1. Using Immune Checkpoint Inhibitors to Transform the Care of Patients With NSCLC
This program is supported by educational grants from Bristol-Myers Squibb, Genentech, and Merck.

2. Faculty
Program Director: Naiyer Rizvi, MD Professor of Medicine Price Chair of Thoracic Translational Oncology Director, Thoracic Oncology & Phase I Immunotherapeutics Columbia University Medical Center New York, New York Edward B. Garon, MD, MS Associate Clinical Professor Director, Thoracic Oncology Program Division of Hematology/Oncology David Geffen School of Medicine at UCLA Los Angeles, California
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
Solange Peters, MD, PhD Associate Professor
Clinical Director, Thoracic Oncology Research Program
Chair, Medical Oncology Department of Oncology   Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland
This slide lists the faculty who were involved in the production of these slides.

3. Faculty Disclosures
Edward B. Garon, MD, MS, has disclosed that he has received funds for research support from AstraZeneca, Bristol-Myers Squibb, Genentech, Lilly, Merck, Novartis, and Pfizer. Leora Horn, MD, MSc, FRCPC, has disclosed that she received consulting fees from Genentech, Lilly, and Merck; has consulted without compensation for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Xcovery; and has received funds for research support paid to her institution from AstraZeneca. Solange Peters, MD, PhD, has disclosed that she has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol- Myers Squibb, Celgene, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Merck Sharp & Dohme, Morphotek, Merrimack, Merck Serono, Novartis, Pfizer, Roche, and Tesaro. Naiyer Rizvi, MD, has disclosed that he has received consulting fees from AstraZeneca, Merck, Novartis, and Roche and has ownership interests in Gritstone Oncology.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

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5. Future Directions With Immune Checkpoint Blockade in Advanced NSCLC

6. New Agents

7. BIRCH: Atezolizumab as First-line or Subsequent Therapy for PD-L1+ NSCLC
Single-arm phase II trial in PD-L1+ (TC2/3 and/or IC2/3) NSCLC
Median DoR: 7 mos (≥ 3 lines) and NR (1 or 2 lines) in TC3 or IC3
Majority of responses ongoing
DoR, duration of response; IC, immune cell; NR, not reported; NSCLC, non-small-cell lung cancer; TC, tumor cell.
Slide credit: clinicaloptions.com
Besse, et al. ECC Abstract 16LBA

8. BIRCH: Efficacy and Safety of Atezolizumab
First Line (n = 139)
Second Line (n = 267)
≥ Third Line (n = 253)
Median OS, mos (95% CI)
TC2/3 or IC2/3
TC3 or IC3
14.0 (14.0-NE)
NE (10.4-NE)
NE (11.2-NE)
NE (10.6-NE)
NE (8.4-NE)
NE (NE-NE)
6-mo OS, % 82 79 76 80 71 75
Median PFS, mos (95% CI)
5.5 ( )
5.5 ( )
2.8 ( )
4.1 ( )
2.8 ( )
4.2 ( )
6-mo PFS, % 46 48 29 34 31 39
AST, aspartate aminotransferase; IC, immune cell; NE, not estimated; TC, tumor cell.
Majority of AEs were grade 1/2 (80%)
Most common AEs (any grade): fatigue, diarrhea and nausea
Most common grade 3/4 AEs: pneumonitis* (1.5%), increased AST (0.8%), colitis (0.5%), hypothyroidism and rash (both 0.3%)
*1 grade 5 pneumonitis occurrence reported
Slide credit: clinicaloptions.com
Besse, et al. ECC Abstract 16LBA

9. Atezolizumab vs Docetaxel in NSCLC (POPLAR): All-Comer Phase II Study
Stratified by PD-L1 IHC expression (0 vs 1 vs 2 vs 3), histology (squamous vs nonsquamous),
prior chemotherapy regimens (1 vs 2)
Atezolizumab
1200 mg IV Q3W
until loss of clinical benefit
(n = 144)
Primary objective
Estimate OS by PD-L1 expression
Secondary objectives
Estimate PFS, ORR, DoR by PD-L1 expression
Evaluate safety
Metastatic or locally advanced NSCLC (2nd/3rd line),
PD on prior platinum-based tx
(N = 287)
Docetaxel
75 mg/m2 IV Q3W until PD
(n = 143)
DoR, duration of response; NSCLC, non-small-cell lung cancer; PD, progressive disease; tx, treatment.
Slide credit: clinicaloptions.com
Spira AI, et al. ASCO Abstract 8010.

