1. Immunotherapy in Cancer: From Principles to Practice
This program is supported by educational grants from Bristol-Myers Squibb and Merck.

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3. Core Faculty
Program Director Michael B. Atkins, MD Deputy Director Lombardi Comprehensive Cancer Center Georgetown University Washington, DC Julie Brahmer, MD Associate Professor of Oncology Oncology/Upper Aerodigestive Cancer Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland
This slide lists the faculty who were involved in the production of these slides.

4. Faculty Disclosures
Michael B. Atkins, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Genentech, and Merck. Julie Brahmer, MD, has disclosed that she has received consulting fees from Eli Lilly and Merck.

5. Tumor Immunology: Overview
perforin granzyme
cytokines
Resting T cell
Activated T cell
TUMOR
LYMPH NODE
T cell clonal expansion
Tumor antigen
TCR
CD28
MHC, major histocompatibility complex; TCR, T cell receptor.
MHC B7
Dendritic cell

6. Tumor-Derived Immune Suppression
Tumors go to great lengths to evade the immune response
Systematic studies have identified multiple mechanisms cancers employ to defeat the immune response
Immunosuppressive cytokines: TGF-β, IL-4, -6, -10
Immunosuppressive immune cells: T-regs, macrophage
Disruption of immune activation signaling: loss of MHC receptor, IDO production
Goal: therapy strategies that “liberate” underlying anticancer immune responses
Immune checkpoints not even in the picture in 2008!
IDO, indoleamine 2,3-dioxygenase; IL, interleukin; MHC, major histocompatibility complex; TGF-β – transforming growth factor beta; T-regs, regulatory T cells.
Weiner LM. N Engl J Med. 2008;358:

7. HD IL-2 Therapy: Durable Responses
HD IL-2 produces durable responses in 6% to 10% of patients with advanced melanoma or RCC
Few relapses in patients responding for over 2.5 years (likely cured)
FDA approval in 1992 (RCC) and 1997 (melanoma)
Metastatic Melanoma (N = 270)
Metastatic RCC (N = 255)
1.0
1.0
CR (n = 17) PR (n = 26) CR + PR (n = 43)
CR PR All
0.8
0.8
0.6
CR, complete response; HD, high-dose; IL-2, interleukin-2; PR, partial response; RCC, renal cell carcinoma.
0.6
Probability of Continuing Response
Probability of Continuing Response
0.4
0.4
0.2
0.2
0.0
0.0 10 20 30 40 50 60 70 80 90
100
110
120
130 10 20 30 40 50 60 70 80 90
100
110
120
130
140
150
160
170
180
Duration of Response (Mos)
Duration of Response (Mos)
Atkins MB, et al. J Clin Oncol. 1999;17: McDermott DF, et al. Expert Opin Biol Ther. 2004;4:

8. HD IL-2 Therapy in Melanoma and RCC
High-dose IL-2 appears to benefit patients, but:
Toxic
Impractical: must be delivered as an inpatient procedure
Use remains limited to selected patients treated at experienced centers
Efforts to develop more tolerable regimens unsuccessful
Efforts to better select patients who might benefit from HD IL-2 therapy have produced modest advances
Proof of principle that immunotherapy can produce durable benefit in patients with cancer, but newer immunotherapies are needed
HD, high-dose; IL-2, interleukin-2; RCC, renal cell carcinoma.

9. Noninflamed Tumor Phenotype
Poor effector cell trafficking due to:
High expression of vascular markers, macrophages, fibroblasts
Low inflammation and chemokine expression, few lymphocytes
Endothelial cells
Macrophage
Poor migration X
Chemokines
Tumor
Cytotoxic
T cell
Fibroblasts
Gajewski TF, et al. Curr Opin Immunol. 2011;23:

10. Inflamed Tumor Phenotype
T cell recruitment
High levels of innate immune signals
Chemokine expression
Nevertheless, negative immune regulators dominate
Inhibitory receptors
Suppressive cells
Suppressive enzymes (IDO, arginase)
Tumor
PD-L1
Migration
Cytotoxic
T cell
Chemokines
IDO, indoleamine 2, 3-dioxygenase; MDSC, myeloid-derived suppressor cells; PD-L1, programmed death-ligand 1; T-reg, regulatory T cell.
Anergy T T
T reg
MDSC
Gajewski TF, et al. Curr Opin Immunol. 2011;23: Spranger S, Gajewski T. J Immunother Cancer. 2013;1:16.

11. Cancer Vaccines: Current Status
Many promising phase II studies compared to historical controls
Whole-cell vaccines: allogeneic melanoma cells/cell lysates
Tumor antigen directed: MAGEA3, MUC1
Manipulated oncolytic virus: T-VEC
Failure to show survival benefit in Phase III trials
Only approved cancer vaccine: Sipuleucel-T in prostate cancer[1]
Encouraging results with T-Vec in melanoma[2]
MAGEA3, melanoma-associated antigen-3; MUC1, mucin-1; T-Vec, talimogene laherparepavec.
1. Di Lorenzo G, et al. BJU Int. 2012;110:E Kaufman HL, et al. ASCO Abstract 9008a.

