your debaters for the eveningd2qrtshcpf0x30.cloudfront.net/nodes/188/asco io final onsite.pdf ·...
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Your Debaters For The Evening:
Current State of Immune Checkpoint Blockade in Selected Types of Solid Tumors
Jeffery Weber, MD, PhD
Naiyer A. Rizvi, MD
Current State of ICI in Melanoma and Bladder Cancers
Jeffrey S. Weber, MD, PhDLaura and Isaac Perlmutter Cancer CenterNYU Langone Medical Center
Current US/EU Approval Status of ICIs
US EU
PD-1 PD-L1 CTLA-4 Combo
Pembrolizumab Nivolumab Atezolizumab Durvalumab Avelumab Ipilimumab Nivo + ipi
Line 1L+ 2L+ 1L+ 2L+ 1L+ 2L+ 2L+ 1L+ 2L+ 1L+ 1L+
mMelanoma
NSCLC
cHL
aRCC
mSCCHN
mUC
Merkel cell
MSI-H
cHL=classical Hodgkin lymphoma; aRCC=advanced renal cell carcinoma; mSCCHN=metastatic head and neck squamous cell carcinoma; mUC=metastatic urothelial cancer; MSI-H=microsatellite instability-high solid tumorsProduct Prescribing Information
Current as of June 2017
Should Immunotherapy be the First-line Therapy in all Stage IV Patients?
Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Pts with Advanced Melanoma
Schadendorf D, et al. J Clin Oncol. 2015; Hodi S, et al. ASCO. 2016; Atkinson V, et al. Presented at: SMR 2015; November 6-9, 2015; Boston, MA.
0 1 2 3 4 5 6 7 8 9 10
100
90
80
70
60
0
50
40
30
20
10
Ove
rall
Surv
ival
(%
)
Years
IPI (Pooled Analysis)
NIVO Monotherapy (Phase 3 Checkmate-066)
N=210
NIVO Monotherapy (Phase 1 CA209-003)
N=107
N=1861
Front-line OS = >50% for Nivolumab
• 33-mo OS rate was 50% in the pooled pembrolizumab arms (n=556)
• 33-mo PFS rate was 31% and ORR was 42%
• Median duration of response was not reached for pembro (range 1.0+ to 33.8+ mo)
• Responses were durable in pts who completed pembro; 9.7 moafter completion of pembro with estimated PFS (95% CI) 91% (80-96) in 104 pts
• Pembro front-line responses were durable!
Long-term Outcomes with Single Agent Pembrolizumab in KEYNOTE-006
Robert C, et al. ASCO. 2017.
First-line Single Agent vs. Concurrent vs. Sequential Immunotherapy?
Updated Survival Data in BMS-067 Trial of IPI vs. NIVO vs. IPI/NIVO
Larkin J, et al. AACR. 2017.
Database lock: September 13, 2016. Minimum follow-up of 28 months
*P<.0001
NIVO + IPI (N=314) NIVO (N=316) IPI (N=315)
Median OS, months (95% CI) NRNR
(29.1-NR)20
(17.1-24.6)
HR (99.5% CI) vs. IPI0.55
(0.42–0.72)*0.63
(0.48–0.81)*-
HR (99.5% CI) vs. NIVO0.88
(0.69-1.12)- -
• Most select AEs were managed and resolved within 3-4 weeks (85-100% across organ categories)
• ORR was 70.7% for patients who discontinued NIVO+IPI due to AEs, with median OS not reached
Patients Reporting Event, %NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)
Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4
Treatment-related adverse event (AE)
95.8 58.5 86.3 20.8 86.2 27.7
Treatment-related AE leading to discontinuation
39.6 31 11.5 7.7 16.1 14.1
Treatment-related death 2 (0.6)a 1 (0.3)b 1 (0.3)b
How Toxic is Combination Checkpoint Blockade?
1Larkin J, et al. N Engl J Med. 2015; Larkin J, et al. AACR. 2017.
• With an additional 19 months of follow-up, safety was consistent with the initial report1
aCardiomyopathy (NIVO+IPI, N=1); Liver necrosis (NIVO+IPI, N=1). Both deaths occurred >100 days after the last treatment.bNeutropenia (NIVO, N=1); Colon perforation (IPI, N=1)1
• Major side effects of immunotherapy are related to development of “autoimmunity”
• Immune-related adverse events, also known as “immune-mediated adverse events” (irAEs, imAEs), may occur in any organ system
• Certain events may be life threatening or fatal
• Prompt recognition of potentially severe irAEs improves outcomes
• Early diagnosis and aggressive systemic corticosteroids are key to prevent life-threatening consequences
• Combining checkpoint inhibitors with agents such as CTLA-4 inhibitors, significantly increases irAEs
Toxicity of Immune Checkpoint Blockade
• Hard to beat the front-line median OS of 30+ months for nivolumabor pembrolizumab alone and 40+ estimated OS for IPI/NIVO
• 2 year OS for IPI/NIVO concurrent or sequential = 62% is unmatched by any targeted phase III trial
First-line Therapy for Melanoma is Immunotherapy for Most Patients
Robert C, et al. ASCO. 2017; Larkin J, et al. AACR. 2017; Schadendorf D, et al. J Clin Oncol. 2015; Hodi S, et al. ASCO. 2016; Atkinson V, et al. Presented at: SMR 2015; November 6-9, 2015; Boston, MA.
What Should be the First Choice for Adjuvant Therapy in High-risk Melanoma?
Overall Survival: Ipilimumab Adjuvant Therapy
Eggermont AMM, et al. N Engl J Med. 2016.
• Accrual was 1,670 including 511 IPI10, 636 HDI and 523 IPI3 pts
• Grade 3+ AEs were seen in 57% of IPI10 and 36% IPI3 pts; discontinuation in 53.8% at IPI10 and 35.2% at IPI3
• At a median follow-up of 3.1 years, unplanned RFS analysis showed 3-year RFS of 54% (95% CI: 49, 60) at IPI10 and 56% (50, 61) at IPI3
Dosing of Ipilimumab as Adjuvant Therapy: 3 vs. 10 mg/kg in E1609
Tarhini A, et al. ASCO. 2017.
Checkpoint Blockade for Bladder Cancer
Efficacy of PD-1 or PD-L1 Immune Checkpoint Inhibitors in Advanced Bladder Cancer
Gill DM, et al. Immunotherapy. 2017.
