recent therapeutic advances in squamous cell … therapeutic advances in squamous cell carcinoma of...

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


- 3 PI decision

11 withdrew

before first evaluation

- 4 no visiting as plan

- 1 symptom deterioration

- 1 protocol violation


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


*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


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


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


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


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.

For more information about other BI events and collaborations, please visit www.inOncology.com

http://www.inoncology.com/

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