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Recent Therapeutic Advances in Squamous Cell Carcinoma of the Lung
2017 Conversations in Oncology in Shanghai, China
Prof. Shun Lu Shanghai Lung Cancer Center
Shanghai Chest Hospital Affiliated to
Medical College of Shanghai Jiaotong University
BI Symposium
2
• Squamous histology represents approximately 20–40% of NSCLC1,2
• SqCC of the lung remains a disease with high unmet medical need
• SqCC of the lung is associated with poor prognosis3
– Median OS after diagnosis of advanced disease is around 4 months for
untreated patients3
– The 5-year survival is ~1.6%3
• Better therapeutic options needed for patients
– Targetable oncogenic alterations are few and have not yet translated to a
therapeutic paradigm
Squamous Cell Carcinoma (SqCC) of the Lung
1. Ho C et al. Curr Oncol. 2015;22:e16 4-e170; 2. Bryant A and Cerfolio RJ. Chest. 2007;132:185-92; 3. Cetin K et al. Clin Epidemiol. 2011;3:139-48.
OS = overall survival; NSCLC = non-small cell lung cancer.
3
Overview of Recent Key Phase III ≥ Second-line
Treatment Studies in Patients With SqCC of the Lung
1. Shepherd FA et al. N Engl J Med. 2005;352:123-132; 2. Clark GM. Mol Oncol. 2008;1:406-412; 3. Gridelli C et al. The Oncologist. 2007;12(7):840-849; 4. Garon E et al.
Lancet. 2014;384:665-73; 5. Brahmer J et al. N Engl J Med. 2015;373:123-35; 6. Herbst R et al. Lancet. 2016;387:1540-50; 7. Soria JC et al. Lancet Oncol. 2015;16:897-907;
8. Rittmeyer A et al. Lancet. 2017;389:255-65.
Trial Treatment Median PFS (mo) HR for PFS Median OS (mo) HR for OS ORR (%)
BR 211-3 Erlotinib vs placebo (n=731)
Squamous (n=222)
2.2 vs 1.8
NR for squamous
0.61
NR for squamous
6.7 vs 4.7
5.6 vs 3.6
0.70
0.67
8.9% vs <1%
NR for squamous
REVEL4
Ramucirumab + doce vs doce
(n=1253)
Squamous (n=328)
4.5 vs 3.0
4.2 vs 2.7
0.76*
0.76*
10.5 vs 9.1
9.5 vs 8.2
0.86*
0.88
22.9 vs 13.6*
26.8 vs 10.5*
CheckMate-0175 Nivolumab vs doce
All squamous (n=272)
3.5 vs 2.8
0.62*
9.2 vs 6.0
0.59*
20.0 vs 9.0*
KEYNOTE-0106
Pembrolizumab vs doce
PD-L1 PS ≥50% (n=442)
Squamous (n=222)
2 mg: 5.0 vs 4.1
10 mg: 5.2 vs 4.1
NR for squamous
2 mg: 0.59*
10 mg: 0.59*
0.86
14.9 vs 8.2
17.3 vs 8.2
NR for squamous
0.54*
0.50*
0.74
30.0 vs 8.0*
29.0 vs 8.0*
NR for squamous
LUX-Lung 87 Afatinib vs erlotinib (n=795)
All squamous
2.6 vs 1.9
0.81*
7.9 vs 6.8
0.81*
6.0 vs 2.8*
OAK8 Atezolizumab vs doce (n=850)
Squamous (n=222)
2.8 vs 4.0
NR for squamous
0.95
NR for squamous
13.8 vs 9.6
8.9 vs 7.7
0.73*
0.73*
14 vs 13
NR for squamous
All agents listed are FDA and EMEA approved for the treatment of SqCC of the lung.
*P<0.05.
doce = docetaxel; EMEA = European Medicines Agency; FDA = US Food and Drug Administration; HR = hazard ratio; mo = months; NR = not reported; ORR = objective
response rate; OS = overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; PS = proportion score; SqCC = squamous cell carcinoma.
4
EGFR-TKI/Ab
I-O Anti-VEGF
Chemotherapy
5
CA031: Weekly nab-paclitaxel + Carboplatin vs
Paclitaxel + Carboplatin
Socinski MA et al. J Clin Oncol. 2012;30:2055-2062.
ITT Squamous Subgroup
ORR (%) nab-PC
(N=521)
sb-PC
(N=531) OR 95% CI P
ITT 33 25 1.313 1.082-1.593 0.005
SQCC 41 (N=229) 24 (N=221) 1.680 1.271-2.221 <0.001
Non-SQCC 26 (N=292) 25 (N=310) 1.034 0.788-1.358 0.808
6
CA 031: Better Safety Profile of nab-paclitaxel
Socinski MA et al. J Clin Oncol. 2012;30:2055-2062.