12. Phase III Trial of Sipuleucel-T Immunotherapy in mCRPC (IMPACT): OS
100
Median OS benefit: 4.1 months
HR : 0.78 (95% CI: ; P = .03) 80 60
Probability of Survival (%)
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos. 40
CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. 20
Placebo (n = 171)
Median Survival: Mos. 12 24 36 48 60 72
Mos Since Randomization
Kantoff PW, et al. N Engl J Med. 2010;363:

13. OPTiM Study of T-Vec in Stage IIIB-IV Melanoma: Overall Survival
100
Median (95% CI)
Events/N (%)
in Mos 80
T-Vec
189/295 (64)
23.3 ( )
GM-CSF
101/141 (72)
18.9 ( ) 60
HR: 0.79 (95% CI: ;
unadjusted log-rank P = .051)
OS, % 40
Survival, %
T-Vec
GM-CSF
Difference,
% (95% CI)
12 mos
73.7
69.1
4.6 (-4.7 to 13.8)
24 mos
49.8
40.3
9.5 (-0.5 to 19.6)
36 mos
38.6
30.1
8.5 (-1.2 to 18.1)
48 mos
32.6
21.3
11.3 (1.0 to 21.5) 20
CI, confidence interval; GM-CSF, granulocyte macrophage colony-stimulating factor; HR, hazard ratio; OS, overall survival; T-Vec, talimogene laherparepvec. 5 10 15 20 25 30 35 40 45 50 55 60
Months
Kaufman HL, et al. ASCO Abstract 9008a.

14. Cancer Vaccines: Issues
Induce immune reaction against vaccine, but not the tumor
Immune system mainly recognizes “neo-antigens” from “passenger” mutations rather than shared antigens
Antigens different for each tumor
Vaccine must involve autologous tumor cells
Most immune-responsive tumors “autovaccinate”, but immune regulation prevents an effective response
Even if vaccine enhances antitumor immunity, cells likely to be suppressed in the tumor microenvironment
Conclusion: Vaccines are unlikely to have a major effect in the absence of immune checkpoint control

15. Inflamed Tumor Phenotype
T cell recruitment
High levels of innate immune signals
Chemokine expression
Nevertheless, negative immune regulators dominate
TIL therapy: remove anti-tumor T cells from immunosuppressive environment, select/expand ex vivo then re-administer
Tumor
PD-L1
Migration
Cytotoxic
T cell
Chemokines
MDSC, myeloid-derived suppressor cells; programmed death-ligand 1; TIL, tumor infiltrating lymphocyte; T-reg, regulatory T cell.
Anergy T T
T reg
MDSC
Gajewski TF, et al. Curr Opin Immunol. 2011;23: Spranger S, Gajewski T. J Immunother cancer. 2013;1:16.

16. Tumor-Infiltrating Lymphocytes + IL-2 in Metastatic Melanoma: OS
1.0
Strong data suggest that mutation- reactive T cells contribute to these responses
0.9
CR (n=20)
0.8
0.7
0.6
Proportion Surviving
0.5
0.4
0.3
CR, complete response; IL-2 interleukin-2; NR, no response; OS, overall survival; PR, partial response.
PR (n=32)
0.2
0.1
NR (n=41)
0.0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
102
Survival Time (Mos)
Robbins PF, et al. Nat Med. 2013;19:

17. Tumor-Infiltrating Lymphocytes: Commentary
Critical components appear to be
Lymphodepletion to eliminate immuno-inhibitory factors within the tumor microenvironment
Removal, reactivation, and ex vivo expansion of tumor-infiltrating (tumor-specific) CD8+ T cells
IL-2 or other immunostimulatory cytokine to sustain transfused TIL function
Corollary: tumors without TIL will not respond
TIL recognize neo-antigens; therefore those with more mutations may be more likely to have TIL
IL-2, interleukin-2; TIL, tumor-infiltrating lymphocytes.
Can immunoinhibitory forces be blocked in vivo, restoring TIL activity without need for lymphodepletion and ex vivo expansion?

18. Regulation of T Cell Responses Via Multiple Co-Stimulatory and Inhibitory Interactions
T cell response to antigen is mediated by peptide-MHC recognized by TCR (first signal – specificity)
B7 family of membrane-bound ligands binds both co- stimulatory and inhibitory receptors (second co- stimulatory signal)
Targeting CTLA-4 and PD-1 inhibitory receptors has been a major clinical focus
MHC, major histocompatibility complex; TCR, T cell receptor.
Pardoll DM. Nat Rev Cancer. 2012;12:

19. Ipilimumab a Member of Novel Class of Immunotherapeutic Abs: Anti–CTLA-4
1. Costimulation via CD28 binding transduces T-cell activating signals
2. CTLA-4 binding on activated T cells down- regulates T-cell responses
3. Blocking CTLA-4 binding enhances T-cell responses
T-cell activation
T-cell inactivation
T-cell activation
T cell
CTLA-4
T cell
T cell
APC, antigen-presenting cell; CTLA, cytotoxic T-lymphocyte antigen; MHC, major histocompatibility complex; TCR, T-cell receptor.
CTLA-4
TCR
TCR
TCR
CTLA-4
MHC
CD28 B7
CD28 B7
MHC
CD28
MHC B7
Ipilimumab
APC
APC
APC

20. Ipilimumab, gp100, or Both in Advanced Melanoma (MDX010-20): Survival
1.0
Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C)
Comparison HR P Value  Arms A vs C Arms B vs C
0.9
0.8
0.7
OS, %
Ipi + gp100 (n = 403)
Ipi + Placebo (n = 137)
gp100 + Placebo (n = 136)
Year 1 44 46 25
Year 2 22 24 14
0.6
Proportion Alive
0.5
0.4
0.3
HR, hazad ratio; Ipi, ipilimumab; OS, overall survival.
0.2
0.1 1 2 3 4
Yrs
Hodi FS, et al. N Engl J Med. 2010;363: 20

21. Anti-CTLA4 Antibodies: Disease Can Get Worse Before It Gets Better
4 distinct response patterns associated with favorable OS
Response in baseline lesions (typical RECIST response)
Stable disease with slow decline in tumor volume
Response following an initial increase in tumor volume
Response following the appearance of new lesions
Infiltration of patient immune cells can cause an initial increase in tumor volume or appearance of new lesions on imaging scans (pseudoprogression)
CTLA-4, cytotoxic T-lymphocyte antigen 4; OS, overall survival; RECIST, Response Evaluation Criteria in Solid Tumors.
Wolchok JD, et al. Clin Cancer Res. 2009;15:

22. Ipilimumab: irRC Identifies Survivors in Patients with Progressive Melanoma
1.0
0.9
0.8
0.7
0.6
Proportion Alive
0.5
0.4
0.3
CR complete response; irRC, immune-related response criteria; irSD, immune-related stable disease; irPR, immune-related partial response; PD, progressive disease; PR, partial response, SD, stable disease; WHO, World Health Organization.
0.2
CR/PR/SD (by WHO criteria) irPR/irSD (by the irRC) PD and unknown response
0.1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Mos
Wolchok JD, et al. Clin Cancer Res. 2009;15:

23. Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma
1.0
0.9
0.8
N = 1861
Median OS (95% CI): 11.4 mo ( )
3-year OS Rate (95% CI): 22% (20% to 24%)
0.7
0.6
Proportion Alive
0.5
0.4
0.3
CI, confidence interval; OS, overall survival.
0.2
0.1
Ipilimumab
CENSORED
0.0 12 24 36 48 60 72 84 96
108
120
Months
Patients at Risk
Ipilimumab
1861
839
370
254
192
170
120 26 15 5
Hodi S, et al European Cancer Congress. Abstract LBA 24.

24. Ipilimumab, gp100, or Both in Advanced Melanoma (MDX010-20): irAEs
All grades (Gr 3/4)
Ipi + gp100
N=380
Ipi +pbo
N=131
gp100 + pbo
N=132
Any
57 (9.7/0.5)
60 (12.2/2.3)
32 (3.0/0)
Dermatologic
39 (2.1/0.3)
42 (1.5/0)
17 (0/0) GI
31 (5.3/0.5)
28 (7.6/0)
14 (0.8/0)
Endocrine
3 (1.1/0)
8 (2.3/1.5)
2 (0/0)
Hepatic
2 (1.1/0)
3 (0/0)
4 (2.3/0)
GI, gastrointestinal; Gr, grade; Ipi, ipilimumab; irAE, immune-related adverse event; pbo, placebo.
Hodi et al. N Engl J Med Aug 19;363(8):711-23 24

25. Kinetics of Appearance of irAEs with Ipilumumab
Rash, pruritis Liver toxicity
Diarrhea, colitis Hypophysitis
Toxicity Grade
irAE, immune-related adverse events. 2 4 6 8 10 12 14
Weeks
Weber JS, et al. J Clin Oncol. 2012;30:

26. Ipilimumab: Managing Immune-Related Adverse Events
System
Symptoms
Management
GI tract
Diarrhea Abdominal pain Dark, bloody stools
Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory patients
Skin
Rash (± itching) Blistering/peeling Oral sores
Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids
Liver
Jaundice Nausea/vomiting
Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory patients
CNS
Weakness in extremities Numbness/tingling Sensory changes
Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids
Endocrine
Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness
Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the patient
Eyes
Vision problems Irritation
Monitor for redness suggesting uveitis, treat with topical steroidal eye drops
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; GI, gastrointestinal; ULN, upper limit of normal.
Ipilimumab adverse reaction management guide.

