1. Expert Perspectives on Immunotherapy for NSCLC: Practical Guidance and Recommendations
NSCLC, non-small-cell lung cancer.
This program is supported by an educational grant from Merck and Co., Inc.

2. About These Slides
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3. Co-Chairs
Leora Horn, MD, MSc, FRCPC Associate Professor of Medicine Clinical Director, Thoracic Oncology Research Program Assistant Vice Chairman for Faculty Development Vanderbilt Ingram Cancer Center Nashville, Tennessee Melissa L. Johnson, MD Associate Director, Lung Cancer Research Sarah Cannon Research Institute Nashville, Tennessee
This slide lists the faculty who were involved in the production of these slides.

4. Faculty Disclosures
Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting fees from AbbVie, Bayer, Bristol-Myers Squibb, Genentech, Lilly, and Merck and fees for non-CME/CE services from Xcovery. Melissa L. Johnson, MD, has disclosed that she has received consulting fees from AbbVie, Celgene, and Genentech and funds for research support from Array, AstraZeneca, BerGenBio, Checkpoint Therapeutics, EMD Serono, Genmab, Genentech/Roche, Janssen, Kadmon, Lilly, Mirati Therapeutics, Novartis, OncoMed, Pfizer, Regeneron, and Stemcentrx.

5. Outline Overview of the Treatment of Advanced NSCLC
Clinical Application of Immunotherapy for Advanced NSCLC
Newly Diagnosed Disease
Progressive Disease
Management of Treatment-Related Adverse Events
Emerging Therapeutic Strategies With Immune Checkpoint Inhibitors
NSCLC, non-small-cell lung cancer.

6. Overview

7. Lung Cancer Remains a Major Global Health Burden
One of the most common cancers and leading cause of cancer deaths in US and worldwide[1,2]
New cases, 2017 (estimated): US, 222,500; global, 1.8 million
Deaths, 2017 (estimated): US, 155,870; global, 1.6 million
~ 80% to 85% of cases are NSCLC (~ 184,000)[3]
Stage IV at diagnosis: ~ 57%[4]
Represented by multiple disease subtypes[5]
Standard of care for stage IV NSCLC: systemic therapy
NSCLC, non-small-cell lung cancer.
1. GLOBOCAN Cancer Fact Sheets Siegel RL, et al. CA Cancer J Clin. 2016;66: American Cancer Society. Non-small-cell Lung Cancer. 4. SEER Cancer Statistics Review, Li T, et al. J Clin Oncol. 2013;31:
Slide credit: clinicaloptions.com

8. Checkpoint Inhibitors subtyping for chemotherapy Genomics-driven TKIs:
What Tools Can Facilitate Personalized Therapy in Advanced-Stage NSCLC?
Chemotherapy
Targeted Therapy
Checkpoint Inhibitors
Histologic
subtyping for chemotherapy
Genomics-driven TKIs:
EGFR
ALK
ROS1
Anti–PD-1
Anti–PD-L1
Anti–CTLA-4
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
How do we optimize therapy in individual pts (ie, first line, second line, third line)?
Slide credit: clinicaloptions.com

9. CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell
Cancer cell
T-cell
T-cell
Dendritic cell
T-cell
MHC
TCR B7
CD28
CTLA-4
TCR
MHC
PD-1 mAbs:
Nivolumab
Pembrolizumab
PD-L1 mAbs:
Atezolizumab
Avelumab
Durvalumab
CTLA-4 mAbs:
Ipilimumab
Tremelimumab
T-cell
PD-1
Cancer cell
PD-L1
Slide credit: clinicaloptions.com
Ribas A. N Engl J Med. 2012;366:

10. Clinical Application of Immunotherapy for Advanced NSCLC

11. Therapeutic Plateau in Metastatic NSCLC ECOG 1594
1.0
Cisplatin/paclitaxel
Cisplatin/gemcitabine
Cisplatin/docetaxel
Carboplatin/paclitaxel
0.8
0.6
OS (%)
0.4
ECOG, Eastern Cooperative Oncology Group; 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.