AE nab-PC (%) N=514 sb-PC (%) N=524
P-value G3 G4 G3 G4
Hematological
Neutropenia 33 14 32 26 <0.001*
Thrombocytopenia 13 5 7 2 <0.001†
Anemia 22 5 6 <1 <0.001†
Febrile Neutropenia <1 <1 1 <1 N/S
Non-Hematological
Fatigue 4 <1 6 <1 N/S
Sensory Neuropathy 3 0 11 <1 <0.001*
Anorexia 2 0 <1 0 N/S
Nausea <1 0 <1 0 N/S
Myalgia <1 0 2 0 0.011*
Arthralgia 0 0 2 0 0.008*
N/S = non-significant difference; *P<0.05: nab-P better; †P<0.05; Paclitaxel better.
7
CA 031: nab-paclitaxel – Pros and Cons
8
WJOG5208L: Nedaplatin vs Cisplatin
Shukuya T et al. 2015 ASCO Abstract 8004.
.
9
WJOG5208L: Primary Endpoints OS
Shukuya T et al. 2015 ASCO Abstract 8004.
N + D C + D
10
Patient Disposition
Nedaplatin Plus Docetaxel Versus Cisplatin Plus Docetaxel as First-Line
Chemotherapy for Advanced Squamous Cell Carcinoma of the Lung—Multi-
centers, Open-label, Randomized, Phase III, Superiority Trial (JUST Study)
Presented by Shun Lu at WCLC, 2017.
Assessed for eligibility
ND group (N=142) CD group (N=144)
141 cases received
treatment (ITT analysis)
139 cases received
treatment (ITT analysis)
130 cases (PPS analysis) 126 cases (PPS analysis)
5 withdrew
before treatment
- 5 consent withdrawal
1 withdrew
before treatment
- 1 protocol violation
13 withdrew
before first evaluation
- 4 no visiting as plan
- 6 consent withdrawal
- 3 PI decision
11 withdrew
before first evaluation
- 4 no visiting as plan
- 1 symptom deterioration
- 1 protocol violation
- 5 consent withdrawal
Stratification factors:
Gender
Stage
ECOG PS
Primary endpoint:PFS
Secondary endpoint:
ORR, TTP, AE Randomized (N=286)
11
Nedaplatin Plus Docetaxel Versus Cisplatin Plus
Docetaxel
Presented by Shun Lu at WCLC, 2017.
*Log-Rank two-sides test.
Primary Endpoint: PFS
N C
Mon 5.47. 4.69
N C
Mon. 5.52 4.65
PPS (P<0.05) FAS (P=0.056)
12
ND
(N=133)
CD
(N=128) P* value
CR 1 0
0.0024
PR 67 48
SD 58 56
PD 7 24
ORR 51.1% 37.5%
DCR 94.7% 81.3%
Recist Ver. 1.1
c2 test.
Nedaplatin Plus Docetaxel Versus Cisplatin Plus
Docetaxel
Presented by Shun Lu at WCLC, 2017.
Best Response Evaluation
13
• There was no significant difference of PFS between ND group and CD
group in the FAS, however significant difference existed in the PPS
• More hematological toxicity and non-hematological toxicity were observed in
the ND group and CD group, respectively
• Nedaplatin plus docetaxel could be a new treatment option for advanced or
relapsed squamous cell lung cancer
Summary
Presented by Shun Lu at WCLC, 2017.
14
EGFR-TKI/Ab
I-O Anti-VEGF
Chemotherapy
15
• High burden of somatic mutations/genomic alterations1
• Overexpression/derangements of EGFR,2,3 HER2,4,5 HER4,6 and/or dysregulation of their downstream pathways
implicated in the pathogenesis of SCC NSCLC
SCC NSCLC: Genetically Complex Malignancy
1. Lawrence et al. Nature. 2013;499:214; 2. López-Malpartida et al. Lung Cancer. 2009;65:23; 3. Hirsch et al. J Clin Oncol. 2003;21:3796; 4. Heinmoller et al. Clin Cancer Res.
2003;9:5238; 5. Ugocsai et al. Anticancer Res. 2005;25:306; 6. Cancer Genome Atlas Research Network. Nature. 2012;489:519.
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16
Multi-gene Alterations:
More Common in Sq NSCLC Than ADC
1. Chen Z et al. Nat Rev Cancer. 2014;14:535-546; 2. Pikor LA et al. Lung Cancer. 2013;82:179-189; 3. Shi Y et al. J Thorac Oncol. 2014;9:154-162; 4. Pao W et al. Lancet
Oncol. 2011;12:175-180.
17
Different Gene Alternation
Fernandez-Cuesta L, McKay JD. Curr Opin Oncol. 2016;28(1):52-7.
18
TAILOR: Erlotinib vs Docetaxel in
Second-Line Treatment for Advanced NSCLC
Garassino MC et al. Lancet Oncol. 2013;14:981-988.