StudyPrevious
Platinum?Comparator Drug PD-L1 Assay
PD-L1 (+) Expression Cutoff
ORRTime to Response
(mo)OS (mo)
Atezolizumab (IMvigor 210)N=310
Yes No SP142IC0: <1% (n=103)IC1: 1-5% (n=108)
IC2/3: >5% (n=100)
All: 15%, IC0: 8%IC1: 10%, IC2/3: 26%
2.1 (95% CI: 2-2.2)
All: 7.9
Atezolizumab (IMvigor 210)N=119
No, first-line**
No SP142IC0: <1% (n=39)IC1: 1-5% (n=48)
IC2/3: >5% (n=32)
All: 19%IC1/2/3: 19%IC2/3: 22%
Not Published All: 10.6
Avelumab(JAVELIN)N=241
Yes No Clone 73-10 >5% (n=81)PD-L1 (-): 14.7%PD-L1 (+): 25%
~2.6PD-L1 (-) 6 month OS: 52.7%PD-L1 (+) 6 month OS: 61.2%
Durvalumab(Study 1108)N=103
Yes No SP263 >25% (n=61)PD-L1 (-): 5.1%
PD-L1 (+): 31.1%
All: 1.41PD-L1 (-): 2.05PD-L1 (+): 1.41
Not Published
Nivolumab(CheckMate-275)N=265
Yes No 28-8 pharmDx>1% (n=122)>5% (n=81)
All: 19.6%, PD-L1 (-): 16.1%PD-L1 >1%: 23.8%PD-L1 >5%: 28.4%
1.87 (95% CI: 1.81-1.97)
All: 8.74PD-L1 (-): 59.95PD-L1 >1%: 11.3
Nivolumab (CheckMate-032)N=78
Yes No 28-8 pharmDx<1% (n=42)>1% (n=25)
All: 24.4%PD-L1 (-): 26.2%PD-L1 (+): 24%
1.5 (95% CI: 1.2-4.1)
All: 9.7PD-L1 (-): 9.9
PD-L1 (+): 16.2
Pembrolizumab (KEYNOTE-045)N=542
YesPaclitaxel, docetaxel
or vinflunine22C3 pharmDx >10% (n=164)*
All: 21.1 vs. 11.4%PD-L1 (+): 21.6 vs. 6.7%
2.1All: 10.3 vs. 7.4
PD-L1 (+): 8 vs. 5.2
Pembrolizumab (KEYNOTE-052)N=100/374
No, first-line**
No 22C3 pharmDx >10% (n=30)All: 24%
PD-L1 (+): 37%2
(95% CI: 0.2-5)6 month OS: 67%
*Cisplatin ineligible patients; **PD-L1 expression included percentage of tumor and infiltrating immune cells with PDL1 expression
Efficacy of PD-1 or PD-L1 Inhibitors in 2nd Line Metastatic Bladder Cancer
Black P. Presented at AUA 2017 (Adapted from Plimack ASCO 2016).
15%
19.6% 20.4%
17.6%
21.1%
0
5
10
15
20
25
%
Objective Response Rate
AtezolizumabN=310Loriot
ESMO 16
NivolumabN=265Sharma
Lancet Oncol 17
DurvalumabN=103Powles
ASCO GU 17
AvelumabN=153Patel
ASCO GU 17
PembrolizumabN=270
BellmuntNew Engl J Med 17
Historic control with chemotherapy
12%
ICI Response According to PD-L1 Expression inAdvanced Bladder Cancer
AtezolizumabN=310Loriot
ESMO 16
NivolumabN=265Sharma
Lancet Oncol 17
DurvalumabN=103Powles
ASCO GU 17
AvelumabN=153Patel
ASCO GU 17
PembrolizumabN=270
BellmuntNew Engl J Med 17
0
5
10
15
20
25
30%
PD-L1 Positive
PD-L1 Negative
Adapted from Black P. Presented at AUA 2017.
Grade >3 Adverse Events from ICIs inAdvanced Bladder Cancer
Adapted from Black P. Presented at AUA 2017.
16%
18%
5.2%
7.5%
15%
0
4
8
12
16
20
%(2nd line Metastatic Trials)
NivolumabN=265Sharma
Lancet Oncol 17
DurvalumabN=103Powles
ASCO GU 17
AvelumabN=153Patel
ASCO GU 17
PembrolizumabN=270
BellmuntNew Engl J Med 17
AtezolizumabN=310Loriot
ESMO 16
Bellmunt J, et al. N Engl J Med. 2017.
43.9%30.7%
KEYNOTE-045 Study (NCT02256436) Overall Survival: Total
Median (95% CI)10.3 mo (8.0-11.8) 7.4 mo (6.1-8.3)
270 226 194 169 147 131 87 54 27 13 4 0 0
272 232 171 138 109 89 55 27 14 3 0 0 0
No. at risk
Events, n HR (95% CI) P
Pembro 155 0.73 (0.59-0.91) 0.0022
Chemo 179
Pembrolizumab
Chemotherapy
• With extended follow-up, single-agent atezolizumabcontinues to be well-tolerated in this phase Ia study mUC cohort
• Most AEs were grade 1-2, and no treatment-related deaths occurred. Incidence declined substantially (including grade 3-4) after the first year.
• Clinical benefit was observed in a heavily pre-treated mUC population
• Confirmed, ORs were durable (40% ongoing), with a median DOR of 22 mo and DOR up to 33+ mo observed
• Median OS was ~10 mo, with 46% and 30% of patients alive after 1 and 2 years, respectively (median survival follow-up duration, ~29 mo)
• Supports a role for atezolizumab as new standard of care in previously treated mUC
• Phase III study IMvigor211 (NCT02302807) is ongoing, with enrollment completed and data expected later this year.
Long-term Survival Follow-up of the Phase I Atezolizumab Trial
Petrylak D, et al. Presented at ASCO GU. 2017.
Median and Landmark OS by PD-L1 Status
IC0/1 (N=44) IC2/3 (N=51) All Pts* (N=95)
Median OS (95% CI) 7.6 mo (4.7, 13.9) 11.3 mo (7.8, NE) 10.1 mo (7.3, 17)
1-year OS rate (95% CI) 40% (25, 56) 50% (36, 64) 46% (35, 56)
2-year OS rate (95% CI) 14% (2, 26) 43% (29, 57) 30% (20, 40)
NE=Not estimable; *Efficacy-evaluable population with >12 wk f/u
- A trend toward longer survival in pts with higher PD-L1 status was observed.
• Primary efficacy endpoint, OS, was to be tested in a successive fashion in study populations defined by PD-L1 expression.
• The first population tested was people with the highest levels of PD-L1 expression (IC2/3), followed by those with any level of PD-L1 expression (IC1/2/3), and followed by the overall study population (ITT).
• Statistical significance needed to be achieved in the IC2/3 population in order to evaluate the IC1/2/3 population for statistical significance, and similarly achieved in the IC1/2/3 population in order to evaluate the overall study population for statistical significance.
Atezolizumab was not Superior to Chemotherapy in Cisplatin-resistant Bladder Cancer??
Atezolizumab
SOC: Docetaxel,
Paclitaxel or Vinflunine
• Urothelial Cancer
• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen
RandomizationN=932
Estimated Completion: Nov 2017
Primary EndpointsOS
Secondary EndpointsORRPFSDOR
Safety
IMvigor211 Study Design (NCT02302807)
www.clinicaltrials.com;NCT02302807.
Study AgentCompanion
IHC AntibodyThreshold for
PositivityTarget Cells
AssayAssociated w/
Response?
Powles T, et al. Nature. 2014. Atezolizumab “Proprietary” 5% TILs Yes
Rosenberg JE, et al. Lancet. 2016. Atezolizumab SP142 5% TILs Yes
Balar AV, et al. Lancet. 2017. (platinum ineligible)
Atezolizumab SP142 5% TILs No
Massard C, et al. J Clin Oncol. 2017. Durvalumab SP263 25% TILs & TCs Yes
Sharma P, et al. Lancet Oncol. 2016. Nivolumab Dako 28-8 1% TCs No
Sharma P, et al. Lancet Oncol. 2017. Nivolumab Dako 28-8 1% TCs Yes
Plimack ER, et al. Lancet Oncol. 2017. Pembrolizumab 22C3 1% TILs & TCs TILs only
Bellmunt J, et al. N Engl J Med. 2017. (chemo vs immuno 2nd line)
Pembrolizumab 22C3 10% TILs & TCs No
Is PD-L1 Staining Associated with Clinical Outcome in Bladder Cancer?