12. KEYNOTE-024: Pembrolizumab vs CT as First-line Therapy for Advanced NSCLC
Open-label phase III trial
Primary endpoint: PFS
Secondary and exploratory endpoints: ORR, OS, DoR, and safety
Pts with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR/ALK mutations, and PD-L1 TPS ≥ 50%*
(N = 305)
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
(n = 154)
Chemotherapy (histology
based) for up to 6 cycles
(n = 151)
Stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and enrollment region
Until PD (crossover to pembrolizumab allowed)
*≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.
Until PD or unacceptable toxicity
CT, chemotherapy; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; TPS, tumor proportion score.
Slide credit: clinicaloptions.com
Reck M, et al. N Engl J Med. 2016;375:

13. KEYNOTE-024: Survival Outcomes
PFS OS
Pembro
(n = 154) CT
(n = 151)
Median PFS, mos
10.3
6.0
HR (95% CI)
0.50 ( ); P < .001
Pembro
(n = 154) CT
(n = 151)
Median OS, mos NR
HR (95% CI)
0.60 ( ); P = .005
100
100 80 80 60 60
PFS (%)
OS (%) 40 40
CT, chemotherapy; NR, not reached; Pembro, pembrolizumab. 20 20 3 6 9 12 15 18 3 6 9 12 15 18 21
Mos
Mos
Slide credit: clinicaloptions.com
Reck M, et al. N Engl J Med. 2016;375:

14. CheckMate-026: Nivolumab vs CT in First-line Therapy for Advanced NSCLC
Randomized, open-label phase III trial
Primary endpoint: PFS (≥ 5% PD-L1 positive)
Secondary endpoints: PFS (≥ 1% PD-L1 positive), ORR, OS
Pts with stage IV/recurrent NSCLC, no previous systemic therapy, no actionable EGFR/ALK mutations, PD-L1 expression ≥ 1%*
(N = 541)
Nivolumab 3 mg/kg IV Q2W
(n = 271)
Chemotherapy (histology
based) for up to 6 cycles
(n = 270)
Until PD or unacceptable toxicity
Stratified by PD-L1 expression (< 5% vs ≥ 5%) and histology (squamous vs nonsquamous)
Until PD (crossover to nivolumab allowed)
CT, chemotherapy; NSCLC, non-small-cell lung cancer; PD, progressive disease.
*≥ 1% tumor cell staining using 28-8 complementary diagnostic IHC assay.
Slide credit: clinicaloptions.com
Socinski M, et al. ESMO Abstract LBA7_PR.

15. CheckMate-026: Survival Outcomes in Pts With ≥ 5% PD-L1 Expression
Nivo
(n = 211) CT
(n = 212)
Median PFS, mos
4.2
5.9
HR (95% CI)
1.15 ( ); P =.2511
Nivo
(n = 211) CT
(n = 212)
Median OS, mos
14.4
13.2
HR (95% CI)
1.02 ( )
100
100 80 80 60 60
PFS (%)
OS (%)
Chemotherapy 40 40
Nivolumab 20 20
CT, chemotherapy; Nivo, nivolumab.
Nivolumab
Chemotherapy 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27
Mos
Mos
Slide credit: clinicaloptions.com
Socinski M, et al. ESMO Abstract LBA7_PR.

16. Blueprint PD-L1 IHC Assay Comparison Project: Phase 1
Analytical comparison of % tumor cell staining (tumor proportion score), by case (n = 39), for each assay
Data points represent the mean score from 3 pathologists for each assay on each case
Superimposed lines/points indicate identical TPS values
No clinical diagnostic cutoff applied
Conclusion: 3 of 4 assays are analytically similar for tumor cell staining
22C3 (pembrolizumab), 28-8 (nivolumab), and SP263 (avelumab)
100
22C3
28-8
SP142
SP263 80 60
% Tumor Cell Staining 40 20
TPS, tumor proportion score. 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39
Cases
SP142 (atezolizumab)
Slide credit: clinicaloptions.com
Hirsch FR et al. J Thorac Oncol. 2017;12:

17. Evaluable Samples for PD-L1 Testing
PD-L1 Testing in FNA and Cytology Samples in the Community Practice Setting
Evaluable Samples for PD-L1 Testing
Evaluable Samples (%) 20 40 60 80
100
90%
82%
79%
75% 90
104
127 50 63 9 12
Evaluable samples, n
Samples analyzed, n
Excisional
Core Needle
FNA
Other Cytology
FNA, fine needle aspiration; NSCLC, non-small-cell lung cancer.
302 NSCLC specimens were analyzed retrospectively for PD-L1 expression using the 28‑8 antibody per the diagnostic label
Slide credit: clinicaloptions.com
Hussein M et al., CMSTO Abstract ORAL01.02