Median overall survival:
Erlotinib: 5.4 mo (95% CI: 4.5-6.8)
Docetaxel: 8.2 mo (95% Cl: 5.8-10.9)
HR=0.73 (95% CI 0.53–1.00); P=0.05
19
TAILOR: Erlotinib vs Docetaxel in
Second-Line Treatment for Advanced NSCLC
Garassino MC et al. Lancet Oncol. 2013;14:981-988.
OS PFS
20
Docetaxel in Squamous vs Nonsquamous Histology IPD Pooled
Analysis (TAILOR, DELTA, PROSE)
Torri et al. ASCO 2015. Abstract 371.
Overall Survival S
urv
iva
l P
rob
ab
ilit
y
3 12 27 15 21
0.2
0.4
0.6
0.8
1.0
0
0
Time (months)
Median survival: squamous
6.3 mo (95% CI: 4.2-9.9)
Median survival: nonsquamous
10.9 mo (95% CI: 8.1-14.1)
6 9 18 24
Nonsquam. 160 67 108 42 27
Squamous 40 10 20 5 4
Squamous
Nonsquamous
21
BR 21: Erlotinib vs Placebo in Second-Line
Treatment for Advanced NSCLC
1. Shepherd FA et al. N Engl J Med. 2005;353:123-132; 2. Clark GM. Mol Oncol. 2008;1:406-412.
CI = confidence interval; HR = hazard ratio; OS = overall survival; QD = once daily.
Overall Survival in Patients With Squamous Histology O
ve
rall
Su
rviv
al
5 10 25 15 20
0.2
0.4
0.6
0.8
1.0
0
0
Time (months)
Placebo
Erlotinib Erlotinib
150 mg QD
(n=144)
Placebo
(n=78)
Median OS
(months) 5.6 3.6
HR 0.67 (95% CI: 0.50–0.90)
22
ErbB Receptor Family is a Valid Therapeutic
Target for SqCC of the Lung
1. Hirsch FR et al. J Clin Oncol. 2003;21:3798-807; 2. Lopez-Malpartida AV et al. Lung Cancer. 2009;65:25-33; 3. Lee HJ et al. Lung Cancer. 2010;68:375-82; 4. Gately K et al. Clin Lung Cancer. 2014;15:58-66; 5. Dacic S et al.
Am J Clin Pathol. 2006;125:860-5; 6. Ji H et al. Proc Natl Acad Sci U S A. 2006;103:7817-22; 7. Dearden S et al. Ann Oncol. 2013;24:2371-6; 8. Jaiswal BS et al. Cancer Cell. 2013;23:603-17; 9. Gorgoulis V et al. Pathol Res Pract.
1995;191:973-81; 10. Kan Z et al. Nature. 2010;466:869-73; 11. Shepherd FA et al. N Engl J Med. 2005;352:123-32; 12. Clark GM et al. Clin Lung Cancer. 2006;7:389-94; 13. Leon et al. ESMO 2008. Abstract 1277 (poster);
14. Pirker R et al. Lancet. 2009;373:1525-31; 15. Pirker R et al. Lancet Oncol. 2012;13:33-42; 16. Thatcher N et al. ASCO 2014. Abstract 8008; 17. Li T et al. J Clin Oncol. 2013;31:1039-49.
ErbB Receptor Frequency
(%)
EGFR overexpression2–5 26–86
EGFR amplification2,5 15–27
EGFRvIII mutation6 5
EGFR kinase domain mutation7 <5%
ERBB2 mutation/amplification2 5
ERBB3 mutation8 1
ERBB3 overexpression9 10
ERBB410 8
Frequency of known genetic drivers in SqCC17
Amp = amplification; EGFR = epidermal growth factor receptor; FGFR = fibroblast growth factor receptor; SqCC = squamous cell carcinoma.
• Dysregulation of the ERBB pathway is
frequently observed in SqCC of the lung
– EGFR overexpression and gene amplification
aberrations of other ErbB receptors, and
dysregulation of the downstream pathways,
have all been implicated in the pathobiology
of SqCC1,2
– These findings likely account for the benefits
these patients derive from erlotinib11–13 and
other EGFR-directed therapies in different
treatment settings,14–16 despite the low
frequency of EGFR-activating mutations17
EGFRvIII
PI3KCA
EGFR
DDR2
FGFR1 Amp
Unknown
~5%
23
Afatinib is the First Irreversible ErbB Family
Blocker
Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342.
