Jarushka Naidoo, MD CBH

1. Advances in Immunotherapy
for Non-Small Cell Lung Cancer
Jarushka Naidoo, MB BCH
Assistant Professor of Oncology
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
Bloomberg-Kimmel Institute for Cancer Immunotherapy
FLASCO Annual Meeting
May 18, 2018

2. Disclosures
• Research Funding
- Merck
- AstraZeneca
- NIH KL2
• Consulting
- AstraZeneca
- Bristol Myers Squibb
- Takeda
• Honoraria
- AstraZeneca
- Bristol Myers Squibb

3. Outline
• Brief Introduction to Immunotherapy in NSCLC
• First-line Immunotherapy in NSCLC
• Immunotherapy for Stage III NSCLC
• Future Directions:
- Neoadjuvant Studies
- Translational Studies

4. T
T
T
Lymph node
T T
T
T
T
PD-L1
GAL9
VISTA
LAG3
BTLA4
OX40
GITR
HVEM
CD137
CD28
Immunotherapy in Cancer
The Cancer-Immunity Cycle
Adapted from DS Chen et al, Immunity 2012
CTLA4
CTLA4
CTLA4
Chemotherapy
Radiation
Targeted Therapy
Vaccines
IFN-alpha
GM-CSF
Anti-CD40
Anti-CTLA4
Anti-CD137
Anti-OX40
IL2
Anti-CXCL12
Anti-VEGF
CAR T-cells
Immune
Checkpoint mAbs
PD-1

5.  Specificity: virtually infinite antigen recognition
 Adaptability: based on tumor genetic & epigenetic changes
 Memory: durable responses even after drug discontinuation
 Universality: potential anti-tumor effect regardless of tumor type
The Human Immune System
The Ultimate Anti-cancer Therapy?
Tumor Types with Objective Response to Anti-PD-1/PD-L1
Melanoma Non-small cell lung carcinoma Renal Cell carcinoma
Urothelial carcinoma Head and Neck carcinoma Merkel Cell carcinoma
MSI-high Colorectal carcinoma Biliary Tract carcinoma Ovarian carcinoma
Breast carcinoma Anal carcinoma Mesothelioma
Gastric adenocarcinoma Hogkins Lymphoma Hepatocellular carcinoma
Naidoo et al, Ann Transl Med 2016

6. Immunotherapy in NSCLC
Second-Line Therapy: Nivolumab vs. Docetaxel
272 patients:
135 (nivolumab); 137 (docetaxel)
Brahmer J, et al. N Engl J Med. 2015 Borghaei H, et al. N Engl J Med. 2015
582 patients:
292 (nivolumab); 290 (docetaxel)

7. PD-L1 Immunohistochemical assay
PD-L1 >50%
All patients (PD-L1 >1%)
1034 patients: 345 (pembro 2mg/kg), 346 (pembro 10mg/kg), 343 (docetaxel)
Garon EB, et al. N Engl J Med; Herbst RS, et al. Lancet. 2016
Immunotherapy in NSCLC
Second-line Therapy: PD-L1+ NSCLC, KEYNOTE studies

8. 8
OS= HR, 0.73
(95% CI, 0.60, 0.89)
P = 0.0015
Median 11.2 mo
(95% CI, 9.3, 12.6)
Median 15.6 mo
(95% CI, 13.3, 17.6)
Atezolizumab
Docetaxel
Median 7.7 mo
(95% CI, 6.3, 8.9)
Median 8.9 mo
(95% CI, 7.4, 12.8)
OS= HR, 0.73
(95% CI, 0.54, 0.98)
P = 0.0383
Non-squamous Squamous
Months Months
Anti-PD-L1 in Second-Line
Atezolizumab vs. Docetaxel: OS by histology
Rittmeyer A et al. Lancet. 2017;389:255-265