27. Ipilimumab Treatment: Commentary
Immune responses and anti-tumor responses noted in some individuals
Activity powerful enough to work in the CNS and overcome concurrent immunosuppression
Response appears to be associated with autoimmunity
Ipilimumab represents an option for the majority of patients with advanced melanoma
Management of immune-related toxicities requires attention
Role in other cancers not established
Activity in RCC not pursued
Prostate and lung cancer studies (negative)
May not address the immunosuppressive microenvironment
CNS, central nervous system; RCC, renal cell carcinoma.

28. Ipilimumab in Melanoma: Current Issues
Dose: 3 mg/kg or 10 mg/kg?
Phase III ongoing in pts with metastatic melanoma (NCT )
Schedule: Maintenance therapy or not?
Role in the adjuvant setting?
EORTC 18071[1]
E1609 (NCT )
In combinations?
Bevacizumab, other immunotherapies (GM-CSF, IFN, IL-2, PD-1 abs, and T-Vec), and radiation therapy
High toxicity when combined with BRAF inhibitors[2]
EORTC, European Organisation for Research and Treatment of Cancer; GM-CSF, granulocyte macrophase colony-stimulating factor; IFN, interferon alfa, IL-2, interleukin-2; irAEs, immune-related adverse events; OS, overall survival; PD1, programmed death 1.
1. Eggermont A, et al. ASCO LBA Ribas A, et al. N Engl J Med. 2013;368:

29. Inflamed Tumor Phenotype
T cell recruitment
High levels of innate immune signals
Chemokine expression
Nevertheless, negative immune regulators dominate
Blocking PD1:PD-L1 binding might activate immunity within the tumor microenvironment
Tumor
PD-L1
Migration
Cytotoxic
T cell
Chemokines
PD1
MDSC, myeloid-derived suppressor cells; PD-1, programmed death 1; PD-L1, programmed death-ligand 1; T-reg, regulatory T cell;
Anergy T T
T reg
MDSC
Gajewski TF, et al. Curr Opin Immunol. 2011;23: Spranger S, Gajewski T. J Immunother cancer. 2013;1:16.

30. PD-1 Adaptive Resistance to Immunotherapy
Anti–PD-1
Anti–PD-L1
Tumor cell
PD-L1
PD-1
TCR
MHC
Interferons
PD-1, programmed death-1; PD-L1, programmed death-ligand 1.
PD-L1 can be expressed on tumor cells either endogenously or induced by association with T cells (adaptive immune resistance)[1,2]
PD-1:PD-L1 interaction results in T cell suppression (anergy, exhaustion, death)
In RCC, melanoma, and other tumors, PD-L1 expression has been shown to be associated with adverse clinical/pathologic features, eg, more aggressive disease and shorter survival[3]
1. Topalian SL, et al. Curr Opin Immunol. 2012;24: Taube JM, et al. Sci Transl Med. 2012;4:127ra Thompson RH, et al. Proc Natl Acad Sci USA. 2004;101:

31. Clinical Development of Inhibitors of PD-1 Immune Checkpoint
Target
Antibody
Molecule
Development stage
PD-1
Nivolumab
(BMS )
Fully human IgG4
Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC)
Pembrolizumab
(MK-3475)
Humanized IgG4
Phase I-II multiple tumors
Phase III NSCLC/melanoma
Pidilizumab
(CT-011)
Humanized IgG1
Phase II multiple tumors
PD-L1
MEDI-4736
Engineered human IgG1
MPDL-3280A
Phase III NSCLC
MSB C
Fully human IgG1
Phase I solid tumors
HNSCC, head and neck squamous cell carcinoma; NSCLC; non-small cell lung cancer; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; RCC, renal cell carcinoma.
Highly Cofidential

32. Nivolumab: Clinical Activity
Tumor Type
Dose, mg/kg
ORR (CR/PR), n (%)
SD ≥ 24 Wks, n (%)
Median PFS,
Mos
Median OS,
1 yr, %
2 yr, %
MEL
(n = 107)
0.1-10
32 (34)
7 (7)
3.7
17.3 68 48
NSCLC
(n = 129)
1-10
22 (17)
13 (10)
2.3
9.9 42 24
RCC
(n = 34)
1 or 10
10 (29)
9 (27)
7.3
> 22 70 50
CR, complete response; MEL, melanoma; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RCC, renal cell carcinoma; SD, stable disease.
28 responses (16 MEL, 6 RCC, and 6 NSCLC) lasted ≥ 1 yr among 54 patients with treatment initiation ≥ 1 yr before data analysis
13 patients (4 MEL, 6 NSCLC, 3 RCC) demonstrated nonconventional patterns of response but were not included as responders
Topalian SL, et al. N Engl J Med. 2012;366: Hodi FS, et al. ASCO Abstract Brahmer JR, et al. ASCO Abstract 8112.