18. CheckMate 017 and 057: Nivolumab vs Docetaxel in Previously Treated Advanced NSCLC
Open-label, randomized phase III trials
Primary endpoint: OS
Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL
CheckMate 017: Squamous NSCLC
CheckMate 057: Nonsquamous NSCLC
Pts with stage IIIB/IV squamous NSCLC and ECOG PS 0-1 with failure of 1 previous platinum doublet chemotherapy
(N = 272)
Nivolumab
3 mg/kg IV Q2W
(n = 135)
Nivolumab
3 mg/kg IV Q2W
(n = 292)
Pts with stage IIIB/IV nonsquamous NSCLC and ECOG PS 0-1 who failed 1 prior platinum doublet chemotherapy ± TKI therapy
(N = 582)
Until disease progression or unacceptable toxicity
Until disease progression or unacceptable toxicity
Docetaxel
75 mg/m2 IV Q3W
(n = 137)
Docetaxel
75 mg/m2 IV Q3W
(n = 290)
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status; QoL, quality of life; TKI, tyrosine kinase inhibitor.
Speaker notes:
017 stratification factors – previous paclitaxel therapy (yes or no) and region
057 stratification factors – previous maintenance therapy ( yes or no) and line of therapy (2nd vs 3rd line)
Brahmer J, et al. N Engl J Med. 2015;373:
Borghaei H, et al. N Engl J Med. 2015;373:
Slide credit: clinicaloptions.com

19. CheckMate 017 and 057: OS With a Minimum 2-Yr Follow-up
CheckMate 017: Squamous
CheckMate 057: Nonsquamous
100
100
Nivo
(n = 135)
Docetaxel
(n = 137)
Median OS, mos
9.2
6.0
1-yr OS, % 42 24
2-yr OS, % 23 8
HR (95% CI)
0.62 ( )
Nivo
(n = 292)
Docetaxel
(n = 290)
Median OS, mos
12.2
9.5
1-yr OS, % 51 39
2-yr OS, % 29 16
HR (95% CI)
0.75 ( ) 80 80 60 60
OS (%)
OS (%) 40 40
Nivolumab 20
Nivolumab 20
Nivo, nivolumab.
Docetaxel
Docetaxel 3 6 9 12 15 18 21 24 27 30 33 36 39 3 6 9 12 15 18 21 24 27 30 33 36 39
Mos
Mos
Pts at Risk, n Nivolumab
Docetaxel
Pts at Risk, n Nivolumab
Docetaxel
135
137
113
104 86 69 69 46 57 33 51 22 38 17 34 14 29 11 19 9 14 6 7 4 1
292
290
233
243
194
171
150
148
111
128 89
112 66 97 53 81 45 46 25 18 6 6 3 1
Slide credit: clinicaloptions.com
Borghaei H, et al. ASCO Abstract 9025.

20. CheckMate 017: OS by PD-L1 Expression in Squamous NSCLC
1% PD-L1 Expression Level
5% PD-L1 Expression Level
10% PD-L1 Expression Level
Median OS, Mos
Nivo
Doc
PD-L1 ≥ 1%
9.3
7.2
PD-L1 < 1%
8.7
5.9
Median OS, Mos
Nivo
Doc
PD-L1 ≥ 5% 10
6.4
PD-L1 < 5%
8.5
6.1
Median OS, Mos
Nivo
Doc
PD-L1 ≥ 10% 11
7.1
PD-L1 < 10%
8.2
6.1
100
100
100 80 80 80 60 60 60
OS (%) 40 40 40 20 20 20
Doc, docetaxel; Nivo, nivolumab; NSCLC, non-small-cell lung cancer. 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 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:

21. CheckMate 057: 2-Yr OS Rates
CheckMate 057: 2-Yr OS Rates* by PD-L1 Expression Level in Nonsquamous NSCLC
PD-L1 expression level associated with magnitude of 2-yr OS benefit starting at lowest level examined (1%)
100
Nivolumab
Docetaxel
Overall
PD-L1 Expression 80 60
OS (%) 40 20 44 45 37 29 25
NSCLC, non-small-cell lung cancer. 16 18 17 14 13
n =
292
290
108
191
123
123 95 86 86 79
All Pts
< 1%
≥ 1%
≥ 5%
≥ 10%
HR† (95% CI) ( ) ( ) ( ) ( ) ( )
*Rates are Kaplan-Meier estimates, error bars indicate 95% CI. †Comparison of full Kaplan-Meier survival curves for each tx group.
Slide credit: clinicaloptions.com
Borghaei H, et al. ASCO Abstract 9025.