• Afatinib covalently binds and
irreversibly blocks EGFR,
HER2, and ErbB4
• Targeting the whole ErbB
Family enhances the effect on
important signalling pathways
24
LUX-Lung 8: Study Design
1. Soria JC et al. Lancet Oncol. 2015;16:897-907.
• Advanced SqCC NSCLC
(Stage IIIB/IV)
• PD after ≥4 cycles of a first-line
platinum doublet
• ECOG PS 0 or 1
• No prior anti-EGFR therapy
• No active brain metastases
Afatinib (n=398)
40 mg qd
Erlotinib (n=397)
150 mg qd
Treatment
until disease
progression
or
unacceptable
AEs
Randomisation
1:1
(N=795)
• Stratification: East Asian vs non-East Asian
• Tumour tissue collected for correlative science
• Radiographic tumour assessment at baseline; Weeks 8, 12, 16; every 8 weeks
thereafter
• Primary endpoint: PFS; key secondary endpoint: OS
AE = adverse event; EGFR = epidermal growth factor receptor; ECOG PS = Eastern Cooperative Oncology Group performance status; NSCLC = non-small cell lung cancer;
OS = overall survival; PD = disease progression; PFS = progression-free survival; qd = once daily; SqCC = squamous cell carcinoma.
25
LUX-Lung 8: Significant Improvement in PFS and
OS With Afatinib Compared With Erlotinib
1. Soria JC et al. Lancet Oncol. 2015;16:897-907.
397 99 34 17 10 2 0 1 1 1 Erlotinib
398 139 50 30 14 10 5 2 2 0
397 99 34 17 10 2 1 1 1 0
398 316 249 170 124 82 47 28 10 4 0
397 305 210 150 94 54 30 11 4 2 0
Afatinib
40 mg QD
(n=398)
Erlotinib
150 mg QD
(n=397)
Patients progressed or died, n (%) 299 (75.1) 306 (77.1)
Median PFS (months) 2.6 1.9
HR 0.81; 95% CI: 0.69–0.96;
P=0.0103
Afatinib
40 mg QD
(n=398)
Erlotinib
150 mg QD
(n=397)
Patients died, n (%) 307 (77.1) 325 (81.9)
Median OS (months) 7.9 6.8
HR 0.81; 95% CI: 0.69–0.95;
P=0.0077
Primary analysis of OS (key secondary endpoint) (n=795)
Pro
bab
ilit
y o
f P
FS
(%
)
Updated PFS analysis by Independent Review (n=795)
3 6 9 12 15 18 21 24
0.2
0.4
0.6
0.8
1.0
0 0 27 3 6 9 12 15 30 18 21 24 27
0.2
0.4
0.6
0.8
1.0
0 0
36.4%
28.2% 22.0%
14.4%
Time (months) Time (months)
Pro
bab
ilit
y o
f O
S (
%) Afatinib
Erlotinib
Afatinib
Erlotinib
No. at risk No. at risk
CI = confidence interval; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; QD = once daily.
Afatinib Afatinib
Erlotinib Erlotinib
26
Factors No. of Patients HR (95% CI)
Overall 795 0.81 (0.69–0.95)
Age
<65 years 399 0.68 (0.55–0.85)
≥65 years 396 0.95 (0.76–1.19)
Gender
Male 666 0.82 (0.69–0.97)
Female 129 0.77 (0.51–1.14)
Race
Non-East Asian 623 0.87 (0.73–1.03)
East Asian 172 0.62 (0.44–0.88)
ECOG at baseline
0 260 0.76 (0.58–1.01)
1 531 0.80 (0.66–0.97)
Smoking history
Never smoker 44 0.77 (0.37–1.57)
Light ex-smoker 23 0.43 (0.16–1.12)
Current and other ex-smoker 728 0.81 (0.69–0.96)
Histology
Squamous 763 0.82 (0.70–0.96)
Mixed 32 0.55 (0.26–1.17)
Best response to first-line
chemotherapy
CR/PR 371 0.91 (0.72–1.15)
SD 328 0.71 (0.56–0.90)
Unknown 89 0.72 (0.44–1.17)
LUX-Lung 8: Consistent OS Benefit With Afatinib
Over Erlotinib Across All Subgroups
Soria JC et al. Lancet Oncol. 2015;16:897-907.
1/16
Favours Afatinib Favours Erlotinib
1/4 1 4 16
27
Greater and More Durable Tumour Control
With Afatinib Compared With Erlotinib
Soria et al. Lancet Oncol. 2015;16:897-907.
Afatinib
Erlotinib
Patient Index Sorted by Maximum Decrease (%)
Ma
xim
um
De
cre
as
e
Fro
m B
as
eli
ne
SL
D (
%)
–100
–80
–60
–40
–20
0
20
40
60
80
100 ≥20% increase (n=62)
0–<20% increase (n=90)
>0–<30% decrease (n=81)
≥30% decrease (n=22)
Patient Index Sorted by Maximum Decrease (%) –100
–80
–60
–40
–20
0
20
40
60
80
100 ≥20% increase (n=74)
0–<20% increase (n=101)
>0–<30% decrease (n=77)
≥30% decrease (n=13)
Ma
xim
um
De
cre
as
e
Fro
m B
as
eli
ne
SL
D (
%)
50.5
5.5
39.5
2.8 0
10
20
30
40
50
60
DCR ORR
Afatinib
Erlotinib
P=0.055
P=0.002
Pe
rce
nt
• Duration of response was 7.29 months for
afatinib and 3.71 months for erlotinib
28
• Afatinib AE profile was consistent with its mechanistic profile and was manageable
• Pattern of AEs was consistent in both arms with similar rates of severe, serious, and
fatal AEs
LUX-Lung 8: Similar Adverse Event Profile for Afatinib and
Erlotinib—Consistent With EGFR Inhibition
Soria et al. Lancet Oncol. 2015;16:897-907.
