1. The Promise of Immunotherapy for Cancer Treatment
Julie R. Brahmer, M.D., M.Sc.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

2. Scott Gettinger 2012

3. It Takes a Village to Control a T Cell?
CTLA-4
Tumor Cell or
Antigen Presenting Cell
T cell
B7.1/2
CD28
Signal 2
Signal 1
HLA
T Cell Receptor
antigen
LAG-3
Class II
MHC
PD-1
B7-H1
(PD-L1)
Others: ICOS, GITR, Tim-3

4. Blocking the Immune Checkpoint CTLA-4 - Ipilimumab
a-CTLA4
Signal 2
B7.1/2
(CD80/86)
CD28
CTLA-4
Signal 1
HLA
T Cell Receptor
antigen
Physiologically, this is the working model. CTLA-4 probably evolved to prevent autoimmunity.
T cell

5. Ipilimumab in Melanoma
Phase III trial:
676 patients with chemo-resistant metastatic melanoma
Randomized to ipilimumab + gp100, or either treatment alone
Median overall survival of ipilimumab group 10 months, vs 6.4 months for gp100
Immune-related adverse events in 60% of patients (skin, GI, endocrine, liver)
FDA decision March, 2011
Hodi et al, NEJM :711

6. Role of PD-1 in Suppressing Antitumor Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
MHC-Ag
B CD28
(+) Signal 2
TCR Signal 1
Tumor
APC: Antigen presenting cell
TCR: T-cell receptor
MHC-Ag: Major Histocompatibility Complex-Antigen
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Highly Confidential

7. Role of PD-1 in Suppressing Antitumor Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
MHC-Ag
B CD28
(+) Signal 2
PD-1
TCR Signal 1
(-)
(-)
(-)
Tumor
PD-L1
Tumor
Inhibition
(anergy, exhaustion, death)
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Highly Confidential

8. Role of PD-1 in Suppressing Antitumor Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
MHC-Ag
B CD28
(+) Signal 2
PD-1
TCR Signal 1
(-)
(-)
(-)
Anti-PD-1
Tumor
PD-L1
Tumor
Inhibition
(anergy, exhaustion, death)
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Highly Confidential

9. Clinical Development of Inhibitors of PD-1 Immune Checkpoint
Target
Antibody
Development stage
PD-1
Nivolumab-
BMS
Phase III
PembrolizumabMK-3475
Approved 9/4/14 for unresectable or metastatic melanoma
PD-L1
MedI-4736
MPDL-3280A

10. Durable Responses to Anti-PD-1 OFF THERAPY
yr yr yr yr
CR Stop Rx
Latest evaluation: CR
Pt 2-
2013
5 yr
yr yr yr yr
Stop Best
Rx resp.(PR)
Latest evaluation: CR
Pt 1-
4033
Sustained PR
? new brain met on MRI
resected: - no viable tumor
5 yr
Sustained PR
yr yr yr yr
Stop Best
Rx resp.(PR)
New mets
Pt 1-
3019
Restart
a-PD1
PD after
2 yr re-Rx
Lipson E et al Clin Cancer Res 2012

11. Pembrolizumab in Melanoma
Phase Ib trial: 24% response rate in patients with melanoma. Responses lasting for months months. 1 yr survival rate of 58%.
6th drug for melanoma approved since 2011
Ribas A, ASCO 2014, FDA 2014

12. Broad Activity of PD-1 or PD-L1 Inhibitors
Lung Cancer- in Phase 3 trials
Kidney Cancer – in Phase 3 trials
Bladder Cancer
Head and Neck Cancer
Ovarian Cancer
Multiple cancers are being studied

13. S1400: MASTER LUNG-1: Squamous Lung Cancer- 2nd Line Therapy
CT*
CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib
FGFRi
Endpoint
PFS/OS
FGFR ampl,
Mut, Fusion
CDK 4/6i
CCND1, CCND2, CCND3, cdk4 ampl
PI3Ki
PiK3CA Mut
Biomarker
Profiling (NGS/CLIA)
HGFi+E E*
C-MET Expr
PD-L1i
Non-Match
Multiple Phase II- III Arms with “rolling” Opening & Closure
PI: V. Papadimitrakopoulou (SWOG)
Steering Committee Chair: R. Herbst (YALE, SWOG)
Lung Committee Chair: D. Gandara
Translational Chair: F. Hirsch
Statistical Chair: M. Redman

14. S1400 Master Protocol Unique Private-Public Partnerships with the NCTN
Alliance
ECOG-Acrin
SWOG
S1400
Master
Protocol
NCI-C
NRG

15. Conclusions
Immunotherapy agents have promising anti-tumor activity in multiple cancers
Many key questions need to be answered.
How best should these agents be used (by themselves or in combination)?
Who will most likely benefit from these agents (personalize treatment)?
Phase 3 trials are ongoing in order to make immunotherapy a reality for the treatment of cancer.