9. Gandara DR, et al. bTMB in POPLAR & OAK
Atezolizumab Blood TMB subgroups
Progression-FreeSurvival(%)
• Blood TMB ≥16 population accounted for 27% of biomarker evaluable group (N = 158)
• PFS benefit with atezolizumab was observed in the TMB ≥16 subgroup
• No prognostic effect was observed: patients with bTMB ≥16 did not have improved
PFS compared with patients with bTMB <16 in the docetaxel arm
Interaction P = 0.036
Progression-FreeSurvival(%)
Blood TMB ≥16 Blood TMB <16
Atezolizumab (N = 216)
Docetaxel (N = 209)
+ Censored
Atezolizumab (N = 77)
Docetaxel (N = 81)
+ Censored
Months Months
Progression-FreeSurvival(%)
Gandara DR et al. ESMO 2017

10. How to Evaluate for Blood-based TMB
Poplar and Oak Studies
• A 394 gene-based NGS assay
- Retrospective test of plasma samples (phase 2 POPLAR; phase 3 OAK study)
• 211/273 samples from POPLAR and 583/797 samples from OAK were evaluable
– The association between TMB and efficacy was analyzed and the cut-point of
TMB ≥16 was selected based on POPLAR
– Validated in OAK
bTMB Computational Methodology and Study Design
Blood collection,
plasma isolation &
cfDNA extraction
bTMB
Sequencing
POPLAR
(training)
OAK
(validation)
• All base substitutions
with ≥0.5% allele
frequency
• Remove germline
polymorphisms &
predicted driver
mutations
Gandara DR et al. ESMO 2017

11. Outline
• Brief Introduction to Immunotherapy in NSCLC
• First-line Immunotherapy in NSCLC
• Immunotherapy for Stage III NSCLC
• Future Directions:
- Neoadjuvant Studies
- Translational Studies

12. Progression-Free Survival
Events,
n
Median,
months
HR
(95% CI)
P
Pembro 73 10.3 0.50
(0.37-0.68)
<.001
Chemo 116 6.0
62%
50%
0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100
Time, months
PFS,%
No. at risk
154 104 89 44 22 3 1
151 99 70 18 9 1 0
48%
15%
ST v1.1 by blinded, independent central review
, 2016
Ann Oncol. 2016;27(suppl 6): Abstract LBA8. Reck M, et al. N Engl J Med. 9 Oct 2016. [Epub ahead of print].
Overall Survival
80%
72%
0 3 6 9 12 15 18 21
0
10
20
30
40
50
60
70
80
90
100
Time, monthsOS,%No. at risk
154 136 121 82 39 11 0
151 123 106 64 34 7 0
2
1
70%
54%
Events,
n
Median,
months
HR
(95% CI)
P
Pembro 44 NR 0.60
(0.41-0.89)
.005
Chemo 64 NR
DMC recommended stopping the trial because of
superior efficacy observed with pembrolizumab
Data cut-off: May 9, 2016
Reck M, et al. Ann Oncol. 2016;27(suppl 6): Abstract LBA8. Reck M, et al. N Engl J Med. 9 Oct 2016. [Epub ahead of print
Progression-Free Survival
5.7 month PFS benefit
HR= 0.5, p<0.001
48% vs. 15% progression-free at 1 year
Median OS results not mature
HR= 0.6, p=0.005
70% vs. 54% alive at 1 year
Reck et al, N Engl J Med 2016
First-line Pembrolizumab in NSCLC
KEYNOTE 024: PFS and OS
Overall Survival

13. Pembro
Responders
n = 69
Chemo
Responders
n = 42
TTR, mo
median
(range)
2.2
(1.4-8.2)
2.2
(1.8-12.2)
DOR,
mo
median
(range)
NR
(1.9+ to
14.5+)
6.3
(2.1+ to
12.6+)
First-line Pembrolizumab in NSCLC
KEYNOTE 024: ORR
Reck et al, N Engl J Med 2016
Objective Response Rate Duration of Response