aInterstitial lung disease (n=2), pneumonia, respiratory failure, acute renal failure, and general physical health deterioration (1 patient each). bInterstitial lung disease, pneumonitis, pneumonia, intestinal obstruction, and peritonitis (1 patient each).
Events
Afatinib
(n=392)
(%)
Erlotinib
(n=395)
(%)
Any AE 99.5 97.5
Drug-related AEs 93.4 81.3
AEs leading to dose reduction 26.5 14.2
AEs leading to discontinuations 20.2 17.0
CTCAE grade 3 or higher 57.1 57.4
Serious AEs 44.1 44.1
Drug-related fatal AEs 1.5a 1.3b
29
• Significantly more patients had improved overall health-related quality-of-life (36% vs 28%;
P=0.041) and improvement in cough (43% vs 35%; P=0.029) than with erlotinib
• Afatinib significantly delayed time to deterioration of dyspnoea compared with erlotinib (median
2.6 months [95% CI 2.0–2.9] vs 1.9 months [1.9–2.3]; HR 0.79 [95% CI 0.66–0.94]; P=0.0078)
Disease-Related Symptom Relief and
Quality of Life
Soria et al. Lancet Oncol. 2015;16:897-907.
GHS = global health status.
No. of Patients HR (95% Cl)
Coughing (Q1
from QLQ-LC13) 793 0.89 (0.72-1.09)
Dyspnoea (Q3–Q5
from QLQ-LC13) 793 0.79 (0.66-0.94)
Pain (Q9, Q19
from QLQ-C30) 793 0.99 (0.82-1.18)
GHS/QoL (Q29–Q30
from QLQ-C30) 793 0.93 (0.78-1.12)
1/4 1/2 1 2 4
Favours
afatinib
Favours
erlotinib
Symptom Improvement Time to Deterioration
Patients With Improvement in
Symptoms (%)
28.3
39.2
44.1
35.2
35.7
40.2
51.3
43.4
0 10 20 30 40 50 60
GHS/QoL (Q29–Q30 from QLQ-C30)
Pain (Q9, Q19from QLQ-C30)
Dyspnea (Q3–Q5 from QLQ-LC13)
Coughing (Q1from QLQ-LC13)
Afatinib Erlotinib
Dyspnoea (Q3–Q5
from QLQ-LC13)
P=0.04
P=0.78
P=0.06
P=0.03
30
Post-hoc Analysis of LUX-Lung 8 ‘Long-term
Responders’ (LTRs)1
1. Yang J et al. ELCC 2017. Poster #102P.
.
*Serum protein test used to assign a ‘Good’ or ‘Poor’ classification, with prognostic and predictive utility for EGFR-targeted agents in NSCLC2.
OS: Primary Analysis
(ITT population) • 12 and 18-month OS rates indicated that
some patients derived prolonged benefit
with afatinib
• Post-hoc analysis identified 21 patients
(LTRs) who received ≥12 months of afatinib
treatment
– Median treatment duration was 17.6 months
(range: 12.3–27.6 months)
• Possible molecular/clinical biomarkers
indicative of long-term response to afatinib
were evaluated
– Baseline characteristics
– Efficacy/safety of afatinib
– Molecular genomic analysis
– VeriStat® classification*
1.0
0.8
0.6
0.4
0.2
0 0 3 6 9 12 15 18 21 24 27 30
Time (months)
Esti
mate
d O
S p
rob
ab
ilit
y
36.4%
22.0%
28.2%
14.4%
Afatinib (n=398)
Erlotinib (n=397)
31
Treatment Response* and OS in LTRs
Yang J et al. ELCC 2017. Poster #102P.
*Stable disease unless noted otherwise (patient 2 was classified as non-evaluable); †Patients were ordered and numbered by treatment duration, with patient 1 being on
treatment longest; ‡First observed response at time of tumour measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death; ‖Received ≥1 line of chemotherapy after afatinib; CR = complete response; PR = partial response.
• Median OS was 21.1 months (range: 12.9–31.6 months)
• Median PFS (independent central review) was 16.6 months (range: 2.8–25.8 months)
32
• ErbB family mutations were more frequent in LTRs than in the overall afatinib-treated population
Genomic Aberrations in LTRs
Yang J et al. ELCC 2017. Poster #102P.