22. KEYNOTE-010: Pembrolizumab vs Docetaxel in Advanced PD-L1–Positive NSCLC
Multicenter, randomized, open-label phase II/III trial
Primary endpoints: OS, PFS
Secondary endpoints: DoR, ORR, safety
Pembrolizumab 2 mg/kg IV Q3W
(n = 345)
Docetaxel 75 mg/m2 IV Q3W (n = 343)
Treatment continued for 24 mos or until PD or unacceptable toxicity
Pts with advanced NSCLC who progressed after platinum-based chemotherapy
(and TKI if EGFR+ or ALK+);
≥ 1% PD-L1+ tumor cells; ECOG PS 0/1
(N = 1034)
Pembrolizumab 10 mg/kg IV Q3W
(n = 346)
DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; TKI, tyrosine kinase inhibitor.
Speaker notes:
Stratification factors - Stratified by ECOG PS (0 vs 1), region (east Asia vs not east Asia), and PD-L1 expression (≥ 50% vs 1% to 49%)
Corticosteroid premedication allowed with docetaxel
Disease progression determined by radiological imaging. In the case of investigator-assessed clinical disease progression, treatment permitted until confirmatory scan completed 4-6 wks later.
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2016;387:

23. KEYNOTE-010: OS in Pts With PD-L1 TPS ≥ 1% and TPS ≥ 50%
mOS, Mos
1-Yr OS, %
HR (95% CI)
Pembrolizumab 2 mg/kg (n = 344)
10.4
43.2
0.71 ( )
Pembrolizumab 10 mg/kg (n = 346)
12.7
52.3
0.50 ( )
Docetaxel (n = 343)
8.5
34.6
mOS, Mos
HR (95% CI)
Pembrolizumab 2 mg/kg
(n = 139)
14.9
0.54 ( )
Pembrolizumab 10 mg/kg
(n = 151)
17.3
0.50 ( )
Docetaxel (n = 152)
8.2
100
100 80 80 60 60
OS (%)
OS (%) 40
mOS, median OS; TPS, tumor proportion score 40 20 20 5 10 15 20 25 5 10 15 20 25
Mos
Mos
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2016;387:

24. KEYNOTE-010: OS in Pts With PD-L1 TPS 1% to 49%
Median OS, Mos
(95% CI)
9-Mo OS, %
HR (95% CI)
Pembrolizumab 2 mg/kg
9.4 ( ) 53
0.79 ( )
Pembrolizumab 10 mg/kg
10.8 ( ) 58
0.71 ( )
Docetaxel
8.6 ( ) 47 –
100 80 60
OS (%) 40 20
TPS, tumor proportion score. 5 10 15 20 25
Pts at Risk, n
Mos
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
205
195
191
149
140
122 64 41 29 31 14 9 5
Slide credit: clinicaloptions.com
Garon EB, et al. ASCO Abstract 9024.

25. OAK: Atezolizumab vs Docetaxel in Progressive Advanced NSCLC
Multicenter, randomized, open-label phase III trial
Primary endpoints (first 850 pts enrolled): OS in ITT population; OS in pts with ≥ 1% PD-L1 expression
Secondary endpoints: ORR, PFS, DoR, safety
Atezolizumab 1200 mg IV Q3W
(n = 425)
Docetaxel 75 mg/m2 IV Q3W (n = 425)
Metastatic or locally advanced NSCLC (2L/3L), PD on prior platinum-based treatment
(N = 1225)
Stratified by PD-L1 expression, histology, prior chemotherapy regimens
No crossover allowed
Until loss of clinical benefit
Until PD
DoR, duration of response; ITT, intent to treat; NSCLC, non-small-cell lung cancer; PD, progressive disease.
Slide credit: clinicaloptions.com
Rittmeyer A, et al. Lancet. 2016;389:

26. OAK: OS in ITT Population
100
Landmark OS, %
12 Mos
18 Mos
Atezolizumab 55 40
Docetaxel 41 27 80 60
OS (%)
HR: 0.73 (95% CI ; P = .0003) 40 20
Median: 9.6 mos
(95% CI: )
Median: 13.8 mos
(95% CI: ) 3 6 9 12 15 18 21 24 27
Mos
Slide credit: clinicaloptions.com
Rittmeyer A, et al. Lancet. 2017;389:

27. OAK: OS by PD-L1 Expression
On-Study Prevalence
Median OS, Mos
Subgroup
TC3 or IC3
TC2/3 or IC2/3
TC1/2/3 or IC1/2/3*
TC0 and IC0
Atezolizumab
20.5
16.3
15.7
12.6
13.8
Docetaxel
8.9
10.8
10.3
9.6
0.41
16%
0.67
31%
0.74
55%
0.75
45% 0%
20%
40%
60%
80%
100%
0.73
100%
ITT*
IC, tumor-infiltrating immune cells; ITT, intent to treat; TC, tumor cells.
0.2 1 2
HR*
In favor of
atezolizumab
In favor of
docetaxel
*Stratified HR for ITT and TC1/2/3 or IC1/2/3 subgroup. Unstratified HR for other subgroups.
Slide credit: clinicaloptions.com
Rittmeyer A, et al. Lancet. 2017;389:

28. Online Interactive Treatment Decision Support Tool for Advanced NSCLC
5 lung cancer experts: Drs. Gandara, Edelman, Ramalingam, Wakelee, and West
Enter specific pt and disease characteristics using drop-down menus
NSCLC, non-small-cell lung cancer.
Available at: clinicaloptions.com/LungTool

29. Management of ICI Treatment-Related Adverse Events
ICI, immune checkpoint inhibitor

30. Immune-Related AEs With Immunotherapy
Endocrine
Hypo- or hyperthyroidism
Adrenal insufficiency
Hypophysitis
Eye
Uveitis
Iritis
Skin
Dermatitis exfoliative
Vitiligo
Alopecia
Hepatic
Hepatitis, autoimmune
Pulmonary
Pneumonitis (< 5% incidence)
Cardiac
Myocarditis
Gastrointestinal
Colitis
Renal
Nephritis
AE, adverse event.
Neurologic
Neuropathy
Guillain-Barre
Myasthenia gravis–like syndrome
If not vigilant, may result in more serious immune-related AEs
Slide credit: clinicaloptions.com

31. Pts With First Event in Category (n)
Time to Onset of First Treatment-Related Select AE With Nivolumab (Any Grade)
Majority of treatment-related AEs occurred within first 3 mos of treatment 10
Skin 9
Gastrointestinal
Pulmonary 8
Endocrine 7
Renal
Pts With First Event in Category (n) 6
Hypersensitivity/infusion reaction 5
Hepatic 4 3 2 1
AE, adverse event
0-3
> 3-6
> 6-12
> 12-24
Mos
Pts still on study, n Pts still on treatment, n Total pts with first event, n
Slide credit: clinicaloptions.com
Reckamp K, et al. WCLC ORAL02.01.

32. Online Interactive Algorithm Tool for Immune-Related AE Management
Developed by Jeffrey S. Weber, MD, PhD
Enter specific organ system affected and severity using drop-down menus
AE, adverse event.
Available at: clinicaloptions.com/irAETool

33. Immune-Mediated Pneumonitis
Fairly uncommon, but potentially serious
Pts at increased risk for pneumonitis
NSCLC in the setting of chronic lung inflammation
Prior radiation to lung
History of COPD
Signs and symptoms
Shortness of breath
Dry cough
Decreasing O2 saturation on room air
New/increasing oxygen requirements
Asymptomatic may be detected just on imaging
COPD, chronic obstructive pulmonary disease; NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com

34. Immune-Mediated Dermatitis
Reported in up to 40% of pts with anti–CTLA-4 and anti–PD-1 agents
Occasionally severe rashes
Onset variable within a few wks of starting to several wks/mos into therapy
Rule out other etiologies
Generally not infusion related
Manage mild/moderate dermatitis with supportive care ± withholding drug
Hodi FS, et al. N Engl J Med. 2010;363: Images courtesy L. Horn, Vanderbilt University.
Slide credit: clinicaloptions.com