Avelumab Atezolizumab Durvalumab Nivolumab Pembrolizumab
Adverse Event, (%) All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4
Gen - Fatigue 41 7 52 6 39 6 46 7 38 4.5
Gen - Periph edema 17 0.4 18 1 15 2 13 0.4 - -
Gen - Pyrexia 16 1 21 1 14 1 17 0.4 14 0.8
GI - Constipation 18 1 21 0.3 21 1 16 0.4 19 1.1
GI - Nausea 24 1 25 2 16 2 22 0.7 21 1.1
GI - Vomiting 14 1 17 1 - - 12 1.9 15 0.4
GI – Abdominal pain 19 2 17 4 14 3 13 1.5 13 1.1
GI – Diarrhea/colitis 18 2 18 1 13 1 17 2.6 18 2.3
Resp - Cough 14 0 14 0.3 10 0 18 0 15 0.4
Resp - Dyspnea 17 2 16 4 13 2 14 3.3 14 1.9
Skin - Rash 15 0.4 15 0.3 11 1 16 1.5 20 0.4
GU - UTI 21 5 22 9 15 4 17 7 15 4.9
GU - Hematuria - - 14 3 - - - - 12 2.3
Musculoskeletal pain 25 3 15 2 24 4 30 2.6 32 3
Reduced appetite 21 2 26 1 19 1 22 2.2 21 3.8
U.S. FDA Prescribing Information
Checkpoint Inhibitor Adverse Events(occurring in ≥10% of those with urothelial cancer that has progressed on platinum-containing regimen)
• Checkpoint inhibitors blocking the PD-1/PD-L1 axis including avelumab, nivolumab, pembrolizumab, durvalumab, and atezolizumab are well tolerated and active in metastatic bladder cancer
• Five drugs are approved in second-line bladder cancer; two of those are also approved first-line if cisplatin-ineligible
• PD-L1 staining is a poor biomarker for outcome, but may be associated with survival in some studies
• New immunotherapy combinations merit testing
Conclusions: Checkpoint Blockade for Bladder Cancer
Immunotherapy Advances in NSCLC
Naiyer A. Rizvi, MDPrice Family Chair, Clinical Translational MedicineProfessor of MedicineDirector, Thoracic OncologyCo-Director, Cancer ImmunotherapyColumbia University Medical Center
CA209-003 Five-Year Update: Phase I Nivolumab in Advanced NSCLC
Brahmer J, et al. AACR. 2017.
Median OS (95% CI), mo
Overall (N=129) 9.9 (7.8, 12.4)
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8
129 49 27 20 17 16 3 1 0
YearsNo. at Risk
OS
(%)
1 y OS, 42%
2 y OS, 24%3 y OS, 18% 5 y OS, 16%
KEYNOTE-024 Study Design
Key Endpoints
Primary: PFS (RECIST v1.1 per blinded, independent central review)
Secondary: OS, ORR, safety
Exploratory: DOR
Key Eligibility Criteria
• Untreated stage IV NSCLC
• PD-L1 TPS ≥50%
• ECOG PS 0-1
• No activating EGFR mutation or ALKtranslocation
• No untreated brain metastases
• No active autoimmune disease requiring systemic therapy
Pembrolizumab 200 mg IV Q3W
(2 years)
R (1:1)N=305
PD Pembrolizumab 200 mg Q3W
for 2 years
Platinum-Doublet Chemotherapy
(4-6 cycles)
aTo be eligible for crossover, PD had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met.Reck M, et al. N Engl J Med. 2016; www.clinicaltrials.gov; NCT02142738.
KEYNOTE-024: Progression Free Survival
Reck M, et al. N Engl J Med. 2016.Assessed per RECIST v1.1 by blinded, independent central review.
Data cut-off: May 9, 2016.
Events, n Median, mo HR (95% CI) P
Pembro 73 10.3 0.50 (0.37-0.68)
<.001Chemo 116 6.062%
50%
0 3 6 9 12 15 180
10
20
30
40
50
60
70
80
90
100
Time, months
PFS
, %
No. at risk
154 104 89 44 22 3 1151 99 70 18 9 1 0
48%15%
Chemotherapy
Pembrolizumab
KEYNOTE-024: Overall Survival
Reck M, et al. N Engl J Med. 2016. Data cut-off: May 9, 2016.
80%72%
0 3 6 9 12 15 18 210
10
20
30
40
50
60
70
80
90
100
Time, months
OS
,%
No. at risk
154 136 121 82 39 11 0151 123 106 64 34 7 0
21
70%54%
Chemotherapy
Pembrolizumab
Events, n Median, mo HR (95% CI) P
Pembro 44 NR 0.60 (0.41-0.89)
.005Chemo 64 NR
CheckMate-026 Study Design
R
Primary Endpoint: PFS per BIRC (≥5% PD-L1 +)Secondary Endpoints: • PFS per BIRC (≥1% PD-L1 +)• OS• ORRExploratory Objective: Predictive biomarkers for outcomes with nivolumab
Nivolumab3 mg/kg Q2W
N=271
Chemotherapy (histology dependent)Maximum of six cycles
N=270
Key Eligibility Criteria:• Stage IV or recurrent
NSCLC• No prior systemic therapy
for advanced disease• No EGFR/ALK mutations
sensitive to available targeted inhibitor therapy
• ≥1% PD-L1 expression
Crossover Nivolumab(optional)
Nivolumab vs. Chemotherapy in First-line NSCLC (Phase III)
Disease Progression or Unacceptable Toxicity
Disease Progression
1:1
Stratification Factors at Randomization:• PD-L1 Expression (<5% vs. ≥5%)• Histology (squamous vs. non-squamous)
Tumor scans Q6W until week 48 then Q12W
Socinski M, et al. ESMO. 2016; www.clinicaltrials.gov.
CheckMate-026: Primary Endpoint
Socinski M, et al. ESMO. 2016.
No. of patients at risk:Nivolumab 211 104 71 49 35 24 6 3 1 0Chemotherapy 212 144 74 47 28 21 8 1 0 0
Nivolumab
Chemotherapy
Months
PFS
(%
)
2421181512963 27
100
80
60
40
0
20
0
Nivolumabn=211
Chemotherapyn=212
Median PFS, months (95% CI)
4.2(3.0, 5.6)
5.9(5.4, 6.9)
1-year PFS rate, % 23.6 23.2
All randomized patients (≥1% PD-L1+): HR = 1.17 (95% CI: 0.95, 1.43)
HR=1.15 (95% CI: 0.91, 1.45), P=.2511
PFS per IRRC in (>5% PD-L1+)
CheckMate-026: TMB Analysis
Adapted from Peters, et al. AACR. 2017.
NivolumabChemotherapy
47 30 26 21 16 12 4 160 42 22 15 9 7 4 1
111 54 30 15 9 7 2 1 194 65 37 23 15 12 5 0 0
Nivolumabn=47 n=60
9.7(5.1, NR)
5.8(4.2, 8.5)
Chemotherapy
Median PFS, months(95% CI)
High TMB
PFS
(%
)
3 6 9 12 15 18 21
No. at RiskMonths
100
90
80
70
60
50
40
30
20
10
0
0
Nivolumab
Chemotherapy
0 3 6 9 12
Months
15 18 21 24
Nivolumab
Chemotherapy
100
90
80
70
60
50
40
30
20
10
0
n=111 n=94
4.1(2.8, 5.4)
6.9(5.5, 8.6)
HR = 1.82 (95% CI: 1.30, 2.55)
Nivolumab Chemotherapy
(95% CI)Median PFS, months
Low/Medium TMB
HR = 0.62 (95% CI: 0.38, 1.00)
Arm 2 (n=234): Placebo IV Q2wks
• Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study (26 countries)
PACIFIC Study: Durvalumab Monotherapy in NSCLC
Arm 1 (n=468): Durvalumab IV 10 mg/kg Q2wks
for up to 12 months
2:1
Patients with locally advanced unresectable NSCLC (Stage III) in a consolidation setting (N=702)
R
Primary endpoints• PFS, OS
Secondary endpoints• ORR, DoR, DSR• Safety/tolerability • PK, immunogenicity, QOL
Est. completion: 2017FPD: Q2 14
LPCD: Q2 16
Absence of progression following at least 2 cycles of platinum-based chemotherapy
concomitant with radiation therapy
www.clinicaltrials.gov. NCT02125461; Creelan B, et al. Ann Oncol. 2015.