33. Nivolumab (10 mg/kg): Response of Metastatic NSCLC
Diagnosis: 2004, EGFR mutation +
Previous treatment: gemcitabine/carboplatin; erlotinib; erlotinib + LBH589 (trial for T790 mutation); and lastly pemetrexed
Nivolumab treatment: initial progression in pulmonary lesions of a NSCLC patient with non-squamous histology was followed by regression
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.
Oxnard GR, et al. J Natl Cancer Inst. 2012;104: Topalian SL, et al. N Engl J Med. 2012;366:

34. Nivolumab: Durability of ORR in Pts With Advanced NSCLC, MEL and RCC
65 of 306 pts had ORR (CR/PR):
30 of 65 (46%) responses were evident at first tumor evaluation (8 wks)
42 of 65 (65%) pts had responses lasting > 1 yr
35 of 65 (54%) responses were ongoing at time of data analysis
Responses persisted off drug
Squamous
Maximum treatment duration
NSCLC
Nonsquamous
MEL
CR, complete response; MEL, melanoma; NSCLC, non-small cell lung cancer; ORR, overall response rate; PR, partial response; RCC, renal cell carcinoma.
Ongoing response
Time to response
RCC 24 48 72 96
120
144
168
Wks since treatment initiation
Topalian SL, et al. ASCO Abstract 3002.

35. Nivolumab: Duration of Response
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Med., mo. (95%CI)
NSCLC (n=22) (9.7 - NE)
Melanoma (n=33) ( NE)
RCC (n=10) ( NE)
Censored
Proportion progression-free
MEL, melanoma; NSCLC, non-small cell lung cancer; NE, not estimable; RCC, renal cell carcinoma.
Months since initiation of response
No. at Risk
NSCLC
MEL
RCC
Topalian SL, et al. ASCO Abstract 3002.

36. Nivolumab Exposure-adjusted irAEs: Toxicity Is Not Cumulative
140
120
Observation period (no. pts; P-Y)
0-6 mo. (n = 306; P-Y = 138) 6-12 mo. (n = 189; P-Y = 59) mo. (n = 85; P –Y = 49)
100
Events per 100 person-years 80 60 40 20 GI
Skin
Renal
Hepatic
Thyroid
Inf. Rxion
AE, adverse event; GI, gastrointestinal; irAE, immune-related adverse event; Inf, infusion; P-Y, person-years; Rxion, reaction.
Pulmonary
Multiple occurrences of all-cause select AEs in individual pts are included in this exposure-adjusted analysis.
Treatment-related Gr 3-4 AEs occurred in 17% of pts, including select AEs in 6%.
Topalian SL, et al. J Clin Oncol. 2014;32:

37. Pembrolizumab (MK-3475) in Melanoma: Response by Prior IPI and Dose/Schedule
34%
Overall
365
2 mg/kg q3w
146
10 mg/kg q3w
168
Pts N
CR, %
ORR, % (95% CI)
IPI-N
168 8
40 (32-48)
IPI-T
197 2
28 (22-35)
Total
365 5
34 (29-39)
10 mg/kg q2w 51
IPI-N
168
2 mg/kg q3w 65
10 mg/kg q3w 66
CR, complete response; IPI-N, ipilimumab naïve; IPI-T, ipilimumab treated; irRC, immune-related response criteria; ORR, overall response rate; q2w, every 2 weeks; q3w, every 3 weeks.
10 mg/kg q2w 37
IPI-T
197
2 mg/kg q3w 81
10 mg/kg q3w
102
10 mg/kg q2w 14 10 20 30 40 50 60 70 80 90
100
ORR (%)
Ribas A, et al. ASCO LBA9000.

38. Individual Patients Treated with Pembrolizumab
Pembrolizumab (MK-3475) in Advanced Melanoma: Max % Change in Tumor Size
100 80 60 40 20
Change from Baseline in Sum of Product Perpendicular Diameters of Index Lesions, %
-20
-40
IPI-N, ipilimumab-naïve; IPI-T, ipilimumab treated; irRC, immune-related response criteria.
-60
IPI-T
-80
IPI-N
-100
Individual Patients Treated with Pembrolizumab
In patients with measurable disease at baseline by irRC by central review and ≥1 postbaseline assessment (n = 319).
Percentage changes >100% were truncated at 100%.
Ribas A, et al. ASCO LBA9000.

39. Pembrolizumab: Time to Response and On-Study Duration
6 months
12 months
18 months
88% of responses ongoinga
Median response duration not reached (range, 6+ to 76+ weeks)
Individual Patients Treated With Pembrolizumab
IPI-T
IPI-N
IPI-N, ipilimumab-naïve; IPI-T, ipilimumab treated
Complete Response
Partial Response
Progression
On Treatment 10 30 50 70 90
Wks
aOngoing response defined as alive, progression free, and without new anticancer therapy.
Ribas A, et al. ASCO LBA9000.