10. ORR (Confirmed; RECIST v1.1; %)
POPLAR: ORR[1] and OS[2,3] 50 42 40
Atezolizumab (n = 144) 30
Docetaxel (n = 143)
ORR (Confirmed; RECIST v1.1; %) 24 20 19 17 15 15 13 15 10 10 8
TC3 or
IC3
TC1/2/3 or
IC1/2/3
TC0 and
IC0
TC2/3 or
IC2/3
ITT
100
Atezolizumab Docetaxel
Minimum follow-up: 13 mos 80
HR: 0.73 (95% CI: ; P = .040) 60
Median: 12.6 mos
IC, immune cells; RECIST, Response Evaluation Criteria In Solid Tumors; TC, tumor cells.
OS (%) 40
Median: 9.7 mos 20 2 4 6 8 10 12 14 16 18 20
Mos
1. Smith D, et al. ASCO Abstract 9028.
2. Fehrenbacher L, et al. Lancet. 2016;387:
Slide credit: clinicaloptions.com

11. POPLAR: OS by PD-L1 Expression
Median OS, Mos (95% CI)
Subgroup
TC3 or IC3 TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0
n (%)
47 (16)
105 (37)
198 (68)
92 (32)
Atezolizumab (n = 144) (9.8-NE)
15.1 (8.4-NE)
15.5 (11.0-NE)
9.7 ( )
Docetaxel (n = 143) ( )
7.4 ( )
9.2 ( )
9.7 ( )
0.49
0.54
0.59
1.04
0.73
12.6 ( )
9.7 ( )
ITT
N = 287
IC, immune cells; ITT, intent to treat; NE, not estimable; TC, tumor cells.
0.2 1 2 HR
In favor of atezolizumab
In favor of docetaxel
Slide credit: clinicaloptions.com
Fehrenbacher L, et al. Lancet. 2016;387:

12. POPLAR: Atezolizumab vs Docetaxel in NSCLC Updated OS, Biomarker AnalysesHR
(95% CI)
P Value n
Median OS,
Mos
ITT
144
12.6
143
9.7
0.69 ( )
.011
TC3 or IC3 24
Not reached 23
11.1
0.45 ( )
.033
TC2/3 or IC2/3 50
15.1 55
7.4
0.50 ( )
.003
TC1/2/3 or IC1/2/3 93
102
9.2
0.59 ( )
TC0 and IC0 51
9.7 41
0.88 ( )
.601
IC, immune cell; ITT, intent to treat; NSCLC, non-small-cell lung cancer; TC, tumor cell.
Squamous 49
10.1 48
8.6
0.66 ( )
.075
Nonsquamous 95
14.8
10.9
0.69 ( )
.039
Smith DA, et al. ASCO Abstract 9028.
Slide credit: clinicaloptions.com

13. JAVELIN: Phase Ib Trial of First-line Avelumab in NSCLC
Open-label, dose-escalation phase Ib trial of avelumab (10 mg/kg Q2W) in advanced NSCLC not previously treated for metastatic disease
Well tolerated, low rate of grade 3/4 AEs
Tx-related AEs: 56.6% (9% grade 3/4)
No tx-related deaths
Outcome, %
N = 75
ORR
18.7
DCR
64.0 CR
1.3 PR
17.3 SD
45.3
Median PFS
11.6 wks
AE, adverse event; DCR, disease control rate; NSCLC, non-small-cell lung cancer; SD, stable disease; tx, treatment.
Slide credit: clinicaloptions.com
Verschraegen CF, et al. ASCO Abstract 9036.