*Next-generation sequencing was undertaken in 10/21 LTRs and 132/398 afatinib-treated patients overall; WT = wild-type.
LTRs (n=10*) All afatinib-treated patients (n=132*)
ErbB3,
0% ErbB4,
10.0%
ErbB WT,
50.0%
ErbB2,
20.0%
EGFR,
20.0%
ErbB4,
2.3%
ErbB WT,
81.1%
ErbB2,
6.8% EGFR,
6.8%
ErbB3,
4.6%
33
• VeriStrat® is a predictive and prognostic serum-based protein test for patients with
advanced NSCLC who test negative for EGFR mutations or whose EGFR mutation
status is unknown
• Commercially available test (Biodesix) designed to identify which patients are likely to
benefit from an oral EGFR tyrosine kinase inhibitor
• The test classifies patients as either VeriStrat Good (VS-G) or VeriStrat Poor (VS-P)
• In addition to being prognostic, VeriStrat is predictive of differential treatment benefit
when selecting between single-agent treatment options
VeriStrat® Analysis of LUX-Lung 8 to Predict
Treatment Benefit Between Afatinib vs Erlotinib
Main Objectives of LUX-Lung 8 Analysis:
1. To assess the utility of VeriStrat as a predictive test of differential clinical benefit between afatinib and
erlotinib
2. To investigate the ability of VeriStrat to stratify patients treated with afatinib as a single agent
34
Afatinib Significantly Improved OS and PFS Over
Erlotinib in VS-G Patients
Gadgeel S et al. Lung Cancer. 2017;109(2017):101-108.
35
In the Entire VeriStrat-classified Population,
VSV-G Patients Had Better OS and PFS
Gadgeel S et al. Lung Cancer. 2017;109(2017):101-108.
36
• Fully human anti-EGFR monoclonal
antibody
• SQUIRE1
– Cisplatin/gemcitabine ± necitumumab in
squamous NSCLC
– Primary endpoint: survival
• INSPIRE2
– Cisplatin/pemetrexed ± necitumumab in
non-squamous NSCLC
– Primary endpoint: survival
– Enrolment (n=634) was prematurely
closed due to thromboembolic events
Anti-EGFR Mab: Necitumumab
1. Thatcher N et al. Lancet Oncol. 2015;16(7):763-74; 2. Paz-Ares L et al. Lancet Oncol. 2015;16(3):328-37.
OS 11.5 VS 9.9 MO
HR = 0.84; P=0.01
37
SQUIRE: EGFR H Score ≥200 OS
Paz-Ares L et al. Lancet Oncol. 2015;16:763-774.
38
EGFR-TKI/Ab
I-O Anti-VEGF
Chemotherapy
39
CheckMate-017 (Nivolumab vs Docetaxel): OS
Felip E et al. Ann Oncol. 2017;28(Supplement 5):abstract 1301PD; Horn L et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.74.3062 [Epub ahead of print].
40
CheckMate-017: OS in PD-L1 Subgroups
Felip E et al. Ann Oncol. 2017;28(Supplement 5):abstract 1301PD.
41
CheckMate-017: PFS
Felip E et al. Ann Oncol. 2017;28(Supplement 5):abstract 1301PD.
aInvestigator-assessed. NC = not calculable.
42
KEYNOTE-010: Pembrolizumab vs Docetaxel
1. Herbst RS et al. Lancet. 2016;387:1540-1550; 2. Herbst RS et al. J Clin Oncol. 2017;35(suppl; abstr 9090).
CI = confidence interval; HR = hazard ratio; OS = overall survival; PD-L1 = programmed death-ligand 1; TPS = tumour proportion score.
OS in Patients With PD-L1 TPS ≥50%1
Treatment arm
Median (95% CI),
months HR (95% CI) P
–– Pembrolizumab 2 mg/kg 14.9 (10.4–NR) 0.54 (0.38–0.77) 0.0002
–– Pembrolizumab 10 mg/kg 17.3 (11.8–NR) 0.50 (0.36–0.70) <0.0001
–– Docetaxel 8.2 (6.4–10.7) – –
• Post hoc multivariate analyses showed that nonsquamous histology was associated with better OS among
patients treated with pembrolizumab (nonsquamous vs squamous histology HR 0.55 [0.43-0.70; P<0.0001])2
43
KEYNOTE 010: OS in Key Subgroups
(PD-L1 TPS 1≥%*)
Herbst RS et al. Lancet. 2016;387:1540-1550.
*Data for pembrolizumab were pooled. CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor;
OS = overall survival; PD-L1 = programmed death-ligand 1; TPS = tumour proportion score.