40. Pembrolizumab: NSCLC Clinical Activity
First-line1
Previously treated2
PD-L1+
(n = 42)
(n = 159)
PD-L1 –
(n = 35)
ORR*, % 26 23 9
DCR*, % 64 42 31
Median duration of response, wks NR
*RECIST v1.1
DCR, disease control rate; NR, not reached; NSCLC, non-small cell lung cancer; ORR, overall response rate; PD-L1, programmed death-ligand 1; RECIST, response evaluation criteria in solid tumors.
~ 80% of screened patients in each study were PD-L1+
Among previously treated patients with NSCLC, ORR was 26% in current/former smokers and 9% in never smokers
1. Rizvi N, et al. ASCO Abstract Garon E, et al. ASCO Abstract 8020.

41. MPDL3280A Phase Ia: Efficacy Summary
26 of 29 responders continued to respond at last assessment
Time on study in responders: 3 to 15+ months
Additional delayed responses not reflected in above ORR
Other tumor types (14) include CRC (PR in 1/4) and gastric cancer (PR in 1/1)
Generally well tolerated
Grade 3/4 related AE 13%; 2% immune related
Population, %
RECIST 1.1 Response Rate (ORR*)
SD of 24 Weeks or Longer
24-Week PFS
Overall population (N = 140) 21 19 42
NSCLC
(n = 41) 22 12 46
Melanoma
(n = 38) 29 5 43
RCC
(n = 47) 13 32 53
AE, adverse event; CR, complete response; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; PFS, progression-free survival; PR, partial response; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
*ORR includes unconfirmed PR/CR and confirmed PR/CR.
Herbst RS, et al. ASCO Abstract 3000.

42. MPDL3280A: Patients With Other Solid Tumors
Tumor Type
Dose, mg/kg
Patients, n
Best Response (Investigator Assessed)
Time on Study for Responders (Mos) PR SD PD
CRC 20 4 1 2
10.4+ GC --
9.8
Sarcoma 3 NA
SCCHN
Breast
10, 20
Pancreato-duodenal
Pancreatic 10
Ovarian
CRC, colorectal cancer; GC, gastric cancer; PD, progressive disease; PR, partial response; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease.
Data cutoff February 1, 2013; only includes patients first dosed at 3-20 mg/kg prior to August 1, 2012.
Best response includes unconfirmed and confirmed PR/CR.
Tabernero J, et al. ASCO Abstract 3622.

43. MPDL3280A: Tumor Burden Over Time in Urothelial Bladder Cancer
Median time to first response was 42 days (range, 38 to 85 days)
Median duration of response has not been reached
0.1+ to weeks IHC (IC) 2 or 3 and 0.1+ to 6.0+ weeks for IHC (IC) 0 or 1
Best response is not known for 7 patients.
Patients dosed by Nov 20, 2013 (≥ 6 wk follow-up) with measurable disease at baseline and at least 1 post-baseline measurement. Clinical data cutoff was Jan 1, 2014.
Powles T, et al. ASCO Abstract 5011.

44. Tumors Shown to Respond to Anti-PD1 or Anti-PD-L1 Therapy
Melanoma
Pembrolizumab approved by the US FDA in September 2014 for unresectable or metastatic disease with progression following ipilimumab and, if appropriate, a BRAF inhibitor
RCC
NSCLC
Bladder
Head and Neck cancer
Lymphomas
???
NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma.

45. Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities
Occasional (5-20%)
Fatigue
Rash: maculopapular and pruritus
Topical treatments
Diarrhea/colitis
Initiate steroids early, taper slowly
Hepatitis/liver enzyme abnormalities
Infusion reactions
Endocrinopathies: thyroid, adrenal, hypophysitis
Infrequent (<5%)
Pneumonitis
Grade 3/4 toxicities uncommon
PD-1, programmed death-1; PD-L1, programmed death-ligand 1.
1. Topalian SL, et al. N Engl J Med. 2012;366: Patnaik A, et al. ASCO Abstract 2512.
3. Brahmer JR, et al. N Engl J Med. 2012;366: Herbst RS, et al. ASCO Abstract 3000.

46. Pembrolizumab: AEs in > 5% of Patients
Adverse Event (N = 135)
All Grades, n (%)
Grades 3/4, n (%)
Any
107 (79.3)
17 (12.6)
Fatigue
41 (30.4)
2 (1.5)
Rash
28 (20.7)
3 (2.2)
Pruritus
1 (0.7)
Diarrhea
27 (20.0)
Myalgia
16 (11.9)
Headache
14 (10.4)
Increased AST
13 (9.6)
Asthenia
Nausea
Vitiligo
12 (8.9)
Hypothyroidism
11 (8.1)
Increased ALT
Cough
Pyrexia
10 (7.4)
Chills
9 (6.7)
Abdominal pain
7 (5.2)
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Ribas A, et al. ASCO Abstract 9009.