14. Phase I/II Trial of Durvalumab in Treatment-Naive Advanced NSCLC
Dose-escalation/dose-expansion phase I/II trial of durvalumab (10 mg/kg Q2W) in pts with treatment-naive PD-L1+ NSCLC
ORR: 27% (N = 59); 29% for PD-L1 high (n = 49); 11% for PD- L1 low or negative (n = 9)
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com
Antonia SJ, et al. ASCO Abstract 9029.

15. Phase III Trials of New Immune Checkpoint Inhibitors in Advanced NSCLC
Est. N
Setting
Treatment Arms
Primary
Endpoint
OAK[1]
1225
Second line
Atezolizumab vs
docetaxel OS
IMpower 110[2]
400
First line
Non-SQ
cisplatin or carboplatin + pemetrexed
PFS
IMpower 111[3] SQ
cisplatin or carboplatin + gemcitabine
JAVELIN Lung 200[4]
650
Avelumab vs
JAVELIN Lung 100[5]
420
platinum-containing chemotherapy
ARCTIC[6]
730
Third line
Durvalumab ± tremelimumab vs
SOC platinum-based chemotherapy
OS, PFS
NSCLC, non-small-cell lung cancer; SOC, standard of care; SQ, squamous.
1. ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT
Slide credit: clinicaloptions.com

16. New Combinations

17. Rationale for Combination Immunotherapy
Immunogenic tumor microenvironment
Immune checkpoint inhibitor
Durable benefit
Nonimmunogenic tumor microenvironment
Combination therapy:
Agent to increase immunogenicity + immune checkpoint inhibitor
Durable benefit
Slide credit: clinicaloptions.com
Sharma P, et al. Science. 2015;348:56-61.

18. KEYNOTE-021: Pembro + Chemo as First-Line Therapy for Advanced NSCLC
Cohort
ORR, %
Median PFS, Mos (95% CI)
Median OS, Mos (95% CI)
Total (N = 74) 57
10 (6-NR)
NR (17-NR)
PD-L1 TPS ≥ 50% (n = 25) 60
15 (6-15)
17 (15-NR)
PD-L1 TPS ≥ 1% (n = 26) 57
14 (6-NR)
NR (14-NR)
PD-L1 TPS < 1% (n = 22) 54
6 (4-NR)
11 (7-NR)
Pembro +
carbo/paclitaxel (n = 25) 52
10 (4-NR)
NR (11-NR)
carbo/paclitaxel/bev (n = 25) 48
NR (4.1-NR)
NR (NR-NR)
carbo/pemetrexed (n = 24) 71
10 (6-15)
NR (14-NR)
AE, adverse event; Bev, bevacizumab; Carbo, carboplatin; irAE, immune-related adverse event; NR, not reached; NSCLC, non-small-cell lung cancer; Pembro, pembrolizumab; TPS, tumor proportion score.
Combination pembro + carbo/paclitaxel/bev possibly associated with more AEs than other cohorts (any irAE: 38% vs 16% or 29%, respectively)
Slide credit: clinicaloptions.com
Gadgeel SM, et al. ASCO Abstract 9016.

19. KEYNOTE-021: Pembro + Ipilimumab as Second-Line Therapy for Advanced NSCLC
Cohort
ORR, %
Median PFS, Mos (95% CI)
Median OS, Mos (95% CI)
Total (N = 44) 25
6.1 ( )
16.6 (61-NR)
PD-L1 TPS ≥ 50% (n = 6) 17
1.0 (< )
1.9 (< 1-NR)
PD-L1 TPS ≥ 1% (n = 24) 29
6.1 (1.1-NR)
NR (1.9-NR)
PD-L1 TPS < 1% (n = 20) 20
5.5 ( )
16.6 ( )
Combination pembro 2 mg/kg + ipilimumab 1 mg/kg Q3W demonstrated significant toxicity with ORR similar to single-agent pembro
Any AE: 93% (49% grade 3-5); 9% discontinued due to AE
Any irAE: 40% (16% grade 3-5; 1 pt each experiencing colitis, pneumonitis, adrenal insufficiency, diabetic ketoacidosis, drug eruption, pancreatitis, maculo-popular rash, pruritic rash)
1 pt with grade 5 AE pancreatitis
AE, adverse event; irAE, immune-related adverse event; NR, not reached; NSCLC, non-small-cell lung cancer; Pembro, pembrolizumab; TPS, tumor proportion score.
Slide credit: clinicaloptions.com
Guben M, et al. ASCO Abstract 9027.

