1. Optimizing the Care of Patients With Squamous Non-Small Cell Lung Cancer
This activity is supported by educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly.

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3. Faculty
Leora Horn, MD, MSc, FRCPC Associate Professor of Medicine Clinical Director, Thoracic Oncology Research Program Assistant Director, Education Development Program Vanderbilt Ingram Cancer Center Nashville, Tennessee
Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting fees from Genentech and Merck, has consulted without personal honorarium for Bayer, Bristol- Myers Squibb, Boehringer Ingelheim, and Xcovery, received fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speakers’ bureaus) from Biodesix, and funds for research support from AstraZeneca.
This slide lists the faculty who were involved in the production of these slides.

4. Agenda Lung Cancer: Overview
Therapeutic Options in Squamous NSCLC: Chemotherapy
Therapeutic Options in Squamous NSCLC: Targeted Therapy
Therapeutic Options in Squamous NSCLC: Checkpoint Inhibitors
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com

5. Lung Cancer Remains Major Global Health Burden
One of the most common cancers and leading cause of cancer deaths in US and worldwide[1,2]
New cases, 2015 (estimated): US, 221,200; global, 2M
Deaths, 2015 (estimated): US, 158,040; global, 1.5M
5-yr US survival rates[3]
Overall: 18%
Metastatic: 4%
1. GLOBOSCAN Cancer Fact Sheets Siegel RL, et al. CA Cancer. 2015; 65: Surveillance, Epidemiology, and End Results (SEER) Program.
Slide credit: clinicaloptions.com

6. Traditional View of Lung Cancer
40% 45
20% 40
10% to 15% 35 30 25
25% to 30%
Cancer Incidence (%) 20 15 10
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other or not otherwise specified 5
NSCLC, non-small-cell lung cancer.
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
Yr of Diagnosis (3-Yr Moving Average)
Adenocarcinoma Squamous cell Large cell
85% of lung cancers are NSCLC
American Cancer Society database.
Wahbah M, et al. Ann Diagn Pathol. 2007;11:89-96.
Slide credit: clinicaloptions.com

7. Histology-Based Subtyping
Evolution of NSCLC Subtyping to a Multitude of Molecular-Defined Subsets
NSCLC
as one disease
Histology-Based Subtyping
Squamous
34%
Other
11%
Adenoca
55%
Adenocarcinoma
Squamous Cell Cancer
ALK
HER2
BRAF
PIK3CA
AKT1
MAP2K1
NRAS
ROS1
RET
EGFR
KRAS
Unknown
EGFRvIII
PI3KCA
DDR2
FGFR1 Amp
First-targeted tx
NSCLC, non-small-cell lung cancer; tx, treatment
Slide credit: clinicaloptions.com
Li T, et al. J Clin Oncol. 2013;31:

8. Biopsy: Establish Diagnosis, Determine Histologic Subtype, Molecular Testing
Adequate tissue for histologic subtyping, molecular analysis critical
Histologic subtyping: squamous or nonsquamous?
Determination of EGFR mutation, ALK, and ROS1 translocations indicated in all nonsquamous cancers
Should other genes be evaluated? KRAS, BRAF, HER2, RET, others?
Should these genes be evaluated in squamous NSCLC?
Rebiopsy at time of progression
Helps in determining resistance in EGFR-mutated and ALK+ cases
Bone biopsy (for molecular testing) contraindicated due to decalcification and degradation of DNA
Liquid biopsies (cell-free DNA in plasma) increasingly used
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com

9. Therapeutic Options in Squamous NSCLC: Chemotherapy
NSCLC, non-small-cell lung cancer.

10. Therapeutic Plateau in Metastatic NSCLC ECOG 1594
1.0
Cisplatin/paclitaxel
Cisplatin/gemcitabine
Cisplatin/docetaxel
Carboplatin/paclitaxel
0.8
0.6
Overall Survival (%)
0.4
NSCLC, non-small-cell lung cancer.
0.2 5 10 15 20 25 30
Mos
Slide credit: clinicaloptions.com
Schiller JH, et al. N Engl J Med. 2002;346:92-98.

11. Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine in Advanced NSCLC
Randomized, noninferiority phase III study
Stratified by stage, PS, history of brain metastasis, sex, pathologic diagnosis, center
Cisplatin 75 mg/m2 on Day 1 +
Pemetrexed 500 mg/m2 on Day 1
(n = 862)
Chemotherapy naive stage IIIB-IV NSCLC, ECOG PS 0-1
(N = 1725)
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status.
Cisplatin 75 mg/m2 on Day 1 +
Gemcitabine 1250 mg/m2 on Days 1 and 8
(n = 863)
Vitamin B12, folate, and dexamethasone administered in both arms
Slide credit: clinicaloptions.com
Scagliotti GV, et al. J Clin Oncol. 2008;26: 11 11

12. Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine: OS by Histology
8832 Post-IASLC Program
Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine: OS by Histology
Nonsquamous
Squamous
C/P C/G C/P vs C/G
Median Survival, Mos
11.8
10.4
Adjusted HR: 0.81 (95% CI: )
Median Survival, Mos
1.0
1.0
C/P C/G C/P vs C/G
9.4
10.8
0.8
0.8
Adjusted HR: 1.23 (95% CI: )
0.6
0.6
Survival Probability
Survival Probability
0.4
0.4
0.2
0.2
C/G, cisplatin/gemcitabine; C/P, cisplatin/pemetrexed; NSCLC, non-small-cell lung cancer. 6 12 18 24 30 6 12 18 24 30
Mos
Mos
No difference in overall group between study arms: C/P 10.3 mos vs C/G 10.3 mos; adjusted HR: 0.94 (95% CI: )
Slide credit: clinicaloptions.com
Scagliotti GV, et al. J Clin Oncol. 2008;26: 12