Ipilimumab and Nivolumab: First-line NSCLC
Hellmann, et al. Lancet Oncol. 2016.
23
43
28
57
92
0
10
20
30
40
50
60
70
80
90
100
CM-012 mono (1L) CM-012 combo (1L)
Unselected
>1% PD-L1
>50% PD-L1
50
Re
spo
nse
Rat
e (
%)
6 CRs
Durvalumab and Tremelimumab in NSCLC
Antonia S, et al. Lancet Oncol. 2016.
KEYNOTE-021: Cohort G
Pembrolizumab 200 mg Q3W for 2 years +Carboplatin AUC 5
mg/mL/min + Pemetrexed 500 mg/m2
Q3W for 4 cyclesb
PDCarboplatin AUC 5
mg/mL/min + Pemetrexed 500 mg/m2
Q3W for 4 cyclesb
aRandomization was stratified by PD-L1 TPS <1% vs ≥1%.bIndefinite maintenance therapy with pemetrexed 500 mg/m2 Q3W permitted.
End PointsPrimary: ORR (RECIST v1.1 per blinded, independent central review)Key secondary: PFSOther secondary: OS, DOR, safetyExploratory: Relationship between antitumor activity and PD-L1 TPS
Pembrolizumab 200 mg Q3W
for 2 years
Key Eligibility Criteria
• Untreated stage IIIB or IV nonsquamous NSCLC
• No activating EGFR mutation or ALK translocation
• Provision of a sample for PD-L1 assessmenta
• ECOG PS 0-1
• No untreated brain metastases
• No ILD or pneumonitis requiring systemic steroids
R (1:1)a
N=123
Langer, et al. Lancet Oncol. 2016; www.clinicaltrials.gov; NCT02039674.
Randomized Phase II: Carbo/Pemetrexed +/-Pembrolizumab
Langer, et al. Lancet Oncol. 2016.
13.0 mo8.9 mo
77%63%
0 5 10 15 200
10
20
30
40
50
60
70
80
90
100
Time, months
PF
S,
%
No. at risk
60 43 20 1 063 32 13 1 0
6
Events, n HR (95% CI)
Pembro + chemo 23 0.53 (0.31-0.91)
P=.0102Chemo alone 33
Δ26%P=.0016
Pembro +Chemo
ChemoAlone
PFS
Pembro + Chemo
Chemo
Objective Response by PD-L1 TPS
Horizontal dotted lines represent the ORR in the total population.
Assessed per RECIST v1.1 by blinded, independent central review.
Data cut-off: August 8, 2016.Langer, et al. Lancet Oncol. 2016.
<1%n=21
≥1%n=39
1%-49%n=19
≥50%n=20
<1%n=23
≥1%n=40
1%-49%n=23
≥50%n=17
Pembrolizumab + Chemotherapy Chemotherapy Alone
Overall Survival
Langer, et al. Lancet Oncol. 2016.
0 5 10 15 20
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS
,%
No. at risk
60 53 33 5 0
63 57 31 6 0
92%92%
6
75%72%
12
Papadimitrakopoulou, et al. ASCO 2017. (Abstract 9094)Updated HR: 0.69
Phase III First-line Combination Trials in Advanced NSCLC
Treatment N Arms
CheckMate227 1980 Nivolumab, Ipilimumab NivolumabPlatinum-doublet
Chemotherapy
MYSTIC 1092Durvalumab,
TremelimumabDurvalumab
SOC Platinum-based Chemotherapy
KEYNOTE-189 570Pembrolizumab,
Pemetrexed, CarboplatinPemetrexed, Carboplatin
Impower 150 1200Atezolizumab,
Paclitaxel/Carboplatin, Bevacizumab
Atezolizumab, Paclitaxel/
CarboplatinPaclitaxel/Carboplatin
www.clinicaltrials.gov.
Current Status and Future Prospects for Development of Robust Prognostic and Predictive Biomarkers of Response in Selected Types of Solid Tumors
POINT: PD-L1 Staining by IHC is Generally a Useful Marker for the Benefit of PD-1 Blockade
Joaquim Bellmunt, MD, PhDAssociate Professor of MedicineDirector, Bladder Cancer CenterDana-Farber Cancer InstituteBoston, MA
Are tumors with high PD-L1 expression more sensitive to immune-mediated approaches compared with tumors that have low or no PD-L1 expression?
The Rationale for PD-L1 Testing in Cancer
PD-L1 Expression as a Predictive Biomarker
The Prognostic Value of PD-L1 Expression
Are tumors with high PD-L1 expression associated with better or worse prognosis compared with tumors that have low or no PD-L1 expression?
High PD-L1 Expression May Be Associated with Poor Prognosis
Wu P, et al. PLoS ONE. 2015.
Zhao T, et al. PLoS ONE. 2017.
Considerations for PD-L1 Expression as a Predictive Biomarker and PD-L1 Testing
Tumor Type
Variability Across PD-L1 Assays
Cell Types That Express PD-L1
PD-L1 Expression Level
PD-L1 Expression Can Vary Between Primary And Metastasis, Different Metastases, and Within One Tissue Sample
In 20 NSCLC samples tested with the anti–PD-L1 28-8 IHC assay, discordant PD-L1 results were observed in 30% of the matched primary versus metastatic cases3
1McLaughlin J, et al. JAMA Oncol. 2016; 2Madore J, et al. Pigment Cell Melanoma Res. 2015; 3Phillips T, et al. Appl Immunohistochem Mol Morphol. 2015.
Variation of PD-L1 Expression Between Primary Tumor Metastases2:
Variation of PD-L1 Expression Within One Single NSCLC Tissue Sample1:
Primary Melanoma
Lymph NodeMetastasis
BrainMetastasis
PD-L1 Expression May Predict Sensitivity to Immune-Mediated Approaches
Study Cancer Type Level of PD-L1 Expression ORR, % (vs. control)
Fehrenbacher 20161 NSCLC
TC3 or IC3*TC2 or IC2*TC1 or IC1*TC0 or IC0*
37.5 (13.0)7.7 (15.6)
14.0 (19.1)7.8 (9.8)
Massard 20162 Bladder PD-L1 positive**PD-L1 negative**
TC46.722.2
IC55.612.5
TC or IC46.4
0
Borghaei 20153 Non-squamous NSCLCPD-L1 ≥10%PD-L1 ≥5%PD-L1 ≥1%
37 (13)36 (13)31 (12)
Ferris 20164 SCCHNPD-L1 ≥10%PD-L1 ≥5%PD-L1 ≥1%
27.9 (2.9)22.2 (2.3)17.0 (1.6)
Rosenberg 20165 BladderIC2/3
IC1/2/3All
261815
1Fehrenbacher L, et al. Lancet. 2016; 2Massard C, et al. J Clin Oncol. 2016; 3Borghaei H, et al. N Engl J Med. 2015; 4Ferris RL, ASCO 2016; 5Rosenberg JE, et al. Lancet. 2016.