20. CheckMate-012: Nivo + Ipilimumab as First-line Therapy for Advanced NSCLC
Outcome
Nivo 3 Q2W +
Ipi 1 Q12W
(n = 38)
Ipi 1 Q6W
(n = 39)
Nivo 3 Q2W
(n = 52)
ORR, %
≥ 50% PD-L1+
≥ 1% PD-L1+
< 1% PD-L1+ 47
100 57 30 39 86 23 50 28 14
Median PFS, mos
8.1
13.6
4.7
3.9 NR
10.6
2.4
3.6
8.4
3.5
6.6
1-Yr OS, % NC 90 69 83 73 79
Ipi, ipilimumab; Nivo, nivolumab; NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com
Hellman MD, et al. ASCO Abstract 3001.

21. CheckMate-012: Nivo + Ipilimumab as First-line Therapy for Advanced NSCLC
Nivo 3 Q3W +
Ipi 1 Q12W
(n = 38)
Nivo 3 Q3W +
Ipi 1 Q6W
(n = 39)
Nivo 3 Q3W
(n = 52)
Grade 1/2
Grade 3/4
Pts With Event (%)
GI, gastrointestinal; Ipi, ipilimumab; Nivo, nivolumab; NSCLC, non-small-cell lung cancer. GI
Skin GI GI
Hepatic
Renal
Hepatic
Renal
Skin
Renal
Skin
Endocrine
Pulmonary
Hepatic
Endocrine
Pulmonary
Endocrine
Pulmonary
Slide credit: clinicaloptions.com
Hellman MD, et al. ASCO Abstract 3001.

22. Phase III First-line Combination Trials in Advanced NSCLC (All PD-L1 Unselected)
Estimated N
Treatment Arms
Primary Endpoint
Checkmate 227[1]
1980
Nivo ± ipilimumab, platinum-based chemo
OS, PFS
KEYNOTE-189[2]
570
Pemetrexed/cisplatin ± pembro
PFS
KEYNOTE-407[3]
560
Platinum-based chemo ± pembro
MYSTIC[4]
675
Durvalumab ± tremelimumab,
SOC platinum-based chemotherapy
NEPTUNE[5]
800
Durvalumab + tremelimumab, OS
IMpower 130[6]
550
Nab-paclitaxel/carboplatin ± atezolizumab
IMpower 150[7]
1200
Paclitaxel/carboplatin + bevacizumab AND/OR atezolizumab
IMpower 131[8]
Nab-paclitaxel/carboplatin ± atezolizumab,
paclitaxel/carboplatin + atezolizumab
Nivo, nivolumab; NSCLC, non-small-cell lung cancer; Pembro, pembrolizumab; SOC, standard of care.
1. ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT ClincalTrials.gov. NCT
Slide credit: clinicaloptions.com

23. Summary
Immune checkpoint inhibitors are a new standard of care for patients with advanced NSCLC who have progressed after platinum-based chemotherapy
Assessing PD-L1 expression can provide information on potential efficacy for certain patient subsets
Ongoing clinical trials with additional immune checkpoint inhibitors and new combination approaches may expand the utility of these agents in clinical practice
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com

24. Go Online for More CCO Coverage of NSCLC!
Downloadable slidesets from the live satellite Downloadable slidesets and expert commentary on key studies in NSCLC from ASCO 2016
clinicaloptions.com/oncology