13. Carboplatin/Albumin-Bound Paclitaxel vs Carboplatin/Paclitaxel in Advanced NSCLC
Stratified by stage (IIIb vs IV), age (< 70 yrs vs > 70 yrs), sex, histology (squamous vs nonsquamous), geographic region
21-day cycles
Albumin-bound Paclitaxel 100 mg/m2 on Days 1, 8, 15 +
Carboplatin AUC 6 on Day 1
No premedication
Pts with stage IIIb/IV NSCLC, ECOG PS 0-1, no previous chemotherapy for metastatic disease
(N = 1050)
Paclitaxel 200 mg/m2 on Day 1 +
Carboplatin AUC 6 on Day 1
Premedication: dexamethasone, antihistamines
AUC, area under the curve; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status.
Phase III Primary endpoint: ORR Secondary endpoints: PFS, OS, safety
Slide credit: clinicaloptions.com
Socinski MA, et al. J Clin Oncol. 2012;30:

14. Carboplatin/Albumin-Bound Paclitaxel vs Carboplatin/Paclitaxel: Response
Carboplatin/albumin-bound paclitaxel Carboplatin/paclitaxel
P < .001 RRR: 1.680 50
Response Rate (%)
P = .005 RRR: 1.31
41% 40
P = .808 RRR: 1.034
33% 30
26%
25%
24%
25% 20
RRR, response rate ratio. 10
n =
521
531
229
221
292
310
Intent to Treat
Squamous*
Nonsquamous*
*Not a prespecified endpoint. Interaction P value for histology = .036
Slide credit: clinicaloptions.com
Socinski MA, et al. J Clin Oncol. 2012;30:

15. Carboplatin/Albumin-Bound Paclitaxel vs Carboplatin/Paclitaxel: OS
ITT
nab-P/ Carbo
Paclitaxel/ Carbo HR
P Value
N/events
521/360
531/384
Median OS, mos (95% CI)
12.1 ( )
11.2 ( )
0.922 ( )
.271
Squamous Cell
nab-P/ Carbo
Paclitaxel/ Carbo HR
P Value
N/events
229/170
221/173
Median OS, mos (95% CI)
10.7 ( )
9.5 ( )
0.890 ( )
.284
nab-P/carbo (n = 521) Paclitaxel/carbo (n = 531)
1.00
1.00
nab-P/carbo (n = 229) Paclitaxel/carbo (n = 221)
0.75
0.75
Probability of Survival
0.50
Carbo, carboplatin; ITT, intent to treat; nab-paclitaxel, albumin-bound paclitaxel.
Probability of Survival
0.50
0.25
0.25 3 6 9 12 15 18 21 24 27 30 33 3 6 9 12 15 18 21 24 27 30 33
Mos
Mos
Slide credit: clinicaloptions.com
Socinski MA, et al. J Clin Oncol. 2012;30:

16. Therapeutic Options in Squamous NSCLC: Targeted Therapy
NSCLC, non-small-cell lung cancer.

17. SQUIRE: Gemcitabine/Cis + Necitumumab vs Gemcitabine/Cis in Stage IV NSCLC
21-day cycles;
maximum of 6 cycles
Necitumumab 800 mg Days 1, 8
Gemcitabine 1250 mg/m² Days 1, 8
Cisplatin 75 mg/m² Day 1
(N = 545)
Necitumumab 800 mg Days 1, 8
Stage IV squamous
NSCLC
ECOG PS 0-2
(N = 1093)
Treatment continued until PD or intolerable AEs
Gemcitabine 1250 mg/m² Days 1, 8 Cisplatin 75 mg/m² Day 1 (N = 548)
Radiographic tumor assessment (investigator read): at baseline and every 6 wks until PD
Mandatory tissue collection
AE, adverse event; Cis, cisplatin; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status
Phase III
Primary endpoint: OS
Slide credit: clinicaloptions.com
Thatcher N, et al. Lancet Oncol. 2015;16:

18. SQUIRE: Progression-Free Survival
HR: 0.85 (95% CI: ; P = .020)
HR (95% CI)
100
0.85
0.82
1.07
0.63
0.90
0.88
0.70
0.84
0.86
0.79
ITT population (N = 1093)
< 70 yrs of age (n = 888)
≥ 70 yrs of age (n = 205)
Female (n = 185)
Male (n = 908)
White (n = 913)
Nonwhite (n = 180)
Ex-light & nonsmoker (n = 97)
Smoker (n = 995)
PS 0 (n = 344)
PS 1 (n = 652)
PS 2 (n = 96) 32 28 24 20 16 12 8 4
Mos Since Randomization
PFS (%)
Median PFS, Mos (95% CI) 80
Gem/Cis + Neci:
Gem/Cis:
5.7 ( )
5.5 ( ) 60 40 20
Cis, cisplatin, Gem, gemcitabine; ITT, intent to treat; Neci, necitumumab; PS, performance status.
0.5
1.0
1.5
Favors
Gem/Cis + Neci
Favors
Gem/Cis
Slide credit: clinicaloptions.com
Thatcher N, et al. Lancet Oncol. 2015;16:

19. SQUIRE: Overall Survival
Gemcitabine/ Cisplatin + Necitumumab (n = 545)
100
Gemcitabine/ Cisplatin
(n = 548)
Pts censored, n (%)
Median OS, mos (95% CI)
Stratified P value (log rank)
Stratified HR (95% CI)
127 (23)
11.5 ( )
.01
0.84 ( )
106 (19)
9.9 ( ) 80 60
OS (%) 40 20
Gemcitabine/cisplatin + necitumumab
Censored pts
Gemcitabine/cisplatin 4 8 12 16 20 24 28 32 36 40
Mos
Slide credit: clinicaloptions.com
Thatcher N, et al. Lancet Oncol. 2015;16:

20. SQUIRE: Adverse Events
AEs, %
Gem/Cis + Neci Overall (N = 538)
Gem/Cis Overall (N = 541)
Any AEs
99.1
97.8
Grade ≥ 3 AEs
72.1
61.6
Serious AEs
47.8
37.5
AEs leading to discontin. of any study drug
31.2
24.6
AEs with outcome of death*
12.3
10.5
Treatment related death†
2.8
1.8
AE, adverse event; Cis, cisplatin, Gem, gemcitabine; Neci, necitumumab; PD, progressive disease.
*Including death due to PD.
†As assessed by investigators; missing relationship was counted as related.
Thatcher N, et al. Lancet Oncol. 2015;16: Thatcher N, et al. ASCO Abstract 8008.
Slide credit: clinicaloptions.com

21. SWOG S089: Carbo/Pac ± Bevacizumab ± Cetuximab in Advanced NSCLC
Randomized phase III trial
Primary endpoints: OS (total); PFS in EGFR-positive pts
Secondary endpoints: OS and PFS by bevacizumab use, safety
Exploratory endpoint: OS in EGFR+ and squamous pts
Stratified by appropriate for bevacizumab treatment (yes/no), smoking status, stage (M1a vs M1b)
Paclitaxel Carboplatin
Bevacizumab*
(n = 657)
Bevacizumab*
Advanced NSCLC
(N = 1313)
Paclitaxel Carboplatin Cetuximab
Bevacizumab*
(n = 656)
Cetuximab
Bevacizumab*
Carbo, carboplatin; NSCLC, non-small-cell lung cancer; Pac, paclitaxel.
*In appropriate pts.
Slide credit: clinicaloptions.com
Herbst RS, et al. WCLC Abstract 3612.

22. SWOG S089: Carbo/Pac ± Bevacizumab ± Cetuximab: OS
100
Median OS, Mos
10.9
9.4
95% CI
Cetuximab arm
Control arm N
656
657
Events, n
536
558 80
HR: 0.94 (95% CI: ; P = .34) 60
OS (%) 40
Carbo, carboplatin; NSCLC, non-small-cell lung cancer; Pac, paclitaxel. 20 12 24 36 48 60
Mos After Registration
Slide credit: clinicaloptions.com
Herbst RS, et al. WCLC Abstract 3612.

23. SWOG S089: OS in EGFR-Positive Squamous NSCLC
Events, n
Median OS, Mos
95% CI
Cetuximab arm 55 50
11.8
Control arm 56 52
6.4
100 80
HR: 0.56 (95% CI: ; P = .006) 60
OS (%) 40
NSCLC, non-small-cell lung cancer. 20 12 24 36 48 60
Mos
Slide credit: clinicaloptions.com
Herbst RS, et al. WCLC Abstract 3612.

24. SWOG S089: OS in EGFR-Positive Pts and by Bevacizumab Use
OS, Mos (95% CI)
Cetuximab
(n = 199)
Control
(n = 201)
EGFR positive
13.4 ( )
9.8 ( )
HR: 0.83 ( ; P = .10)
Bevacizumab appropriate*
Yes (all)
12.7 ( )
11.6 ( )
n = 279/275
HR: 1.04 ( ; P = .70)
No (all)
9.2 ( )
8.2 ( )
n = 377/382
HR: 0.88 ( ; P = .12)
Yes (EGFR+)
15.5 ( )
13.2 ( )
n = NR
HR: 0.97 ( ; P = .88)
No (EGFR+)
11.2 ( )
8.7 ( )
n = 113/121
HR: 0.75 ( ; P = .05)
*Patients with squamous-cell NSCLC were not eligible for bevacizumab therapy.
Slide credit: clinicaloptions.com
Herbst RS, et al. WCLC Abstract 3612.

25. SWOG S089: Adverse Events AEs, % Cetuximab Arm Control Arm
No Bev (n = 365)
Bev (n = 262)
No Bev (n = 367)
Bev (n = 265)
Grade 3/4
Grade 5
Grade
3/4 5
Blood/bone marrow 44 33 37
Metabolic/laboratory 18 20 12 14
Gastrointestinal 16 1 10
Infection 9 11
Pulmonary/upper respiratory 7 8 3
Dermatology/skin 17
0.3
0.4
Allergy/immunology 6 2
Renal/genitourinary
Total 66 4 77 54 69
AE, adverse event; Bev, bevacizumab.
Slide credit: clinicaloptions.com
Herbst RS, et al. WCLC Abstract 3612.

26. REVEL: Docetaxel ± Ramucirumab in Second-line NSCLC: Study Design
Stratified by ECOG PS 0 vs 1,
sex, prior maintenance,
East Asia vs ROW
Phase III study
Ramucirumab 10 mg/kg +
Docetaxel 75 mg/m2 q3w
(n = 628)
Stage IV NSCLC after 1 platinum- based chemo ± maintenance,
prior Bev allowed,
all histologies,
ECOG PS 0 or 1
(N = 1253)
Treatment until disease progression
or unacceptable toxicity
Placebo +
Docetaxel 75 mg/m2 q3w
(n = 625)
Bev, bevacizumab; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status; ROW, rest of world
Ramucirumab: VEGFR2 antibody
Primary endpoint: OS
Secondary endpoints: PFS, ORR, safety, pt-reported outcomes
Slide credit: clinicaloptions.com
Garon EB, et al. Lancet. 2014;384:

27. REVEL: Docetaxel ± Ramucirumab in Second-line NSCLC: Response
Phase III Study
Ram + Doc
Pl +
Doc
HR P Value
ORR, %
(95% CI)
22.9
( )
13.6 ( )
< .001
Median PFS, mos
4.5
( )
3.0
( )
0.72
< .0001
Median OS, mos
10.5 ( )
9.1
( )
0.86
.0235
100 80 60 40 20
OS (%)
Ram + Doc Pl + Doc 3 6 9 12 15 18 21 24 27 30 33 36
Doc, docetaxel; NSCLC, non-small-cell lung cancer; Pl, placebo; Ram, ramucirumab.
Survival Time (Mos)
First study in the second-line setting to show an OS advantage for the addition of a “targeted” agent to docetaxel compared with docetaxel alone
First and only study of angiogenesis inhibition in advanced NSCLC to show a benefit in a squamous cell cancer cohort
Slide credit: clinicaloptions.com
Perol M, et al. ASCO Abstract LBA8006^.

28. REVEL: Tumor Response by RECIST v1.1
Response, n (%)
Ramucirumab + Docetaxel (n = 628)
Placebo + Docetaxel (n = 625)
P Value CR
3 (0.5)
2 (0.3) PR
141 (22.5)
83 (13.3) SD
258 (41.1)
244 (39.0) PD
128 (20.4)
206 (33.0)
NE/NA
98 (15.6)
90 (14.4)
ORR (CR + PR), % (95% CI)
22.9 ( )
13.6 ( )
< .001
DCR (CR + PR + SD), % (95% CI)
64.0 ( )
52.6 ( )
DCR, disease control rate; NE, not evaluable; NA, not available; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
Garon EB, et al. Lancet. 2014;384: Perol M, et al. ASCO Abstract LBA8006.
Slide credit: clinicaloptions.com

29. REVEL: Progression-Free Survival
Censoring Rate, % 20 40 60 80
100
Median (95% CI)
Ram + Doc
Pbo + Doc
Ram + Doc vs Pbo + Doc:
HR: (95% CI: ; P < .0001)
4.5 ( )
3.0 ( )
11.1
6.7
PFS (%)
Ram + Doc
Pbo + Doc
Censored
Doc, docetaxel; Pbo, placebo; Ram, ramucirumab. 3 6 9 12 15 18 21 24 27 30 33 36
Mos
Slide credit: clinicaloptions.com
Garon EB, et al. Lancet. 2014;384:

30. REVEL: Overall Survival
Censoring Rate, % 20 40 60 80
100
Median (95% CI)
Ram + Doc
Pbo + Doc
Ram + Doc vs Pbo + Doc:
HR: (95% CI: ; P = .0235)
10.5 ( )
9.1 ( )
31.8
27.0
OS (%)
Doc, docetaxel; Pbo, placebo; Ram, ramucirumab.
Ram + Doc
Pbo + Doc
Censored 3 6 9 12 15 18 21 24 27 30 33 36
Mos
Slide credit: clinicaloptions.com
Garon EB, et al. Lancet. 2014;384:

31. LUX-Lung 8: Afatinib vs Erlotinib Study Design
Stratified by East Asian vs non-East Asian
Afatinib 40 mg* QD
(n = 398)
SCC of the lung (stage IIIB/IV);; progressed after ≥ 4 cycles of a first-line platinum doublet; ECOG PS 0-1; adequate organ function
(N = 795)
Erlotinib 150 mg† QD
(n = 397)
*Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted. †Dose reduction to 100 or 50 mg permitted. Tumor assessment at baseline, Wks 8, 12, 16; every 8 wks thereafter.
DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; PRO, patient-reported outcomes; PS, performance status; SCC, squamous cell carcinoma.
Primary endpoint: PFS by independent review
Secondary endpoints: OS, ORR, DCR, tumor shrinkage, PRO, safety
Slide credit: clinicaloptions.com
Soria JC, et al. Lancet Oncol. 2015;16:

32. Objective Response Rate
LUX-Lung 8: Response
P = .002 60
Afatinib
Erlotinib
50.5 50
p=0.002
39.5 40 30
Patients (%) 20
P = .055 10
5.5
2.8
Disease Control Rate
Objective Response Rate
Duration of response was 7.29 mos for afatinib and mos for erlotinib
Slide credit: clinicaloptions.com
Soria JC, et al. Lancet Oncol. 2015;16:

33. LUX-Lung 8: Progression-Free Survival
Afatinib (n = 398)
Erlotinib (n = 397)
1.0
Pts progressed/died, n (%)
Median PFS, mos
299 (75.1)
2.6
306 (77.1)
1.9
0.8
HR (95% CI) = 0.81 ( ; P = .010)
0.6
PFS (%)
0.4
0.2 3 6 9 12 15 18 21 24 27
Mos
Pts at Risk, n
Afatinib
Erlotinib
398
397
139 99 50 34 30 17 14 10 10 2 5 1 2 1 2 1
Slide credit: clinicaloptions.com
Soria JC, et al. Lancet Oncol. 2015;16:

34. LUX-Lung 8: Overall Survival
Afatinib (n = 398)
Erlotinib (n = 397)
1.0
Median OS, mos
7.9
6.8
HR (95% CI) = 0.81 ( ; P = .008)
0.8
0.6
OS (%)
0.4
36.4%
22.0%
0.2
28.2%
Afatinib
Erlotinib
14.4% 3 6 9 12 15 18 21 24 27 30
Mos
Median follow-up: 18.4 mos
Slide credit: clinicaloptions.com
Soria JC, et al. Lancet Oncol. 2015;16:

35. LUX-Lung 8: Drug-Related AEs (> 10%)
Events, %
Afatinib (n = 392)
Erlotinib
(n = 395)
Grade 1
Grade 2
Grade 3
Diarrhea 42 17 10 24 7 2
Rash or acne 40 21 6 36
Stomatitis 8 4 5 3
Fatigue
Nausea 9 1
< 1
Decreased appetite
Paronychia
Dry skin
Pruritus
Vomiting
Dehydration
AE, adverse event.
Grade 4 AEs: afatinib, diarrhea < 1%, dehydration 1%; erlotinib, diarrhea < 1.
Slide credit: clinicaloptions.com
Soria JC, et al. Lancet Oncol. 2015;16:

36. Therapeutic Options in Squamous NSCLC: Checkpoint Inhibitors
NSCLC, non-small-cell lung cancer.

37. PD-1 as a Target in Cancer Therapy
Exhausted T cell
Persistent antigen stimulation
Tumor
or APC
Tumor
or APC
Activated T cell
Initial immune response
CD80
CD86
CD28
Cytokines
Proliferation
Activation
APC, antigen-presenting cell.
CD80
CD86
CD28
PD-L1
PD-1
Atezolizumab
Durvalumab
MSB C
Nivolumab
Pembrolizumab
Pidilizumab
Slide credit: clinicaloptions.com
McDermott DF, et al. Cancer Med. 2013;2:

38. Treatment continued until progressive disease or unacceptable toxicity
CheckMate-063: Nivolumab in Previously Treated Squamous NSCLC: Study Design
Stage IIIB/IV squamous NSCLC; ≥ 2 previous systemic therapies; ECOG PS 0-1
(N = 140)
Treatment continued until progressive disease or unacceptable toxicity
Nivolumab 3 mg/kg IV Q2W
(n = 117)
Planned to treat approximately 100 pts
Expected ORR of 10% to 50%, with 20% maximum width of exact 2-sided 95% CI
Assessments (RECIST v1.1) performed at Wk 8 and every 6 wks
Primary endpoint: ORR and DoR by IRC (July 2014 database lock)
Secondary endpoint: ORR and DoR by investigator (March 2014 database lock)
Exploratory: safety and tolerability, PFS/OS, PD-L1 expression and efficacy
DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; NSCLC; nonsmall cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors; PS, performance status.
Slide credit: clinicaloptions.com
Rizvi NA, et al. Lancet Oncol. 2015;16:

39. Best Reduction From Baseline in Target Lesion ( by IRC) (%)
CheckMate-063: Response and Survival Status by Best Reduction in Target Lesion
Outcome
IRC Assessment (n = 95)
ORR, % (95% CI)
15 (9-22)
Median DoR,
mos (95% CI)
NR (8.3-NR)
Ongoing response, n/N (%)
13/17 (77)
Median time to
response, mos (range)
3.3 ( )
Median OS,
8.2 (6-11)
1-yr OS,
% (95% CI)
41 (32-50)
18-mo OS, % (95% CI)
27 (19-35)
100 75 50
-100 25
-25
-50
-75
Alive
Deceased
Confirmed responders
n = 95 response evaluable
Best Reduction From Baseline in Target Lesion ( by IRC) (%)
DoR, duration of response; IRC, independent radiology review committee; NR, not reached
Pts
Rizvi NA, et al. Lancet Oncol. 2015;16:
Horn L, et al. WCLC Abstract 828.
Slide credit: clinicaloptions.com

40. CheckMate-063: Overall Survival
Median Follow-up, Mos (Range)
Median OS, Mos (95% CI)
1-Yr OS Rate, % (95% CI)
18-Mo OS Rate, % (95% CI)
Events, n/N
July 2014
8.0 (0-17.3)
8.2 ( )
41 (32-50) –
72/117
June 2015
8.0 (0-26.8)
8.1 ( )
39 (30-48)
27 (19-35)
90/117 20 40 60 80
100
8.1 mos
OS (%)
39%
8.2 mos
41%
27% 6 12 18 24 3 9 15 21 27
Mos
Rizvi NA, et al. Lancet Oncol. 2015;16: Horn L, et al. WCLC Abstract 828.
Slide credit: clinicaloptions.com

41. CheckMate-063: Exploratory Analysis of ORR by PD-L1 Expression
Subgroups
ORR, % (n/N)
Overall
15 (17/117)
PD-L1
≥ 1%
20 (9/45)
< 1%
13 (4/31)
≥ 5%
24 (6/25)
< 5%
14 (7/51)
Indeterminate/not evaluable
30 (3/10)
86 available samples (76 evaluable)
Slide credit: clinicaloptions.com
Rizvi NA, et al. Lancet Oncol. 2015;16:

42. CheckMate-063: OS by PD-L1 Expression
Median OS, Mos (95% CI)
Events, n/N
PD-L1 < 1%
8.3 ( )
23/31
PD-L1 ≥ 1%
10.1 ( )
32/45
Not evaluable
13.0 ( )
8/10
100 80 60
OS (%) 40
< 1%
≥ 1%
Not evaluable 20 3 6 9 12 15 18 21 24 27
Mos
Slide credit: clinicaloptions.com
Horn L et al. WCLC Abstract 828.