IC=immune cells; IHC=immunohistochemistry; TC=tumor cells
*TC3 ≥50%, TC2 ≥5% and <50%, TC1 ≥1% and <5%, and TC0 <1%; IC3 ≥10%, IC2 ≥5% and <10%, IC1 ≥1% and <5%, and IC0 <1%**PD-L1 positive: either TC or IC ≥25%, PD-L1 negative: both TC and IC <25%
3,a
a
Time (months)
0.5 (0.36, 0.7)P<.0001
0.61 (0.49, 0.75) P<.0001
0.79 (0.66, 0.94) P=.004
Pembrolizumab treatment setting: Indicated for first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 in ≥50% of cells and who do not have EGFR- or ALK-positive tumor mutations. Also indicated for patients with locally advanced ormetastatic NSCLC progressing after ≥1 prior chemotherapy regimen and whose tumors express PD-L1 with ≥1% of cells. Patients withEGFR- or ALK-positive tumor mutations should also have received targeted therapy prior to treatment with pembrolizumab1
Results from a randomized Phase III clinical trial:2
Advances in Other Treatment Settings in Advanced NSCLC: Pembrolizumab Immunotherapy (KEYNOTE 010 & 024)
1FDA Prescribing Information; 2Herbst RS, et al. Lancet 2016; 3Reck M, et al. N Engl J Med. 2016.
4.0
8.5
8.2
3.9
10.4
14.9
4.0
12.7
17.3
0 4 8 12 16 20
Median PFS
Median OS
Median OS TPS ≥50%
Pembrolizumab 10 mg/kg (n=346) Pembrolizumab 2 mg/kg (n=345) Docetaxel (n=343)
HR (95% CI)
0.71 (0.58, 0.88)P=.0008
p=0.0008
0.88 (0.74, 1.05) P=.07
aPrimary endpoint
0.38 (0.38, 0.77)P=.0002
4,a
Summary of FDA-Approved and Investigational PD-L1 Assays in Urothelial Carcinoma*
Ab clone/epitope
Cell type scored
Scoring method
FDA status for urothelial carcinoma
PD-L1 thresholds under evaluation
1Bellmunt J, et al. N Engl J Med. 2017; 2Loriot Y, et al. Poster presentation at ESMO 2016. Abstract 83P; 3Ventana. Roche receives FDA Approval for novel PD-L1 biomarker assay [press release]. May 18, 2016; 4Sharma P, et al. Lancet Oncol. 2017; 5Powles T, et al. Poster presentation at ASCO GU 2017. Abstract 286; 6Patel M, et al. Poster presentation at ESMO 2017. Abstract 777PD.
Nivolumab4
28-8
TCs
% of PD-L1expressing TCs
NA
≥1% ≥5%
Durvalumab5
SP263
TCs or ICs
% of PD-L1 expressing TCs or ICs
NA
≥25%
Atezolizumab2,3
SP142
ICs
% of PD-L1 expressing ICs
Complementary
IC2/3 (≥5%), IC1 (≥1% but <5%),
IC0 (<1%)
Pembrolizumab1
22C3
TCs and ICs
CPS: % of PD-L1positive TCs and ICs relative to the total number of tumor
cells
NA
≥1%≥10%
Avelumab6
73-10
TCs
% of PD-L1expressing TCs
NA
≥5%
* No head-to-head studies have been conducted and direct comparisons cannot be made between these studies.
PD-L1 Antibody Atezolimumab in Cisplatin-resistant Bladder Cancer
Rosenberg JE, et al. Lancet. 2016.
Outcome, %All
N=265PD-L1 <1%
n=143PD-L1 ≥1%
n=122PD-L1<5%
n=184PD-L1 ≥5%
n=81
Confirmed ORR by BIRCa 19.6 16.1 23.8 15.8 28.4
95% CI 15.0–24.9 10.5–23.1 16.5–32.3 10.8–21.8 18.9–39.5
Median PFS in months (95% CI)
2.00 (1.87–2.63)
1.87 (1.77–2.04)
3.55 (1.94–3.71)
Median OS in months (95% CI)
8.74 (6.05–NR)
5.95 (4.30–8.08)
11.30 (8.74–NR)
Responders (N=52)• Time to response: 1.9 months (1.6–5.9)• Duration of response: NR (7.4-NR)• Ongoing responders at time of response: 40/52 (77%)
Safety: No new safety profile compare to prior reports
aBIRC, blinded independent review committee
Phase II CheckMate 275 Study in Chemo-resistant Bladder Cancer: Nivolumab is Active
Sharma P, et al. Lancet Oncol. 2017.
• Clinical activity seen in all patient subgroups
• Greater efficacy occurred in patients with PD-L1 high expression
• Efficacy is still observed in the PD-L1 low/neg group consistent with the level seen with SoC
• PD-L1 SP263 assay is especially helpful in informing patients on the likelihood of response to durvalumab
Clinical Response to Durvalumab Monotherapy in UC Correlates with PD-L1 Expression
Powles, et al. Presented at 2017 ASCO GU.
Total PD-L1 High PD-L1 Low/Neg
ORR by BICR assessment Primary Efficacy Population (103pts, ≥13 weeks follow-up)
N=103 N=61 N=39
ORR, n (%)(95% CI)
21 (20.4)
(13.1, 29.5)
19 (31.1)
(19.9, 44.3)
2 (5.1)
(0.6, 17.3)
ORR by BICR assessment (≥2L) post-platinum subgroup
N=94 N=58 N=33
ORR, n (%)(95% CI)
19 (20.2)
(12.6, 29.8)
18 (31.0)
(19.5, 44.5)
1 (3.0)
(0.1, 15.8)
Antitumour Activity of Durvalumab per BICR in the Primary Efficacy Population of the UC Cohort, including the Second-line or Greater (≥2L)
Post-platinum Subgroup
Objective Response (by PD-L1 Subgroups)
N = 100
CPS <1%†
N=33CPS ≥1% to <10%
N=33CPS ≥10%
N=30
n % (95% CI) n % (95% CI) n % (95% CI)
ORR (24%) 6 18% (7-36%) 5 15% (5-32%) 11 37% (20-56%)
Complete response 1 3% (0.1-16%) 0 – 4 13% (4-31%)
Partial response 5 15% (5-32%) 5 15% (5-32%) 7 23% (10-42%)
Stable disease 3 9% (2-24%) 5 15% (5-32%) 7 23% (10-42%)†Excluding those with CPS unknown*CPS=Combined positive score for PD-L1–positive cells (tumor, immune cells)
• Median time to response: 2.0 months (range, 1.9-4.8) • Median duration of response : Not reached (range, 1.4+ to 9.8+ months)• Duration of response rate ≥6 months: 83% • The PD-L1 high expression cut point was determined to be CPS ≥10% (PD-L1 positive tumor, immune cells) and enriched
for response; this cut point will be validated in the remaining patients in the cohort (n=274 additional patients)
KEYNOTE-052: Pembrolizumab as 1st-Line Therapy for Cisplatin-Ineligible Bladder Cancer
Balar A, et al. Ann Oncol. 2016.