14. Ph III First-Line Pembrolizumab
KEYNOTE 042: Study Design
Data to be presented
ASCO 2018

15. First-Line Nivolumab in NSCLC
Checkmate 026: OS
Socinski et al, ESMO 2016

16. TMB as a Biomarker
First-Line Nivolumab in NSCLC: PFS
High TMB Low/Intermediate TMB
Garon et al, ASCO 2017

17. First-line PD-1 Monotherapy in NSCLC
Summary
• Pembrolizumab
- Improved survival compared to chemotherapy in advanced
NSCLC patients
- Relevance: PD-L1 > 50% and in patients PD-L1 > 1%
• Nivolumab
- Did not improve survival compared to chemotherapy for
advanced NSCLC patients whose PD-L1 > 5%

18. Pembrolizumab 200 mg
Q3W for 2 years
+
Pemetrexed 500 mg/m2
+ Carboplatin AUC
5 mg/mL/min Q3W for 4
cycles
Pemetrexed 500 mg/m2
+ Carboplatin AUC
5 mg/mL/min
Q3W for 4 cycles
R
(1:1)a
N = 123
First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE-021 Cohort G: Study Design
Pemetrexed
500 mg/m2
Q3W permitted
as
maintenance
therapy
Study Population
•Untreated stage IIIB or IV
nonsquamous NSCLC
•No activating EGFR mutation or
ALK translocation
•Provision of a sample for PD-L1
assessmenta
•ECOG PS 0 or 1
•No untreated brain metastases
•No ILD or pneumonitis requiring
systemic steroids
End Points
•Primary: ORR (RECIST v1.1 per blinded, independent central review)
•Key secondary: PFS: OS, safety, relationship between antitumor activity and PD-L1 TPS
Langer et al, Lancet Oncol 2017

19. 0 3 6 9 12 15 18 21 24 27
0
10
20
30
40
50
60
70
80
90
100
Time, months
OverallSurvival,%
60 57 55 51 46 44 36 22 7 1
63 58 57 51 43 39 29 18 9 0
No. at risk
HR= 0.59
77% vs. 69% alive at 1 year
Pembro/Chemo vs, Chemo
p=0.03
HR= 0.54
Pembro/Chemo vs, Chemo
57% vs. 35% PFS at 1 year
p=0.006
Progression-Free Survival Overall Survival
First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE-021 Cohort G: PFS and OS
Langer et al, Lancet Oncol 2017

20. Δ24.8%
(95% CI, 7.2% 40.9%)‒
P = 0.0029a
Pembro + PC
Responders
n = 34
PC Alone
Responders
N = 20
Median (range)
duration of response,
mo
NR
(1.4+ to
22.7+)
NR
(2.8 to 23.7+)
Ongoing response, % 50 40
First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE 021-G: ORR
Langer et al, Lancet Oncol 2017

21. First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE 189: Ph III: Study Design
Gandhi et al, NEJM 2018

22. Overall SurvivalProgression-Free Survival
First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE 189: Ph III: PFS and OS
HR= 0.49
69% vs. 49% OS at 1 year
Pembro/Chemo vs. Chemo
p<0.001
HR= 0.52
34% vs. 17% PFS at 1 year
Pembro/Chemo vs. Chemo
p<0.001
Gandhi et al, NEJM 2018

23. First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE 189: Ph III: Subgroup Analyses
Gandhi et al, NEJM 2018

24. First-line Pembrolizumab+Chemo in NSCLC
KEYNOTE 189: ORR
Gandhi et al, NEJM 2018

25. Co-Primary Endpoints: PFS: OS,
First-line Atezolizumab+Chemo+Bevacizumab
IMpower150: Study Design
Gandara et al, ESMO 2017

26. First-line Atezolizumab+Chemo+Bevacizumab
IMpower150: PFS and OS
Progression-Free
Survival
Overall Survival
Gandara et al, ESMO 2017