43. CheckMate-063: Treatment-Related AEs
AEs, % (≥ 10% Pts)
Nivolumab 3 mg/kg (N = 117)
Any Grade
Grade 3/4
Total pts with an AE 74 17
Fatigue 33 4
Decreased appetite 19
Nausea 15
Asthenia 12
Rash 11 1
Diarrhea 10 3
85% of pts received at least 90% of planned dose intensity
12% discontinued treatment due to study drug toxicity (4% pneumonitis)
Grade 3 treatment-related pneumonitis reported in 4 pts (3%); 1 additional grade 3 occurred between days after last nivolumab dose
62% had died at time of analysis (including 54% PD and 2% study drug toxicity)
2 treatment-related deaths (1 hypoxic pneumonia and 1 ischemic stroke) occurred in pts with multiple comorbidities and concurrent PD
AE, adverse event; PD, progressive disease.
Slide credit: clinicaloptions.com
Rizvi NA, et al. Lancet Oncol. 2015;16:

44. CheckMate-017: Nivolumab vs Docetaxel in Previously Treated Squamous NSCLC
Open-label, randomized phase III trial
Primary endpoint: OS
Secondary endpoint: ORR, PFS, associations with PD-L1 expression, QoL
Nivolumab
3 mg/kg IV q2w
(n = 135)
Stage IIIB/IV squamous NSCLC; after failure of 1 previous platinum-based tx; ECOG PS 0-1
(N = 272)
Docetaxel
75 mg/m2 IV q3w
(n = 137)
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status; QoL, quality of life; tx, treatment.
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

45. CheckMate-017: Overall Survival
100 80 60 40 20
Median OS,
Mos (95% CI) 9.2 ( )
6.0 ( )
1-Yr OS,
% 42 24
18-Mo OS,
% 28 13
Nivolumab Docetaxel
HR: 0.59 (95% CI: ; P < .001)
OS (%) 3 6 9 12 15 18 21 24
Mos
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

46. CheckMate-017: ORR by PD-L1 Expression
PD-L1 Expression Level*
ORR,† %
< 1%
≥ 1%
< 5%
≥ 5%
< 10%
≥ 10% NE
Nivolumab 17 15 21 16 19 39
Docetaxel 10 11 12 8 9 3
Interaction P value
.94
.29
.64
*Percent membranous staining in ≥100 tumor cells. †CR + PR per RECIST v1.1 criteria confirmation of response required (investigator assessment).
NE, not evaluable; RECIST, Response Evaluation Criteria in Solid Tumors.
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

47. CheckMate-017: OS by PD-L1 Expression
1% PD-L1 Expression Level
5% PD-L1 Expression Level
10% PD-L1 Expression Level
Median OS, Mos
Median OS, Mos
Median OS, Mos
PD-L1 ≥ 1%
PD-L1 < 1%
Nivolumab
9.3
8.7
Docetaxel
7.2
5.9
PD-L1 ≥ 5%
PD-L1 < 5%
Nivolumab
10.0
8.5
Docetaxel
6.4
6.1
PD-L1 ≥ 10%
PD-L1 < 10%
Nivolumab
11.0
8.2
Docetaxel
7.1
6.1
100 80 60
OS (%) 40 20 6 12 18 24 6 12 18 24 6 12 18 24
Mos
Mos
Mos
Nivolumab PD-L1+
Nivolumab PD-L1-
Docetaxel PD-L1+
Docetaxel PD-L1-
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

48. CheckMate-017: Safety Treatment-related AEs in ≥ 5% of pts AE, %
Nivolumab (n = 131)
DocetaxeL (n = 129)
Any Grade
Grade 3/4
Total pts with an AE 58 7 86 55
Fatigue 16 1 33 8
Asthenia 10 14 4
Decreased appetite 11 19
Nausea 9 23 2
Diarrhea 20
Vomiting 3
Anemia 22
Myalgia
Neutropenia 30
Peripheral neuropathy 12
Alopecia
Febrile neutropenia
AE, adverse event.
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

49. KEYNOTE-001: Pembrolizumab in NSCLC: Subanalysis of Phase I Trial
Mandatory tumor biopsy
Pembrolizumab IV
2 mg/kg q3w (n = 6)
Continue dosing and assessments
every 9 wks
CR, PR, SD
Treatment-naive or previously treated advanced NSCLC (N = 495)
Pembrolizumab IV
10 mg/kg q3w (n = 287)
PD, unacceptable AE, or investigator decision
Off study
Pembrolizumab IV
10 mg/kg q2w (n = 202)
Administered tumor assessment: imaging every 9 wks
Primary: Response rate (RECIST)
Secondary: immune-related response criteria (irRC)
Tumor biopsy
Tumor biopsy within 60 days prior to first dose of pembrolizumab required
Tumor PD-L1 expression determined by prototype assay to inform enrollment; samples were independently reanalyzed using clinical trial IHC assay
AE, adverse event; irRC, immune-related response criteria; NSCLC, non-small-cell lung cancer; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease;
Slide credit: clinicaloptions.com
Garon EB, et al. N Engl J Med. 2015;372:

50. KEYNOTE-001: Pembrolizumab Efficacy in Overall Population
ORR
Pts, n
All Cohorts, % (95% CI)
Total
495
19.4 ( )
Treatment naive
101
24.8 ( )
Previously treated
394
18.0 ( )
Nonsquamous
401
18.7 ( )
Squamous 85
23.5 ( )
Slide credit: clinicaloptions.com
Garon EB, et al. N Engl J Med. 2015;372:

51. KEYNOTE-001: Pembrolizumab Efficacy by PD-L1 Expression
ORR
Pts, n
All Cohorts, % (95% CI)
Percent PD-L1 staining
≥ 50% 73
45.2 ( )
1% to 49%
103
16.5 ( )
< 1% 28
10.7 ( )
100
PFS
100 OS 80 80
PS ≥ 50% (n = 119) 60 60
PFS (%)
OS (%)
PS, proportion score.
PS ≥ 50% (n = 119) 40 40
PS % (n = 161)
PS < 1% (n = 76) 20
PS < 1% (n = 76) 20
PS % (n = 161) 2 4 6 8 10 12 14 16 18 20 22 24 26 4 8 12 16 20 24 28
Mos
Mos
Slide credit: clinicaloptions.com
Garon EB, et al. N Engl J Med. 2015;372:

52. KEYNOTE-001: Antitumor Activity by Histology
TPS ≥ 50%
TPS 1-49%
TPS < 1%
Total n
ORR, % (95% CI) N
Overall
144
38.2 ( )
185
11.9 ( ) 80
10.0 ( )
550
20.2 ( )
Squamous 24
50.0 ( ) 29
17.2 ( ) 13
0.0 ( ) 95
26.3 ( )
Non-squamous
117
35.9 ( )
153
11.1 ( ) 65
12.3 ( )
446
19.1 ( )
TPS, tumor proportion score.
Patients with squamous histology represent
17% of the total population
17% of the TPS ≥50% group
16% of the TPS 1-49% group
16% of the TPS <1% group
Histology is not associated with response after adjusting for smoking status or smoking status and PD-L1 TPS
PD-L1 score is strongly associated with response after adjusting for histology and smoking status
There is no strong evidence of an interactive effect on ORR between histology and PD-L1 TPS (P = 0.81)
Slide credit: clinicaloptions.com
Hellman MD, et al. WCLC Abstract 3057.

53. KEYNOTE-001: PFS by Histology
Squamous
Nonsquamous
Median PFS, Mos (95% CI)
Median PFS, Mos (95% CI) 4 8 12 16 20 24 28 32 40 60 80
100
Mos
PFS (%) 6 4 8 12 16 20 24 28 32 40 60 80
100
Mos
PFS (%) 6
TPS ≥ 50%
TPS 1-49%
TPS < 1%
10.3 ( )
6.0 ( )
3.5 ( )
TPS ≥ 50%
TPS 1-49%
TPS < 1%
4.3 ( )
2.3 ( )
2.2 ( )
TPS, tumor proportion score.
Median (range) duration of follow-up
Squamous: 14.6 mo ( )
Nonsquamous: 15.3 mo ( )
TPS ≥ 50%
TPS 1-49%
TPS < 1% 24 29 13 17 21 6 11 8 3 6 3 2 1
117
153 65 62 57 23 46 20 7 29 8 4 7 2 5 4 2
Slide credit: clinicaloptions.com
Hellman MD, et al. WCLC Abstract 3057.

54. KEYNOTE-001: OS by Histology
Squamous
Nonsquamous
Median OS, Mos (95% CI)
Median OS, Mos (95% CI)
100
100
TPS ≥ 50%
TPS 1-49%
TPS < 1%
14.0 ( )
9.2 (6.0-NR)
15.8 (3.4-NR)
TPS ≥ 50%
TPS 1-49%
TPS < 1%
18.5 (11.3-NR)
9.0 ( )
8.8 ( ) 80 80 60 60
OS (%)
OS (%) 40 40 20 20
NR, not reached; TPS, tumor proportion score. 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32
Mos
Mos
TPS ≥ 50%
TPS 1-49%
TPS < 1% 24 29 13 20 24 10 16 15 7 8 12 5 2
117
153 65 91
109 47 70 69 32 49 47 19 22 13 9 9 6 4 3 3 1
Slide credit: clinicaloptions.com
Hellman MD, et al. WCLC Abstract 3057.

55. KEYNOTE-010: Pembrolizumab vs Doc in Previously Treated PD-L1+ NSCLC
Phase II Study
Stratified by ECOG PS (0 vs 1); region (East Asia vs non-East Asia); PD-L1 status (TPS ≥50% vs 1%-49%)
Pembrolizumab 2 mg/kg IV q3w/24 mos
(n = 345)
Advanced NSCLC; confirmed PD after ≥ 1 line of chemotherapy; no active brain metastases; ECOG PS 0-1; PD-L1 TPS ≥ 1%; no serious autoimmune disease; no ILD or pneumonitis requiring systemic steroids
(N = 1034)
Pembrolizumab 10 mg/kg IV q3w/24 mos
(n = 346)
Docetaxel 75 mg/m2 IV q3w
(n = 343)
Doc, docetaxel; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ILD, interstitial lung disease; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; TPS, tumor proportion score.
End points in the TPS ≥ 50% stratum and TPS ≥ 1% population
Primary: PFS and OS
Secondary: ORR, DoR, safety
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

56. KEYNOTE-010: Overall Survival
Total Pt Population
Pts With PD-L1 TPS ≥ 50%*
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
100
100 80 80 60 60
OS (%)
OS (%) 40 40 20 20
TPS, tumor proportion score. 5 10 15 20 25 5 10 15 20 25
Mos
Mos
*Treatment Arm
Median, mo (95% CI)
HR (95% CI) P
Pembro 2 mg/kg
14.9 (10.4-NR)
0.54 ( )
.0002
Pembro 10 mg/kg
17.3 (11.8-NR)
0.50 ( )
< .0001
Docetaxel
8.2 ( ) —
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

57. KEYNOTE-010: OS Subgroup Analysis
Events/Pts, n
HR (95% CI)
Sex
Male
Female
< 65
≥ 65 1
≥ 50%
1-49%
Archival
New
Squamous
Adenocarcinoma
Mutant
Wild type
332/634
189/399
317/604
204/429
149/348
367/678
204/442
317/591
266/455
255/578
128/222
333/708
46/86
447/875
521/1033
0.65 ( )
0.69 ( )
0.63 ( )
0.76 ( )
0.73 ( )
0.63 ( )
0.53 ( )
0.76 ( )
0.70 ( )
0.64 ( )
0.74 ( )
0.88 ( )
0.66 ( )
0.67 ( )
Age, yrs
ECOG PS
PD-L1 TPS
Tumor sample
Histology
ECOG, Eastern Cooperative Oncology Group; PS, performance status; TPS, tumor proportion score.
EGFR status
Overall
0.1 1 10
Favors pembrolizumab
Favors docetaxel
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