Data cutoff date: June 1, 2016
KEYNOTE-045: Overall Survival*
Overall Survival: CPS ≥10%†2Overall Survival: Total1
0102030405060708090
100
0 4 6 8 20 24
Ove
rall
Surv
ival
, (%
)
Time (months)No. at Risk
Pembro 7490
2 10 12 14 16 18 22
51 42 35 0 060 31 18 12 7 3 051 36 28 0 076 24 16 8 4 1 0
0102030405060708090
100
0 4 6 8 20 24
Ove
rall
Surv
ival
, (%
)
Time (months)No. at Risk270272
2 10 12 14 16 18 22
194 169 147 4 0226 131 87 54 27 13 0171 138 109 0 0232 89 55 27 14 3 0
Adapted from 1Bellmunt J, et al. N Engl J Med. 2017; 2Bellmunt J, et al. Oral presentation at SITC 2016; 3http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda-pembrolizumab-significantly-improves-overall-survival.
Median OS, months (95% CI)
Pembrolizumab 10.3 (8.0–11.8)
Chemotherapy 7.4 (6.1–8.3)
HR: 0.73; 95% CI, 0.59–0.91; P=.002
Median OS, months (95% CI)
Pembrolizumab 8.0 (5.0–12.3)
Chemotherapy 5.2 (4.0–7.4)
HR: 0.57; 95% CI, 0.37–0.88; P=.00483
PembroChemo Chemo
*Assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: Sep 7, 2016.†CPS is the % of PD-L1–positive tumor cells and tumor-infiltrating immune cells relative to the total number of tumor cells.
• Powles, et al. Nature. 2014. Phase I Atezolizumab
• Rosenberg, et al. Lancet. 2016. Phase II Atezolizumab
• Balar, et al. Lancet. 2017. Phase II Atezolizumab
• Massard, et al. J Clin Oncol. 2016. Phase I Durvalumab
• Sharma, et al. Lancet Oncol. 2016. Phase I/II Nivolumab
• Sharma, et al. Lancet Oncol. 2017. Phase I/II Nivolumab
• Plimack, et al. Lancet Oncol. 2017. Phase I Pembrolizumab
• Bellmunt, et al. N Engl J Med. 2017. Phase III Pembrolizumab
PD-L1 Expression as a Predictor of Checkpoint Blockade Sensitivity in UC
5/8 studies reported positive association with PD-L1 staining
Key Diagnostic Challenges in UC
In-clinic use of PD-L1 expression is likely to differ across lines of therapy
Multiple diagnostic assays & algorithms used in clinical development:
confusion regarding the impact of the test used
OR
IC area with PD-L1 expression
Immune Cell (IC) area
UC: SP263 Uses Tumor and Immune Cell ScoresDurvalumab
Tumour Cell:Proportion of tumour cells with membrane staining for PD-L1 at any intensity above background staining
Immune Cell:Proportion of tumour associated immune cells with staining for PD-L1 at any intensity above background staining
Definition
Assay Cut-offs for PD-L1 High
SP263TC ≥25%orIC ≥25%
Tumour Cell (TC) AreaTC area with PD-L1 expression
https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160046c.pdf
UC: SP142 Uses Tumor and Immune Cell ScoresAtezolizumab
Assay Cut-offs for PD-L1 High
SP142 ≥5%
The proportion of tumour area occupied by PD-L1 expressing tumour-infiltrating immune cells of any intensity
Tumour Area
IC area with PD-L1 expression
Definition
https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160002c.pdf
UC: 22C3 Uses Combined Proportion ScorePembrolizumab
+
IC area with PD-L1 expression
Tumour Cell (TC) AreaTC area with PD-L1 expression The percentage of PD-L1 expressing tumour and
infiltrating immune cells relative to the total number of immune cells.
Definition
Assay Cut-offs for PD-L1 High
22C3 ≥10%
https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150013s001c.pdf
CheckMate 025: OS by PD-L1 Expression in aRCC
Adapted from Motzer, et al. N Engl J Med. 2015; Sharma P, et al. Oral presentation at ESMO 2015. Abstract 3LBA.
Overall Survival: PD-L1 <1%
Median OS, months (95% CI)Nivolumab 21.8 (16.5–28.1)Everolimus 18.8 (11.9–19.9)
Overall Survival: PD-L1 ≥1%
Median OS, months (95% CI)Nivolumab 27.4 (21.4–NE)Everolimus 21.2 (17.7–26.2)
No. of patients at riskNivolumabEverolimus
94 86 79 73 66 58 45 31 18 4 1 087 77 68 59 52 47 40 19 9 4 1 0
0.00 3 6 129 15
Time (months)
18 21 24 27 30 33
0.3
0.10.2
0.40.50.60.70.80.91.0
Ove
rall
Surv
ival
(P
rob
abili
ty)
Nivolumab
Everolimus
276 265 245 233 210 189 145 94 48 22 2 0299 267 238 214 200 182 137 92 51 16 1 0
Nivolumab
Time (months)
0 3 6 129 15 18 21 24 27 30 33
Everolimus
HR (95% CI): 0.79 (0.53–1.17) HR (95% CI): 0.77 (0.60–0.97)
No. of patients at riskNivolumabEverolimus
0.0
0.3
0.10.2
0.40.50.60.70.80.91.0
Ove
rall
Surv
ival
(P
rob
abili
ty)
Based on data cut-off of June 2015.
IMmotion 150: IRF-Assessed PFS
ITT Population
No. at RiskAtezo + bev
AtezoSunitinib
101 73 62 55 48 40 34 21 13 5 1 1103 59 43 35 31 29 24 14 10 4 2 1101 69 53 37 30 26 22 11 7 4 2
Atezo + bevAtezo
Sunitinib
50 36 31 26 24 22 19 12 7 3 1 154 29 19 15 14 13 13 7 6 3 160 40 29 21 16 13 12 6 3 1 1
No. at Risk
≥1% of IC expressing PD-L1
Adapted from McDermott D, et al. Poster presentation at ASCO GU 2017. Abstract 431.
mPFS, mos (95% CI) Stratified HR* (95% CI)
Atezo + bev
(n=101)11.7 (8.4–17.3)
1.00 (0.69–1.45)
P=.982†
Atezo
(n=103)6.1 (5.4–13.6)
1.19 (0.82–1.71)
P=.358†
Sunitinib
(n=101)8.4 (7.0–14.0) --
mPFS, mos (95% CI) Stratified HR* (95% CI)
Atezo + bev
(n=50)14.7 (8.2–25.1)
0.64 (0.38–1.08)
P=.095†
Atezo
(n=54)5.5 (3.0–13.9)
1.03 (0.63–1.67)
P=.917†
Sunitinib
(n=60)7.8 (3.8–10.8) --
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36
PFS
0 3 6 9 12 15 18 21 24 27 30 33 360
20
40
60
80
100
Time (months)
PFS
Time (months)
*Compared with sunitinib. †P values for descriptive purposes only and not adjusted for multiple comparisons.
Phase II Study of Atezolizumab + Bevacizumab vs. Sunitinib
• Phase I study: ORR 40%
• Phase II: PFS did not pan out but response seen in both PD-L1 high/low
• Overall survival a better metric
• Subsets of “high” PD-L1 cancers?
McDermott D, et al. IMmotion150 biomarkers: AACR. 2017.
PD-L1 in SCCHN Treated with Nivolumab
Exploratory analysis: Patients with a tumor PD-L1 expression level of 1% or more may have a greater magnitude of effect from nivolumab therapy than those whose PD-L1 level was less than 1%.
Ferris RL, et al. N Engl J Med. 2016.