27. • In advanced non-squamous NSCLC
- Carboplatin+Pemetrexed+Pembro is superior to
chemotherapy alone, independent of PD-L1
- Carboplatin+Paclitaxel+Atezo+Bevavizumab is superior to
chemotherapy + bevacizumab, independent of PD-L1
- Carboplatin+Paclitaxel+Atezo+Bevavizumab benefitted
patients with EGFR/ALK alterations
• PD-L1 > 50% is relevant to select
- Pembrolizumab alone vs. Pembrolizumab + Chemotherapy
First-line PD-1+Chemotherapy in NSCLC
Summary

28. First-line Durvalumab + Tremelimumab in NSCLC
MYSTIC study: Design

29. First-line Nivolumab+Ipilimumab in NSCLC
Phase III Checkmate 227: Study Design
Hellmann et al, NEJM 2018

30. First-line Nivolumab+Ipilimumab in NSCLC
Phase III Checkmate 227: Analytic Plan
Hellmann et al, NEJM 2018

31. First-line Nivolumab+Ipilimumab in NSCLC
PFS in High-TMB NSLC (>10 mut/Mb)
Hellmann et al, NEJM 2018

32. First-line Nivolumab+Ipilimumab in NSCLC
Preliminary OS in High-TMB NSLC (>10 mut/Mb)
Hellmann et al, NEJM 2018

33. First-line Nivolumab+Ipilimumab in NSCLC
ORR and DOR in High-TMB NSLC (>10 mut/Mb)
Hellmann et al, NEJM 2018

34. • Durvalumab-Tremelimumab
- Was no better than chemotherapy in treatment-naïve
patients (press release)
• Ipilumumab-Nivolumab
- Demonstrates superior PFS vs. chemotherapy in patients
- with NSCLCs that have a high-TMB (10mut/Mb)
First-line PD-1/PD-L1 +CTLA-4 in NSCLC
Summary

35. Outline
• Brief Introduction to Immunotherapy in NSCLC
• First-line Immunotherapy in NSCLC
• Immunotherapy for Stage III NSCLC
• Future Directions:
- Neoadjuvant Studies
- Translational Studies

36. Durvalumab in Stage III NSCLC
Phase III PACIFIC Trial: Study Design
Antonia et al, NEJM 2017

37. Antonia et al, NEJM 2017
Durvalumab in Stage III NSCLC
Phase III PACIFIC Trial: PFS

38. Durvalumab in Stage III NSCLC
Phase III PACIFIC Trial: Safety
Antonia et al, NEJM 2017

39. • Durvalumab Maintenance Therapy
- Is a new standard of care after definitive chemoradiation for
stage III NSCLC
Stage III NSCLC
Summary

40. Neoadjuvant Clinical Trials
General Principles
• Clinical and translational advantage over adjuvant approach
• No advances in resectable lung cancers since 2004
• Anti-PD-1/PD-L1 induces deep and durable responses in a
subset of patients with advanced NSCLC
• Neoadjuvant Anti-PD-1 may:
• Induce immunity against micrometastases
• Allow for a pre and post PD-1 pathologic assessment
• Provide tissue for correlative analyses
Forde et al, NEJM 2018

41. Slide 3
Neoadjuvant Nivolumab in Resectable NSCLC
Study Design
Primary Endpoint: Safety (drug-related adverse events 90-days post PD-1/30 days post surgery
Feasibility (resection without delay >37 days from pre-planned surgery)
Sample Size: 6 patient safety run-in, 20 patients in total
Exploratory Endpoints: Pathologic response, RFS, OS, immunologic correlates
Forde et al, NEJM 2018

42. Neoadjuvant Nivolumab in Resectable NSCLC
Patient Characteristics
Safety
-1 death in the postoperative period, unrelated
to study drug
Feasibility
- All patients underwent surgery without delay
- No complications in the postoperative period
22 enrolled
21 treated with
pre-op intent
1 withdrew
(SCLC histology)
20 resected
1 unresectable
Forde et al, NEJM 2018