47. Pneumonitis Associated With PD-1 Pathway Blockade
Treatment algorithms for early detection and management implemented (dose delay/discontinuation, immunosuppression)[1]
Clinical Trial
Tumor Histology
Any Grade % (n/N)
Grade 3/4 % (n/N)
Nivolumab monotherapy[2]
Multiple
3 (9/296)
1 (3/296)*
Nivolumab + ipilimumab[3]
Concurrent treatment
Sequential treatment (ipi → nivo)
Melanoma
6 (3/53)
3 (1/33)
2 (1/53)
0 (0/33)
Nivolumab ± peptide vaccine[4]
3 (3/90)
2 (2/90)
Nivolumab ± peptide vaccine adjuvant[5]
0 (0/153)
Nivolumab + chemotherapy[6]
NSCLC
14 (8/56)
7 (4/56)
All nivolumab trials total
All Tumors
4 (27/691)
2 (11/691)
Anti-PD-L1 (BMS ) monotherapy[7]
1 (3/284)
0 (0/284)
CRC, colorectal cancer; NSCLC, non-small cell carcinoma; PD, programmed death.
*3 pts with grade 3/4 pneumonitis died (1 CRC, 2 NSCLC). Data analysis in February /March 2013.
Hodi FS, et al. 12th International Congress on Targeted Anticancer Therapies. Abstract O2.3.
Topalian SL, et al. N Engl J Med. 2012;366: Wolchok JD, et al. J Clin Oncol. 2013;31(18 suppl):abstr 9012.
4. Weber JS, et al. J Clin Oncol. 2013;31(18 suppl):abstr Gibney GT, et al. J Clin Oncol. 2013;31(18 suppl):abstr 9056.
6. Rizvi NA, et al. J Clin Oncol. 2013;31(18 suppl):abstr Topalian SL, et al. J Clin Oncol. 2013;31(18 suppl):abstr 3002.

48. CTLA-4 and PD-1/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
CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; TCR, T cell receptor.
T cell
PD-1
Cancer cell
PD-L1
Ribas A. N Engl J Med. 2012;366:

49. Ipilimumab + Nivolumab: Change in Target Lesions
All patients in concurrent cohorts
300
250
250
First occurrence of new lesion
200
200
150
Cohort 2:
1 mg/kg nivolumab + 3 mg/kg ipilimumab
150
100 50
100
Change in target lesions from baseline (%)
Change in target lesions from baseline
-20 50
-40
-60
-80
-50
ORR, overall response rate.
-100
-100 10 20 30 40 50 60 70 80 90
100
110
120
Patients
Weeks since treatment initiation
Therapy, %
ORR
≥ 80% Tumor Reduction
Ipilimumab 7
< 3
Nivolumab 28
< 2
Combination (cohort 2) 53 41
Wolchok JD, et al. N Engl J Med. 2013;356: Wolchok JD, et al. ASCO Abstract 9012.

50. Phase I Study of Nivolumab + Ipilimumab in Melanoma: OS for Concurrent Tx
100
2-yr OS 88% 90 80 70
2-yr OS 79% 60
Survival (%) 50
2-yr OS 50% 40
Censored 30
Nivo 0.3 mg/kg + IPI 3 mg/kg Nivo 1 mg/kg + IPI 3 mg/kg Nivo 3 mg/kg + IPI 1 mg/kg Nivo 3 mg/kg + IPI 3 mg/kg Concurrent cohort
IPI, ipilimumab; Nivo, nivolimumab; OS, overall survival; Tx, treatment. 20 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Mos
Pts at Risk
Nivo 0.3/IPI 3 Nivo 1/IPI 3
Nivo 3/IPI 1
Nivo 3/IPI 3
Concurrent
Sznol M, et al. ASCO LBA9003.

51. Nivolumab + Ipilimumab Adverse Events
Treatment-Related AE,
Number of Patients (%)
Concurrent
All Cohorts (n = 53)
All Grades
Grades 3/4
Any adverse event
49 (93)
28 (53)
Rash
29 (55)
2 (4)
Pruritus
25 (47)
Fatigue
20 (38)
Diarrhea
18 (34)
3 (6)
Nausea
11 (21)
Pyrexia
 AST
7 (13)
 ALT
6 (11)
 Lipase
10 (19)
 Amylase
8 (15)
Cough
Vomiting
1 (2)
Vitiligo
Headache
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Wolchok J, et al. ASCO Abstract 9012.

52. Phase I Study of Nivolumab + Ipilimumab in mRCC
120
120
100
100 80 80 60 60 40 40 20 20
Change in baseline (%)
1st occurrence of new lesion
-20
-20
-40
-40
-60
-60
-80
-80
-100
-100 6 12 18 24 30 36 42 48 54 6 12 18 24 30 36 42
Wks Since First Dose
Wks Since First Dose
120.00
mRCC, metastatic renal cell carcinoma.
100.00
80.00
60.00
40.00
N3 + I1 (n=20)
N1 + I3 (n=22)
20.00
Change in baseline target lesions (%)
0.00
-20.00
-40.00
-60.00
-80.00
Hammers HJ, et al. ASCO Abstract 4504.