35. Management of Grade 1 Gastrointestinal Treatment-Related Adverse Event

36. Case 4: Management of Grade 3 Gastrointestinal Treatment-Related Adverse Event
A few days later, the pt’s wife calls saying that as of that day he is having approximately episodes of diarrhea/day and is complaining about some abdominal pain

37. General Principles of Immune-Related Toxicity Management
Management generally based on severity of symptoms
Grade 1: supportive care ± withhold drug
Grade 2: withhold drug, consider redose if toxicity resolves to grade ≤ 1; low-dose corticosteroids (prednisone 1-2 mg/kg/day or equivalent)
Grade 3/4: discontinue drug; high-dose corticosteroids (prednisone mg/kg/day or equivalent) tapered over ≥ 1 mo once toxicity resolves to grade ≤ 1
Atezolizumab adverse reaction management brochure. Nivolumab adverse reaction management guide. Pembrolizumab adverse reaction management guide.
Slide credit: clinicaloptions.com

38. Future Directions

39. KEYNOTE-021: Pembrolizumab + CT as First-line Therapy for Advanced Nonsquamous NSCLC
Randomized phase II cohort of open-label multicohort trial
Primary endpoint: ORR (RECIST v1.1)
Secondary endpoints included: PFS, DoR, OS, and safety
Pts with stage IIIB/IV nonsquamous NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR/ALK mutations
(N = 123)
Pembrolizumab 200 mg IV
+ Cb/Pem* Q3W x 4
(n = 60)
Cb/Pem* Q3W x 4
(n = 63)
Stratified by PD-L1 TPS (< 1% vs ≥ 1%)
Pembrolizumab up to 24 mos
+ Pemetrexed maintenance
(optional)
Pemetrexed maintenance
*Cb AUC 5 mg/mL/min; pem 500 mg/m2.
AUC, area under the concentration curve; Cb, carboplatin; CT, chemotherapy; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; Pem, pembrolizumab; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score.
Slide credit: clinicaloptions.com
Langer CJ, et al. Lancet Oncol. 2016;17:

40. KEYNOTE-021: First-line CT ± Pembrolizumab in Advanced NSCLC
CT With Pembrolizumab (n = 56)
CT Only (n = 55)
100
100 80 80
ORR: 55%
98% of pts with decrease in tumor burden
ORR: 29%
82% of pts with decrease in tumor burden 60 60 40 40 20 20
Best Change From Baseline Tumor Size (%)
Best Change From Baseline Tumor Size (%)
-20
-20
CT, chemotherapy; NSCLC, non-small-cell lung cancer.
-40
-40
-60
-60
-80
-80
-100
-100
Slide credit: clinicaloptions.com
Langer CJ, et al. Lancet Oncol. 2016;17:

41. KEYNOTE-021: First-line CT + Pembrolizumab vs CT Only
PFS OS
Pembro + CT
CT Alone
Median PFS, mos
13.0
8.9
HR (95% CI)
0.53 ( )
P value
.01
100
100 80 80 60 60
Pembro + CT
CT Alone
Estimated 6-mo survival, % 92
HR (95% CI)
0.90 ( )
P value
.39
PFS (%) 40
OS (%) 40 20 20
CT, chemotherapy; Pembro, pembrolizumab. 5 10 15 20 5 10 15 20
Mos
Pts at Risk, n
(number censored)
Pembro + CT CT
Pts at Risk, n
(number censored)
Pembro + CT CT
Mos
60 (0)
63 (0)
43 (5)
32 (10)
20 (20)
13 (21)
1 (36)
1 (29)
0 (37)
3 (30)
60 (0)
63 (0)
53 (3)
57 (1)
33 (18)
31 (20)
5 (42)
6 (43)
0 (47)
0 (49)
Slide credit: clinicaloptions.com
Langer CJ, et al. Lancet Oncol. 2016;17:

42. KEYNOTE-021: Treatment-Related Adverse Events With Incidence ≥15%
Increased AST
Increased ALT
Decreased Neutrophils
1/2
Grade
3/4
Pembro + CT
CT alone
Fatigue
Nausea
Anemia
Rash
Vomiting
Diarrhea
Constipation
Decreased Appetite
Dysgeusia 32 54 20 11 19 10 64 40 58 44 17 12 13 27 15 18
ALT, alanine aminotransferase; CT, chemotherapy; Pembro, pembrolizumab.
Slide credit: clinicaloptions.com
Langer CJ, et al. Lancet Oncol. 2016;17:

43. Dual Checkpoint Blockade in Advanced NSCLC: Phase I Experience
Trial
Pt Population
Treatment
Key Toxicity Outcomes
Key Efficacy Outcomes
Study 006
(NCT )
Immunotherapy naive
(n = 102)
Durvalumab + tremelimumab
Multiple dosing cohorts for up to 1 yr
Grade 3/4*: 30%
Most common (any grade): GI and skin
ORR*: 23%
Similar ORR for
PD-L1 pos or neg
CheckMate 012
(NCT )
First line
(n = 78)
Nivolumab + ipilimumab
Multiple dosing cohorts
Grade 3/4†: 33%
Grade 3/4‡: 37%
ORR†: 38%
ORR‡: 47%
↑ ORR with ↑ PD-L1
GI, gastrointestinal; neg, negative; NSCLC, non-small-cell lung cancer; pos, positive.
*Duravlumab mg/kg Q2W or Q4W + tremelimumab 1 mg/kg Q4W x 6, then Q12W x 3.
†Nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W.
‡Nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg Q12W.
Slide credit: clinicaloptions.com
Hellmann MD, et al. Lancet Oncol. 2017;18: Antonia S, et al. Lancet Oncol. 2016;17:

44. Select Ongoing Randomized Phase III Trials of PD-1/PD-L1 Therapy in Advanced NSCLC
Disease Setting
Treatment
CheckMate 227 (NCT )
First line
Nivolumab or nivolumab + ipilimumab or nivolumab + Plt doublet CT vs Plt doublet CT
KEYNOTE-042 (NCT )
First line/PD-L1+
Pembrolizumab vs Plt doublet CT
KEYNOTE-189 (NCT )
First line (nonsq)
Plt/pemetrexed ± pembrolizumab
KEYNOTE-407 (NCT )
First line (sq)
Cb/pac or nab-pac ± pembrolizumab
IMpower 110 (NCT )
Atezolizumab vs Plt doublet CT
IMpower 130 (NCT )
Cb/nab-pac vs Cb/nab-pac ± atezolizumab
IMpower 131 (NCT )
Cb/pac or nab-pac + atezolizumab vs Cb/nab-pac
IMpower 132 (NCT )
Plt/pemetrexed ± atezolizumab
IMpower 150 (NCT )
Atezolizumab + Cb/pac ± bev vs Cb/pac/bev
JAVELIN Lung 100 (NCT )
Avelumab vs Plt doublet CT
JAVELIN Lung 200 (NCT )
Post-CT/PD-L1+
Avelumab vs docetaxel
NEPTUNE (NCT )
Durvalumab + tremelimumab vs Plt doublet CT
Cb, carboplatin; CT, chemotherapy; nonsq, nonsquamous; NSCLC, non-small-cell lung cancer; pac, paclitaxel; Plt, platinum; sq, squamous
Slide credit: clinicaloptions.com
*All trials enrolling pts as of February 2017.

45. Conclusions
PD-1/PD-L1 inhibitors have expanded treatment options for pts with advanced NSCLC with a potential for durable benefit
First-line, high PD-L1 expression (≥ 50%): pembrolizumab
Progressive disease: atezolizumab, nivolumab, or pembrolizumab (≥ 1% PD-L1)
PD-L1 expression in the tumor is associated with an increased likelihood of response but the predictive validity of this biomarker is still debated
Vigilance for immune-related AEs by the entire healthcare team along with rapid intervention is key to optimal management
Phase III clinical trials evaluating new combination strategies including checkpoint blockade plus chemotherapy and dual checkpoint blockade are enrolling pts
AE, adverse event; NSCLC, non-small-cell lung cancer.

46. Go Online for More CCO Coverage of NSCLC!
Downloadable slidesets on NSCLC CME-certified expert analyses on NSCLC and immunotherapy with expert faculty commentary on all the key studies Interactive Treatment Decision Support Tool for NSCLC— see treatment choices of 5 experts for your patient scenarios
clinicaloptions.com/oncology