44
Key eligibility criteria
• Untreated Stage IV NSCLC
• PD-L1 TPS ≥50%
• ECOG PS 0–1
• No activating EGFR mutation or ALK
translocation
• No untreated brain metastases
• No active autoimmune disease requiring
systemic therapy
Pembrolizumab
200 mg IV Q3W (2 years)
R (1:1)
N=305
PD* Crossover to
Pembrolizumab
200 mg Q3W
for 2 years
Platinum-doublet
chemotherapy
(4–6 cycles)
KEYNOTE-024: Pembrolizumab Versus
Chemotherapy in 1L Advanced NSCLC1–2
1. Reck M et al. Ann Oncol. 2016;27(suppl 6):abstract LBA08; 2. Reck M et al. N Engl J Med. 2016;375:1823-33.
*To be eligible for crossover, PD had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met.
ALK = anaplastic lymphoma kinase; DOR = duration of response; ECOG PS = Eastern Cooperative Group performance status; EGFR = epidermal growth factor receptor;
NSCLC = non-small cell lung cancer; PD = disease progression; ORR = objective response rate; OS = overall survival; PFS = progression free survival; R = randomization;
PD-L1 = programmed death ligand 1; Q3W = every three weeks; TPS = tumor proportion score.
Key endpoints
• Primary: PFS (RECIST v1.1 per blinded, independent central review)
• Secondary: OS, ORR and safety
• Exploratory: DOR
45
KEYNOTE-024: Pembrolizumab Versus Platinum-
doublet Chemotherapy1–3
1. Reck M et al. N Engl J Med. 2016;375:1823-33; 2. NICE Single Technology Appraisal committee papers [ID990]; 3. Brahmer J et al. J Clin Oncol. 2017;35(suppl; abstr 9000).
Chemo = chemotherapy; CI = confidence interval; HR = hazard ratio; mo = months; OS = overall survival; PFS = progression free survival; Pembro = pembrolizumab.
PFS (primary endpoint) OS (secondary endpoint)
Update from ASCO 2017, abstract 9000
46
OAK Trial: Overall Survival, ITT (n=850)
Rittmeyer A et al. Lancet. 2017;389(1066):255-265.
aStratified HR.
Atezolizumab
Docetaxel
Median 9.6 mo
(95% CI, 8.6, 11.2)
Median 13.8 mo
(95% CI, 11.8, 15.7)
Minimum follow
up = 19 months O
ve
rall
Su
rviv
al
(%)
Months
HR, 0.73a
(95% CI, 0.62, 0.87)
P=0.0003
47
OAK: OS by PD-L1 Expression
Barlesi et al. Atezolizumab Phase III OAK Study.
TC3 or
IC3
16%
TC2/3 or
IC2/3
31%
TC1/2/3 or
IC1/2/3
54%
TC0 and
IC0
45%
0.2 2
In favour of docetaxel
Hazard Ratioa
In favour of atezolizumab
ITTa 13.8 9.6
TC0 and IC0 12.6 8.9
TC1/2/3 or IC1/2/3a 15.7 10.3
TC2/3 or IC2/3 16.3 10.8
TC3 or IC3 20.5 8.9 0.41
0.67
0.74
0.75
0.73
1
Subgroup
Median OS, mo
Atezolizumab
n=425
Docetaxel
n=425
aStratified HR for ITT and TC1/2/3 or IC1/2/3. Rest unstratified.
48
OAK: OS by Histology
1. Rittmeyer A et al. Lancet. 2017;389(1066):255-265; 2. Satouchi M et al. WCLC. 2017;abstract OA 17.07.
Atezolizumab
Docetaxel
Median 15.6 mo
(95% CI, 13.3, 17.6)
Median 7.7 mo
(95% CI, 6.3, 8.9)
Median 8.9 mo
(95% CI, 7.4, 128)
Non-squamous1 Squamous1
HR, 0.73a
(95% CI, 0.60, 0.89)
P=0.0015
Median 11.2 mo
(95% CI, 9.3, 12.6)
Minimum follow
up = 19 months
Ove
rall S
urv
iva
l (%
)
Months
Minimum follow
up = 19 months
HR, 0.73a
(95% CI, 0.54, 0.98)
P=0.0383
Ove
rall S
urv
iva
l (%
)
Months
Atezolizumab
Docetaxel
• In an analysis of long-term survivors (n=119) with a minimum follow-up of 26 months, 15.1% of patients had squamous histology,
compared to 84.9% of patients with non-squamous histology2
• In non-long-term responders (n=279), 30.1% of patients had squamous histology, compared to 69.9% of patients with non-squamous
histology2
49
OAK: OS in Non-Squamous and Squamous
NSCLC by BOR Subgroups
de Marinis F et al. Annals of Oncology. 2017;28(Supplement 5) [poster 1310P].
50
EGFR-TKI/Ab
I-O Anti-VEGF
Chemotherapy
51
REVEL: Ramucirumab Plus Docetaxel vs
Docetaxel
Garon EB et al. Lancet. 2014;384:665-673.