• The rationale includes potential prognostic and predictive value of PD-L1 testing
• PD-L1 “positivity” enriches for clinical benefit for selected drugs, diseases and settings
• IHC is unreliable for measuring PD-L1 expression
• Need to look beyond a single static biomarker
• Ergo, PD-L1 staining is not a useful helpful biomarker “setting-based”
Conclusions
Current Status and Future Prospects for Development of Robust Prognostic and Predictive Biomarkers of Response in Selected Types of Solid Tumors
COUNTERPOINT: PD-L1 Staining is Not All It’s Purported to Be
Jeffrey S. Weber, MD, PhD
Laura and Isaac Perlmutter Cancer Center
NYU Langone Medical Center
PD-L1 tumor staining makes little difference in melanoma, bladder, and RCC, but has some
impact in lung cancer; with combined therapy, it is not useful
Nivolumab vs. DTIC-OS by PD-L1 Status in Front-line Melanoma
Atkinson, et al. SMR. 2015.
PD-L1 Staining is Associated with Superior OS and PFS with Pembrolizumab in Melanoma, but Does Not Rule Out Benefit
Daud A, et al. J Clin Oncol. 2016.
PD-L1 positive
PD-L1 negative
PD-L1 negative
PD-L1 positive
PD-L1 positivePD-L1 negative
No. at risk
PD-L1 positivePD-L1 negative
No. at risk
344107
20130
15422
13218
11816
7710
587
434
222
202
90
00
00
344107
32083
28367
25460
23151
17535
12523
9318
4611
348
171
00
00
Larkin J, et al. AACR. 2017.
PD-L1 Staining Falls Out as a Factor with Combined Checkpoint Blockade in Melanoma
No Impact of PD-L1 Staining on Outcome in Squamous NSCLC Treated with Nivolumab
Brahmer J, et al. N Engl J Med. 2015.
No Impact of PD-L1 Staining on OS for Atezolizumab in Second-line NSCLC vs. Chemotherapy
Rittmeyer A, et al. Lancet. 2017.
No Impact of PD-L1 Expression on Outcome with Front-line NIVO + Chemotherapy in NSCLC
Rizvi N, et al. J Clin Oncol. 2016.
No Impact of PD-L1 Staining on Efficacy of Pembrolizumab in Refractory SCCHN
Bauml J, et al. J Clin Oncol. 2017.
PD-L1-positive patients
PD-L1-negative patients
PD-L1-positive patients
PD-L1-negative patients
Benefit of Nivolumab Compared to Everolimus in Renal Cell Cancer is Independent of PD-L1 Staining
Motzer R, et al. N Engl J Med. 2015.
Kaplan-Meier Curve for Overall Survival, According to Programmed Death 1 Ligand (PD-L1) Expression Level
Little Impact of PD-L1 Staining on Survival in Renal Cell Cancer Patients Treated with Atezolizumab
McDermott D, et al. J Clin Oncol. 2016.
No Impact of PD-L1 Staining on OS in Refractory Bladder Cancer Patients Treated with Atezolimumab
Balar A, et al. Lancet. 2017.
Almost All Cells were PD-L1 Positive in Relapsed/Refractory Hodgkin’s Lymphoma - Not Useful
Chen, et al. J Clin Oncol. 2017.
PD-L1 Status Summary
Presented By Noah Hahn at 2015 ASCO Annual Meeting
• In non-squamous NSCLC, clear association of PD-L1 staining level and OS benefit from nivolumab versus chemotherapy1
• However, in all other histologies in phase II/III trials, there is unclear benefit of PD-L1 staining
• With combination immune checkpoint blockade, PD-L1 staining is not a useful biomarker
• The utility of a predictive biomarker is to inform who not to treat: by that criterion, PD-L1 staining falls short
• Choosing patients by PD-L1 staining will increase response rates
• PD-L1 staining can be difficult to quantitate, may vary from tumor to tumor, and may vary over time within a tumor, and is inducible
• Ergo, PD-L1 staining is not a useful biomarker
What are the Facts?
1Borghaei, et al. N Engl J Med. 2015.
Emerging Concepts of Combined Immune Checkpoint Blockade
POINT:The Efficacy of CTLA-4 + PD-1 is Superior to PD-1 Blockade Alone
Robert L. Ferris, MD, PhDUPMC Endowed Professor and Chief
Division of Head and Neck Surgery
Associate Director for Translational Research
Co-Leader, Cancer Immunology Program
University of Pittsburgh Cancer Institute
Pittsburgh, PA
• Checkpoint blockade (Abs blocking CTLA4, PD-1, PD-L1)
• Vaccines• Adoptive T-cell
therapies− CAR-T− TIL therapy
• Cytokines• TLR agonists• Agonist Abs (4-
1BB, OX-40)
Therapies to “Drive” an Immune Response
Not Pictured: TIGIT, B7-H4, B7-H5/VISTA
Multiple Immuno-Inhibitory Pathways Regulate T-cell Tolerance and T-cell Exhaustion
• Potent ability to limit T-cell function
• Numerous therapeutic opportunities
• Many unanswered questions
Freeman GJ, Sharpe AH. Nat Immunol. 2012.
Mellman I, et al. Nature. 2011.
Activating and Inhibitory Co-Receptors
CD28
OX40
GITR
CD137
CD27
HVEM LAG-3
VISTA
BTLA
TIM-3
PD-1
CTLA-4
Agonistic antibodies
Blocking antibodies
T-cell stimulation
Activating Receptors
Inhibitory Receptors Ipilimumab
Tremelimumab
Pembrolizumab
Nivolumab
Durvalumab
Patients at RiskIpilimumab 4846 1786 612 392 200 170 120 26 15 5 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60 72 84 96 108 120
IpilimumabCENSORED
Pooled OS Including EAP Data: 4846 pts
Median OS (95% CI): 9.5 (9.0–10.0)
3-year OS Rate (95% CI): 21% (20–22%)
Pro
po
rtio
n A
live
Months
Schadendorf D, et al. J Clin Oncol. 2015.
CheckMate-141 Study Design: Phase III Trial of Nivolumab in Recurrent/Metastatic SCCHN
R2:1
Nivolumab 3mg/kg IV Q2W
Investigator’s Choice
• Methotrexate 40mg/m² IV weekly
• Docetaxel 30mg/m² IV weekly
• Cetuximab 400mg/m² IV once, then 250mg/m² weekly
Key Eligibility Criteria
• R/M SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx
• ECOG PS 0–1
• Not amenable to curative therapy
• Progression ≤6 months of last dose of platinum-based therapy
• Documentation of p16 to determine HPV status
• No active CNS metastases
Stratification factor• Prior cetuximab treatment
Primary endpoint• OS
Other endpoints• PFS• ORR• Safety• DOR• Biomarkers• Quality of life
Randomized 360/360
Ferris RL, et al. N Engl J Med. 2016.
Ferris RL, et al. N Engl J Med. 2016.
