinorelbine
N=550
Primary endpoint: OS
Secondary 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
Overall Survival Time: ITT
CT + Erbitux
(n=557)
CT
(n=568)
421
447
11.3
[9.4–12.4]
10.1
[9.1–10.9]
No. of events
100
Median OS, months
[95% CI]
Overall Survival (%)
75
50
HR
[95% CI]
0.871
[0.762–0.996]
p-value
0.044
1-year survival, %
47
42
25
10.1
0
0
At risk
CT 568
CT/Erbitux 557
11.3
6
12
18
24
30
36
383
225
134
48
0
0
383
251
155
53
3
0
Months
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)
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)
FLEX survival: high EGFR expression
Squamous cell carcinoma (N=144)
Survival
100
Overall survival (%)
90
Median
1-year
80
▬ CT + cetuximab
11.2 mo
44%
70
▬ CT
8.9 mo
25%
60
HR=0.62 [95% CI 0.43–0.88]
50
40
30
20
10
0
0
Number of patients at risk
CT + cetuximab
75
CT
69
6
12
18
24
30
19
7
10
2
0
0
Months
52
42
32
17
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
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
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
16
Maintenance
Pemetrexed - Overall Survival by Histology
Non-squamous (n=481)
HR=1.07 (95% CI: 0.49–1.73)
P =0.678
HR=0.70 (95% CI: 0.56-0.88)
P =0.002
1.0
Survival Probability
Squamous (n=182)
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Pemetrexed 15.5 mos
0.5
0.4
Pemetrexed 9.9 mos
0.5
0.4
0.3
Placebo
10.3 mos
0.2
0.3
0.1
0.1
0.0
0.0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
Placebo
10.8 mos
0.2
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
SATURN study design
Erlotinib
150mg/day
Chemonaïve
advanced NSCLC
n=1,949
4 cycles of
1st-line platinumbased doublet*
Non-PD
n=889
PD
1:1
Placebo
PD
Mandatory tumour
sampling
Stratification factors:
Co-primary endpoints:
•
•
•
•
•
•

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

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)
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine;
carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel
EGFR = epidermal growth factor receptor; IHC = immunohistochemistry
OS*: all patients (ITT)
1.0
HR=0.81 (0.70–0.95)
OS probability
0.8
Log-rank p=0.0088
0.6
Erlotinib (n=438)
Placebo (n=451)
0.4
0.2
11.0
0
0
3
6
9
12.0
12
15 18 21
Time (months)
24
27
*OS is measured from time of randomisation into the maintenance phase;
ITT = intent-to-treat population
30
33
36
Subgroup analysis of PFS
All
HR (95% CI)
0.71 (0.62–0.82)
n
884
Male
0.78 (0.66–0.92)
654
Female
0.56 (0.42–0.76)
230
Caucasian
0.75 (0.64–0.88)
744
Asian
0.58 (0.38–0.87)
128
Adenocarcinoma
0.60 (0.48–0.75)
401
Squamous-cell
0.76 (0.60–0.95)
359
Never smoker
0.56 (0.38–0.81)
152
Former smoker
0.66 (0.50–0.88)
242
Current smoker
0.80 (0.67–0.97)
490
0.4
0.6
0.8
1.0
Favours
erlotinib
HR
1.2
Favours
placebo
SATURN: OS in patients with SD on first-line
chemotherapy according to histology
1.0
Squamous-cell
HR=0.67 (0.48–0.92)
OS probability
0.8
Log-rank p=0.0116
0.6
Erlotinib (n=97)
Placebo (n=93)
1.0
Log-rank p=0.0457
Erlotinib (n=155)
Placebo (n=142)
0.6
0.4
0.2
0.2
11.3
0
HR=0.76 (0.59–1.00)
0.8
0.4
8.3
Non-squamous
10.6
13.7
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
Measured from time of randomisation into the maintenance phase
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
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
Immunotherapy
Novel molecular targets
CANCER AND IMMUNE SYSTEM
IMMUNOEDITING
Mechanism of Action of Ipilimumab
T-cell
inhibition
T-cell
activation
T-cell activation
and proliferation
CTLA-4
T cell
T cell
CD28
CD28
TCR
TCR
MHC
T cell
CD80/
CD86
APC
MHC
CTLA-4
CD80/
CD86
APC
Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010.