53. PD-1/PD-L1 Therapy: Select Pivotal Trials
Tumor Type
Phase III (unless otherwise indicated)
Melanoma
Pembro (2 doses) vs ipi[NCT ]
Nivo vs ipi vs ipi/nivo[NCT ]
Nivo vs chemo (ipi progression)[NCT ,NCT ]
Pembro vs chemo (ipi progression; Phase 2)[NCT ]
RCC
Nivo vs everolimus (TKI progression)[NCT ]
Nivo/ipi vs sunitinib
MPDL + bev vs MPDL vs sunitinib (Phase 2)[NCT ]
NSCLC
Pembro (2 doses) vs doc[NCT ]
Nivo vs doc (squamous or nonsquamous)[NCT ,NCT ]
Nivo vs chemo choice[NCT ]
HNSCC
Nivo vs investigator’s choice[NCT ]
bev, bevacizumab; HNSCC, head and neck squamous cell carcinma; ipi, ipilimumab; nivo, nivolumab; NSCLC, non-small cell lung cancer; PD-1; programmed death 1; PD-L1, programmed death-ligand 1; pembro, pembrolizumab; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.
Patients with known or suspected autoimmune disease are generally excluded
from these trials.

54. Key Translational Questions for PD-1 Pathway Blockade
Predictive Biomarkers
Which tumors to treat?
Which patients to treat?
Other combinations?
Line of therapy?
What to do for tumors without immune infiltrates?

55. Biomarkers of Activity for Checkpoint Inhibitors

56. ORR by PD-L1 Expression in Patients with Solid Tumors
Rx Antibody
Testing Method N
PD-L1 + RR
PD-L1 - RR
Nivolumab[1]
Manual staining – 5H1
5% cutoff
Tumor staining 49
13/31
42%
0/18 0%
Nivolumab[2]
Dako automated 38
7/17
41%
3/21
14%
MPDL3280A[3]
Automated
Roche Dx IHC
1% cutoff
Tumor immune cell staining
103
13/36
36%
9/67
13%
Ipi/Nivo[4] 56
8/14
57%
17/42
40%
IHC, immunohistochemistry; Ipi, ipilimumab; Nivo, nivolumab; ORR, overall response rate; PD-L1, programmed death-ligand 1; RR, response rate.
1. Topalian SL, et al. N Engl J Med. 2012;366: Grosso J, et al. ASCO Abstract Herbst RS, et al. ASCO Abstract Sznol M, et al. ASCO LBA9003.

57. Issues with PD-L1 as a Biomarker
PD-L1 negativity an unreliable biomarker
Assays are technically difficult, imperfect; results may differ depending on the antibody/assay (tumor vs immune cells)
5% expression, tumor heterogeneity, and inducible gene = sampling error (false negative)
Archived tissue different than recent biopsy
May be more useful in determining which tumors rather than which patients to treat
PD-L1 expression may be less relevant for combination therapies
PD-L1 expression might be constitutive (no immune infiltrate)
PD-L1, programmed death-ligand 1.

58. Other Combinations with PD-1 Checkpoint Inhibitors
Other coinhibitory pathways
TIM-3, LAG-3, IDO
Co- or immunostimulatory pathways
OX40, 4-1BB, GITR, IL-2, IFN, IL-21
Standard of care
Chemotherapy, TKI, VEGF inhibitor, XRT
Cancer vaccines
Epigenetic therapy
GITR, glucocorticoid-induced TNFR family related gene; IDO, indoleamine,3-dioxygenase; IFN, interferon; IL-2, interleukin-2; IL-21, interleukin-21; LAG-3, lymphocyte activation gene 3; PD-1, programmed death-1; TIM-3, T cell immunoglobulin and mucin protein 3; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; XRT, radiation therapy.

59. How to Approach Tumors Without Immune Infiltrates
Combination immunotherapies
4-1BB, IL-2, OX40, others
Adoptive Cellular Therapy (ACT)
Genetically manipulated cells
CAR T cells
Professional killers. Don’t need to have pre-existing immunity
CAR T cells are not HLA restricted
Issue is finding antigens expressed only on the tumor
ACT, adoptive cell therapy; CAR, chimeric antigen receptor; HLA, human leukocyte antigen.

60. Conclusions
Immunotherapy can produce durable antitumor responses in some patients with cancer
Treatment of patients with immune checkpoint inhibitors can be different than with conventional therapies, including
Identifying unconventional responses to immune checkpoint inhibitors (eg, pseudo-progression)
Understanding and managing immune-related adverse events
Mounting data indicate that checkpoint inhibitors targeting PD- 1/PD-L1 are active in multiple tumor types
Ongoing studies will help define the optimal use of checkpoint inhibitors in different tumor types as single agents or as part of combination therapy

61. Go Online for More CCO Coverage of Immunotherapy!
Additional CME-certified slideset on immunotherapy in melanoma with expert faculty commentary on all the key studies Downloadable slidesets on immunotherapy across tumor types for self- study or use in your own presentations
clinicaloptions.com/oncology