CI = confidence interval; HR = hazard ratio; OS = overall survival.
Overall Survival in the Squamous Histology Subgroup
Ove
rall
Su
rviv
al
Patients at risk
Ramucirumab + docetaxel
Placebo + docetaxel
3 6 9 12 15 36 18 21
0.2
0.4
0.6
0.8
1.0
0
0
Time (months)
24 27 30 33
124 103 78 49 31 0 23 16 157 6 2 1 1
132 99 75 48 31 0 20 14 171 8 5 4 0
Ramucirumab +
Docetaxel 10 mg/kg +
75 mg/m2 q3wk
(n=157)
Placebo +
docetaxel
75 mg/m2 q3wk
(n=171)
Median OS
(months) 9.5 8.2
HR 0.883; 95% CI: 0.692–1.127
P=0.319
Placebo + docetaxel
Ramucirumab + docetaxel
52
REVEL: SQCC Subgroup
Garon EB et al. The Lancet. 2014;384(9944):665-673.
PFS OS*
The most common grade 3 or worse neutropenia, febrile neutropenia, fatigue, leucopenia and hypertension in the
ramucirumab group. The numbers of deaths from adverse events and grade 3 or worse pulmonary haemorrhage did not differ
between groups
.
*Difference in OS was non-significant
53
Second-line Therapy
NCCN Guidelines Version 5.2017 Non-Small Cell Lung Cancer.
NCCN NSCLC 2017V5
54
S1400 (MASTER LUNG-1) 2nd Line on SqNSCLC
Project Chair; V. Papadimitrakopoulou; Steering Committee Chair: R. Herbst; SWOG Lung Chair: D. Gandara.
Biomarker
Nonmatch
CT
PD-L1i
MEDI4736 Multiple Phase II-III Arms With “Rolling Opening and Closure”
Biomarker Profiling
(NGS/CLIA)
CT PIK3i
Primary Endpoint
OS
GDC0032
PiK3CA mut
CT CDK 4/6i
Primary Endpoint
OS
Palbociclib
CCND1 amp or CDKN2
loss + RB WT
CT FGFRi + CT
Primary Endpoint
OS
AZD4547
FGFR amp,
mut, fusion
E HGFi + E
Primary Endpoint
OS
AMG102+E
MET expr
(IHC score)
55
Current Treatment Recommendations for
Metastatic SqCC of the Lung
1. Novello S et al. Ann Oncol. 2016;27(suppl 5):v1–v27.
*ESMO guidelines do not recommend maintenance therapy in the treatment of squamous cell carcinoma NSCLC.1 BSC = Best Standard of Care; EGFR = epidermal growth factor receptor;
MCBS = Magnitude of Clinical Benefit Scale; NSCLC = non-small cell lung cancer; PD-L = programmed death-ligand; PS = Performance Status; SqCC = squamous cell carcinoma.
Nivolumab (I, A; MCBS 5)
Pembrolizumab if PD-L1>1%
(I, A; MCBS 3 if PD-L1 >1%; MSBC 5 if PD-L1
>50%
Docetaxel (I, B)
Ramucirumab – docetaxel (I, B; MCBS 2)
Erlotinib (II, C)
Afatinib (I, C; MCBS 1)
PS 3–4
Disease progression
Never or former light
smoker (<15 pack/year)
I) Age
II) PS
<70 years and PS 2
or
>70 years and PS 0–2
PS 0–2
Molecular test
(ALK/EGFR)
Molecular test
positive
Molecular test
negative
Targeted therapy
<70 years and PS 0-1
PS 3–4
BSC (II, B)
4–6 cycles:
Cisplatin – gemcitabine (I, A)
Cisplatin – docetaxel (I, A)
Cisplatin – vinorelbine (I, A)
Carboplatin – paclitaxel (I, A)
Carboplatin – nab-paclitaxel (I, B)
Cisplatin – gemcitabine – necitumumab
(if EGFR expression by IHC)
(I, B; MCBS 1)
4–6 cycles:
Carboplatin-based doublets (II, B)
Single-agent chemotherapy
(gemcitabine, vinorelbine or docetaxel)
(I,A)
BSC
Stage IV SqCC
56
• Platinum doublet chemotherapy remains the gold standard of care for 1st line
treatment of advanced lung SqCC
• Afatinib should be considered the treatment of choice in the 2nd line setting in certain
populations (eg, patients who are not eligible for I-O therapy) as a treatment option in
SqCC patients who have failed chemotherapy and I-O therapy
• Anti-angiogenic agents are generally contraindicated in SqCC due to safety concerns,
with the exception of Ramucirumab
• Despite of the complex genomic profile of SqCC, some potentially functionable
molecular targeted agents are under investigation
• I-O therapy has emerged as a promising novel treatment option for advanced SqCC
Summary
I-O = immune checkpoint inhibitor; SqCC = squamous cell carcinoma.
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