26
CTLA-4
TCR
MHC
APC
CD80/
CD86
ipilimumab
blocks
CTLA-4
CA184-041: Study Schema
First-line
Stage IIIb/IV NSCLC (n=204)
ED-SCLC (n=130)
C
1:1:1
R
A
N
D
O
M
I
Z
E
Concurrent
IPI + Pac/Carbo
Phased
IPI + Pac/Carbo
n=130
Maintenance Phase
Treatment Phase
C
C
C
C
C
IPI
IPI
Follow-up
phase
IPI
IPI
IPI
IPI
p
p
C
C
C
C
C
C
p
p
IPI
IPI
C
C
C
C
IPI
C
IPI
IPI
Follow-up
phase
IPI
C
Control
p + Pac/Carbo
p
p
Follow-up
phase
p
p
p
q3w
p
p
p
q12w
C: chemotherapy doublet (Pac 175mg/m2)/Carbo (AUC=6); IPI: Ipilimumab (10 mg IV); p: Placebo
*Phased : 2 doses of paclitaxel /carboplatin given prior to start of ipilimumab
Note: Steroids were given as premedication for chemotherapy
27
Summary Efficacy Results
CA184041
First-line
Stage IIIb/IV NSCLC (n=204)
ED-SCLC (n=130)
End-point
irPFS
HR versus control (95%CI)
mWHO PFS
HR versus control (95%CI)
OS
HR versus control (95%CI)
NSCLC
Concurrent
Phased
0.806
0.724 *
(0.553, 1.174) (0.495, 1.059)
SCLC
Concurrent
Phased
0.751
0.640 *
(0.475, 1.188) (0.403, 1.016)
0.882
(0.612, 1.271) ,
0.691 *
(0.478, 0.999)
0.933
(0.588, 1.481)
0.927
(0.591, 1.453)
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.
28
Activity by Baseline Histology
(CA184041, NSCLC)
Phased-Ipi
vs Control
Response
Patient group
irPFS
All
Non-Squamous
Squamous
mWHO-PFS
All
Non-Squamous
Squamous
OS
All
Non-Squamous
Squamous
0.5
1
1.5
HR and 95% CI
Favors
Phased
Control
Concurrent-Ipi
vs Control
0.5
1
HR and 95% CI
Favors
Concurrent Control
Lynch T, et al. Presented at the 2011 World Congress of Lung Cancer; July 3-7, 2011; Amsterdam, Netherlands. Abstract 701.
29
1.5
CA184104 – Study Design in Stage IV
Squamous NSCLC
PD or AE leading to DC
Arm A
Induction
CCCCCC
+ + ++
I I I I
Screening
CR
PR
SD
Maintenance
I I I…
Toxicity
Progression
Follow-up
Randomize
Induction
CCCCCC
+ + ++
P PPP
Stage IV sqNSCLC
PS ≤1
No brain mets
CR
PR
SD
Maintenance
P P P…
Arm B
I = ipilimumab
P = placebo
C = chemotherapy
PD or AE leading to DC
N=920
90% power for HR = 1 during chemotherapy alone
period and 0.75 post chemotherapy alone period.
Approximately 250sites, 36 countries, 920 subjects treated
30
Overall
Survival
PD-1 DIRECTED IMMUNOTHERAPY
Ribas A. N Engl J Med 2012;366:2517-2519.