58. KEYNOTE-010: Progression-Free Survival
Total Pt Population
Pts With PD-L1 TPS ≥ 50%
100
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
100
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel 80 80 60 60
PFS (%)
PFS (%) 40 40 20 20
TPS, tumor proportion score. 5 10 15 20 25 5 10 15 20 25
Mos
Mos
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

59. KEYNOTE-010: Adverse Events
AE, %
Pembrolizumab 2 mg/kg (n = 339)
Pembrolizumab 10 mg/kg (n = 343)
Docetaxel
(n = 309)
Any Grade
Grades 3-5
Related to treatment
Any 63 13 66 16 81 35
Occurring in ≥ 10% of pts in any group
Decreased appetite 14 1 10
< 1
Fatigue 2 25 4
Nausea 11 9 15
Rash 5
Diarrhea 7 6 18
Asthenia
Stomatitis
Anaemia 3
Alopecia 33
Neutropenia 12
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

60. POPLAR: Atezolizumab vs Docetaxel in Previously Treated NSCLC
Phase II Study
Pts with locally advanced or metastatic NSCLC and ECOG PS 0-1 who failed prior platinum-containing chemotherapy
(N = 287)
Atezolizumab 1200 mg IV q3w
(n = 144)
Docetaxel 75 mg/m2 IV q3w
(n = 143)
Stratified by PD-L1 immune cell expression (0 vs 1 vs 2 vs 3), histology (squamous vs nonsquamous), and line of therapy (second vs third line)
DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; NSCLC, non-small-cell lung cancer; PS, performance status.
Primary endpoint: OS in PD-L1–selected and ITT populations
Secondary endpoints: overall safety as well as PFS, ORR, DoR in PD-L1– selected and ITT populations
Slide credit: clinicaloptions.com
Spira AI, et al. ASCO Abstract 8010.

61. POPLAR : Overall Response Rates and Overall Survival50
Atezolizumab (n = 144) 38
Docetaxel (n = 143) 40 30
ORR (%) 22 20 18 18 15 15 15 13 10 10 8
TC3 or IC3
TC1/2/3 or
IC1/2/3
TC0 and
IC0
TC2/3 or
IC2/3
ITT
Median OS, Mos (Range)
TC3 or IC3
(n = 47)
TC2/3 or IC2/3
(n = 105)
TC or IC1/2/3
(n = 195)
TC0 or IC0
(n = 92)
Atezolizumab
15.5 (9.8-NE)
15.1 (8.4-NE)
11.5 (11.0-NE)
9.7 ( )
Docetaxel
11.1 (6.4-14)
7.4 ( )
9.2 ( )
9.7 ( )
HR (95% CI) P value
0.49 ( )
.068
0.54 ( )
.014
0.63 ( )
.005
1.12 ( )
.871
IC, tumor-infiltrating immune cells; ITT, intent to treat; NE, not estimable; TC, tumor cells.
Spira AI, et al. ASCO Abstract Vansteenkiste J, et al. ESMO Abstract LBA14.
Slide credit: clinicaloptions.com

62. POPLAR: OS by Histology
Median OS, Mos (95% CI)
Subgroup
n (%)
0.80
Atezolizumab
Docetaxel
Squamous
97 (34)
10.1 ( )
8.6 ( )
0.69
Nonsquamous
190 (66)
15.5 (9.8-NE)
10.9 ( )
0.73
ITT
N = 287
12.6 ( )
9.7 ( )
0.2 1 2
HR*
ITT, intent to treat; NE, not estimable.
Favors atezolizumab
Favors docetaxel
*Unstratified HR for subgroups and stratified HR for ITT. Data cutoff May 8, 2015.
Event/pt ratio:
Squamous 69% (63% for atezolizumab, 75% for docetaxel)
Nonsquamous 56% (49% for atezolizumab, 62% for docetaxel)
Slide credit: clinicaloptions.com
Vansteenkiste J, et al. ESMO Abstract LBA14.

63. POPLAR: All-Cause AEs (≥ 5% Difference Between Arms)
Myalgia
Decreased appetite
Dyspnea
Arthralgia
Insomnia
Musculoskeletal pain
Pneumonia
Hypothyroidism
Alopecia
Nausea
Diarrhea
Asthenia
Neutropenia
Febrile neutropenia
Peripheral sensory neuropathy
Peripheral neuropathy
Anemia
AEs more frequent with docetaxel
AEs more frequent with atezolizumab
AE, adverse event.
More respiratory events were reported for atezolizumab. When adjusted for exposure, there was no difference between study arms
Grade 1/2 AEs
Grades 3-5 AEs
Grade 1/2 AEs
Grades 3-5 AEs 40 30 20 10
Docetaxel
Atezolizumab
Dry skin, stomatitis, and nail disorder were additional AEs with ≥ 5% higher frequency in docetaxel
Safety population includes pts who received any amount of either study treatment
Slide credit: clinicaloptions.com
Spira AI, et al. ASCO Abstract 8010.

64. Conclusions
First line platinum-based therapy remains standard of care in pts with squamous cell NSCLC
Immune checkpoint inhibitors are approved as second-line therapy: nivolumab in unselected pts, pembrolizumab in pts with tumors positive for PD-L1 expression
Docetaxel combined with ramucirumab is a reasonable second-line option
EGFR TKIs have a limited role in this pt population
Novel targets are still needed
Slide credit: clinicaloptions.com

65. Go Online for More CCO Coverage of NSCLC!
Expert reviews of key non-small cell lung cancer data Additional slidesets on NSCLC management with expert faculty commentary on key studies Webcast presentations by expert faculty regarding treatment strategies for patients with NSCLC
clinicaloptions.com/oncology