43. Neoadjuvant Nivolumab in Resectable NSCLC
Response to Therapy
Radiologic Response after 2 doses
neoadjuvant nivolumab
Pleomorphic
NSCLC
Pathologic CR
Squamous
NSCLC
Pathologic CR
Pathologic Response after 2 doses
neoadjuvant nivolumab
Major Pathologic Response: <10% viable tumor
MPR in 43% (9/21) patients
Pre-nivo PD-L1 (>1%) did not correlate with MPR
Forde et al, NEJM 2018

44. Slide 14
Neoadjuvant Nivolumab in Resectable NSCLC
T-cell specific for dominant MANA
expand in peripheral blood
With thanks K. Smith and D. Pardoll

45. Slide 15
With thanks K. Smith and D. Pardoll
Neoadjuvant Nivolumab in Resectable NSCLC
T-cell specific for dominant MANA
expand in peripheral blood

46. Slide 16
With thanks K. Smith and D. Pardoll
Neoadjuvant Nivolumab in Resectable NSCLC
T-cell specific for dominant MANA
expand in peripheral blood

47. Neoadjuvant Nivolumab in Resectable NSCLC
TMB and Neoantigen density associates with MPR
With thanks K. Smith and D. Pardoll

48. Neoadjuvant Nivolumab in Resectable NSCLC
Conclusions
• Nivolumab prior to lung cancer resection did not delay time to surgery
• There were no unacceptable safety signals with neoadjuvant nivolumab
• 43% of tumors had MPRs
• Correlative analyses in a subset of tumors demonstrated
• Associations between mutation, MANA burden and pathologic response
• Identified MANA-specific TCRs in the blood and tumor
• Observed temporal increases in MANA-specific TCRs in the peripheral
blood post nivolumab: a potential biomarker of response
Forde et al, NEJM 2018

49. • Neoadjuvant chemoradiation for Resectable Stage IIIA NSCLC
- Used for a subset of patients with stage IIIA disease, deemed resectable
- Increased rate of pathologic CR, reduced rate of locoregional recurrence1,2
• Immunologic Synergy between PD-1/PD-L1 Blockade and RT
- Anti-CTLA-4 diversifies the TCR, which is associated with improved OS3
- Anti-PD-1+RT demonstrates TCR diversification in tumor and systemically4
Neoadjuvant Studies in Resectable NSCLC
Future Directions
1. Ettinger et al, JNCCN 2017
2. Albain et al, Lancet 2009
3. Demaria et al, Clin Cancer Res 2005
4. Deng et al, J Clin Investig 2014
4. Twyman-Saint Victor et al, Nature 2015

50. Neoadjuvant Immunoradiation
in Stage IIIA Resectable NSCLC
Cohort 2 opens when safety and feasibility of
cohort 1 established
IRB: J1772,
PI: Naidoo

51. JHH Thoracic Oncology Program
Julie R. Brahmer, MD
Patrick M. Forde, MD
David S. Ettinger, MD
Ronan J. Kelly, MD MBA
Christine L. Hann, MD PhD
Benjamin Levy, MD
Josephine Feliciano, MD
Kristen M. Marrone, MD
Jessica Wakefield, MS
Rachel Levy, MS
Joanne Riemer, RN
Cancer Biology Program
Valsamo Anagnostou, MD PhD
Victor E. Velculescu, MD PhD
Department of Radiology
Tony Lin, MD
Funding Sources
Stand Up To Cancer (SU2C)
Lungevity
IASLC
NIH KL2 program
JHH Bloomberg Kimmel Institute
for Cancer Immunotherapy (BKI)
Drew M. Pardoll, MD PhD
Elizabeth M. Jaffee, MD PhD
Kellie Smith, PhD
Suzanne Topalian MD
Department of Pathology
Tricia Cottrell, MD PhD
Janis Taube, MD
Peter Illei, MD
Colleagues and Collaborators