Clinical Activity of BMS-936558 in
NSCLC Patients
Pop
Dose
(mg/kg)
Pts
n
ORR
n (%)
Duration of
Response
(mo)
SD 24 wk
n (%)
PFSR at
24 wk
(%)
ALL
NSCLC
1-10
76
14 (18)
1.9+ to 30.8+
5 (7)
26
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
NSCLC
•
•
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
Clinical Activity by Histology,
Efficacy Population
BMS-936558 Dose, mg/kg
Parameter
1
3
10
Squamous
0
n=5
3 (50)
n=6
3 (43)
n=7
Non-squamous
0
n=12
3 (23)
n=13
4 (13)
n=31
0
0
0
1 (8)
2 (15)
2 (6)
Squamous
0
50
43
Non-squamous
14
37
21
ORR, No. patients* (%)
SD 24 wk, No. patients (%)
Squamous
Non-squamous
PFSR at 24 wk, (%)
*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 (CA209017/NCT01642004)
Primary Endpoints
Phase 3 Trial
Stage IIIB/IV or recurrent
squamous cell NSCLC
N=264
Docetaxel
75 mg/m2 IV
Q3W
Anti-PD-1
3 mg/kg IV
Q2W
Treat until progression or
unacceptable toxicity or
withdrawal of consent
Co-Primary Objective Response Rate (ORR) &
Overall Survival (OS)
Start Date: September 2012
Estimated Study Completion Date: August 2014
Estimated Primary Completion Date: August 2014
Status: Recruiting
Study Director: BMS
• 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
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
Primary Endpoints
• ORR (investigator assessed)
Secondary Endpoints
• ORR (by independent radiology review committee)
Anti-PD-1
3 mg/kg IV
Q2W
Treat until progression or
unacceptable toxicity or
withdrawal of consent
Objective Response Rate (ORR)
Start Date: November 2012
Estimated Study Completion Date: February 2014
Estimated Primary Completion Date: February 2014
Status: Recruiting
Study Director: BMS
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
Therapeutic targets in squamous cell
lung carcinoma
Nature. 2012 Sep 27;489(7417):519-25
37
Therapeutic targets in squamous cell
lung carcinoma
38
Gene
Event Type
Frequency
CDKN2A
Deletion/Mutation/
Methylation
72%
PI3KCA
Mutation
16%
PTEN
Mutation/Deletion
15%
FGFR1
Amplification
15%
EGFR
Amplification
9%
PDGFRA Amplification/Mutati
on
9%
CCND1
Amplification
8%
DDR2
Mutation
4%
BRAF
Mutation
4%
ERBB2
Amplification
4%
FGFR2
Mutation
3%
Nature. 2012 Sep 27;489(7417):519-25
Therapeutic targets in squamous cell
lung carcinomas, defined by TCGA
Nature. 2012 Sep 27;489(7417):519-25
39
CDKN2A: Loss of Function Through
Multiple Mechanisms
Three most common
mechanisms
Homozygous deletion
Methylation
Mutation
Tumor samples
40
30%
21%
17%
Open clinical trials with targeted agents in SCC- Lung
Trial ID
Sponsor
Phase
Targeted agent
Target class
NCT01491633
Dana-Farber Cancer Institute II
NCT01514864
Dasatinib
BCR/ABL, SRC
NCT01041781
Bristol-Myers Squibb
II
Cancer and Leukemia Group
B
III
Celecoxib
COX
NCT01702714
Hoffmann-La Roche
I
RO5083945
NCT01485809
II
Gefitinib
NCT01523587
Seoul Veterans Hospital
Boehringer Ingelheim
Pharmaceuticals
III
Afatinib/Erlotinib
EGFR
NCT01561456
Axelar AB
II
IGF-1R
NCT01642004
Bristol-Myers Squibb
III
AXL1717
BMS-936558 (antiPD1)
NCT01285609
Bristol-Myers Squibb
III
Ipilimumab
NCT01519804
Genentech
II
NCT01346540
Boehringer Ingelheim
I/II
Onartuzumab
BIBF-1120
(Nintedanib)
VEGFR
NCT00998192
Oncolytics Biotech
II
Reolysin (Reovirus)
Virus
Immune based
MET
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