Overall Survival
1-y OS Rate (95% CI)36.0% (28.5-43.4)
NivolumabInvestigator’s Choice
90
100O
vera
ll Su
rviv
al (
% o
f p
atie
nts
)
Months0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
240 167 109 52 24 7 0
015174287121
No. at RiskNivolumab
Investigator’s Choice
Median OS, mo (95% CI)
HR (97.73% CI)
Nivolumab (n=240) 7.5 (5.5–9.1)0.70
(0.51–0.96)Investigator’s Choice (n=121)
5.1 (4.0–6.0)
1-y OS Rate (95% CI)36.0% (28.5-43.4)
16.6% (8.6-26.8)
Overall Survival By PD-L1 Expression
Nivolumab
Investigator’s ChoiceNivolumab
Investigator’s Choice
PD-L1 Expression <1%
Treatment ArmMedian OS, mo
(95% CI)HR
(95% CI)
Nivolumab (n=73) 5.7 (4.4–12.7)0.89
(0.54–1.45)Investigator’s Choice (n=38)
5.8 (4.0–9.8)
PD-L1 Expression ≥1%
Treatment ArmMedian OS, mo
(95% CI)HR
(95% CI)
Nivolumab (n=88) 8.7 (5.7–9.1)0.55
(0.36–0.83)Investigator’s Choice (n=61)
4.6 (3.8–5.8)
90
100
Ove
rall
Surv
ival
(%
of
pat
ien
ts)
Months0 3 6 9 12 15 18
010203040506070
80
88 67 44 18 6 0
026204261
No. at RiskNivolumabInvestigator’s Choice 0
0
90
100
Months0 3 6 9 12 15 18
010203040506070
80
73 52 33 17 8 3
026142938
Investigator’s Choice
Investigator’s Choice
Nivolumab
Nivolumab
Ferris RL, et al. N Engl J Med. 2016.
Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone
N=314
CheckMate-067: Study Design
N=316
N=315
NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4 then
NIVO 3 mg/kg Q2W
Previously untreated,
unresectable or metastatic melanoma
N=945
Stratify by:• PD-L1
expression*• BRAF status• AJCC M Stage
Randomize 1:1:1
NIVO 3 mg/kg Q2W + IPI-matched placebo
IPI 3 mg/kg Q3W x4 + NIVO-matched placebo
Treat until progression**
or unacceptable
toxicity
*Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses.
**Patients could have been treated beyond progression under protocol-defined circumstances.
Wolchok JD, et al. ASCO. 2015.
NIVO + IPI (N=314) NIVO (N=316) IPI (N=315)
ORR, % (95% CI) 57.6 (52-63.2) 43.7 (37.1-49.3) 19 (14.9-23.8)
Two-sided P value vs IPI <.001 <.001 -
Best Overall Response - %
Complete Response 11.5 8.9 2.2
Partial Response 46.2 34.8 16.8
Stable Disease 13.1 10.8 21.9
Progressive Disease 22.6 37.7 48.9
Unknown 6.7 7.9 10.2
Duration of Response (months)
Median (95% CI) NR (13.1, NR) NR (11.7, NR) NR (6.9, NR)
Response to Treatment
Wolchok JD, et al. ASCO. 2015.
*By RECISTv1.1; NR, not reached
PFS by PD-L1 Expression Level (1%)
Wolchok JD, et al. ASCO. 2015.
*Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells
• 67.5% of patients (81/120) who discontinued the NIVO + IPI due to treatment-related AEs developed a response
Safety Summary
Patients Reporting Event, %
NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)
Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4
Treatment-relatedadverse event (AE)
95.5 55.0 82.1 16.3 86.2 27.3
Treatment-related AE leading to discontinuation
36.4 29.4 7.7 5.1 14.8 13.2
Treatment-relateddeath*
0 0.3 0.3
Wolchok JD, et al. ASCO. 2015.
*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).
CTLA4 + PD-1 Targeting in Lung Cancer: CheckMate-012
NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q12W (N=38)
NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W (N=39)
NIVO 3 mg/kg Q2W(N=52)
Confirmed ORR, % (95% CI) 47 (31-64) 39 (23-55) 23 (13-37)
Median Duration of Response, months (95% CI)
NR (11.3, NR) NR (8.4, NR) NR (5.7, NR)
Median Length of Follow-up, months (range)
12.9 (0.9-18) 11.8 (1.1-18.2) 14.3(0.2-30.1)
Best Overall Response, %
Complete Response 0 0 8
Partial Response 47 39 15
Stable Disease 32 18 27
Progressive Disease 13 28 38
Unable to Determine 8 15 12
Median PFS, months (95% CI) 8.1 (5.6-13.6) 3.9 (2.6-13.2) 3.6 (2.3, 6.6)
1-year OS rate, % (95% CI) NC 69 (52-81) 73 (59-83)NC= Not calculated (when >25% of patients are censored); NR= Not reached
Combination data based on a February 2016 database lock, monotherapy data based on a March 2015 database lock except for OS data, which are based on an August 2015 database lockAntonia SJ, et al. J Thorac Oncol. 2016; Hellmann MD, et al. Lancet Oncol. 2017.
Durvalumab (Anti–PD-L1) +Tremelimumab (Anti–CTLA-4) Trials in SCCHN
• Accelerated approval of the Monotherapy
in PD-L1+
• Accelerated approval of the Combination in PD-L1−• Establishes individual
component contribution to combination in PD-L1−
• Confirmatory trial• Combination approval
in all-comers
Regimen PD-L1 status Rationale
Phase IIHAWK
Phase IICONDOR
Durvalumab
Durvalumab+ Tremelimumab
Durvalumab
Tremelimumab
+N=112
Setting
2L SCCHN post plat in R/M
setting
2L SCCHNpost plat in R/M setting
−N=120
−N=60^
−N=60^
Durvalumab+ Tremelimumab
−N=140
+N=100
2L SCCHN post plat
1L pts who progressed within
6 mo of multi-modal tx w/pt in
the locally advanced setting
Durvalumab
SOC
−N=Adaptive
140*
+N=100
−N=140
+N=100
Phase IIIEAGLE
Zandberg
Siu
Ferris and Licitra
www.clinicaltrials.gov.
Potential of IO Therapies: 1L Trials with IO/IO Combinations
Phase IIICheckMate 651
Phase IICheckMate 714
Phase IIIKESTREL EAGLE
Phase IIIKEYNOTE-048
No prior systemic therapy, platinum
sensitive
No prior therapy, platinum
sensitive/refractory
No prior CT/IO, platinum-sensitive (KESTREL) or
refractory (EAGLE)
1L+ R/M No prior systemic therapy, platinum sensitive
Nivolumab + Ipilimumab
SOC (EXTREME)
Nivolumab + Ipilimumab
Nivolumab
Durvalumab
Durvalumab + Tremelimumab
SOC (EXTREME)
Pembrolizumab + Platinum/5-FU
Pembrolizumab
SOC (EXTREME)
Primary Endpoints
PFS, OS
ORR
PFS, OS
PFS, OS
www.clinicaltrials.gov.
• Immune checkpoint therapy, specifically anti-PD1 or -CTLA-4 monotherapy, improves survival in patients with metastatic cancers
• Several questions remain:• Does combining two different checkpoint inhibitors add benefit? YES
• Do all patients benefit from combination therapy? NO
• Do we need to incorporate biomarkers for patient selection? YES
• Do we need to consider acute and chronic AE profile, and patient PS? YES
Conclusions
Emerging Concepts of Combined Immune Checkpoint Blockade
COUNTERPOINT:The Efficacy of CTLA-4 + PD-1 is NOT Superior to PD-1 Blockade Alone
Joaquim Bellmunt, MD, PhDAssociate Professor of MedicineDirector, Bladder Cancer CenterDana-Farber Cancer InstituteBoston, MA
CTLA-4 + PD-1
PD-1 Blockade Alone
Slide courtesy of A. Ribas
Matching the images using the ipi+nivo combo approach
CTLA-4 + PD-1
PD-1 Blockade Alone
Slide courtesy of A. Ribas
Central radiology review by RECIST v1.1Data as of October 18, 2014; median follow-up: 21 months
ORR: 33%ORR in previously untreated: 45%
Ribas A, et al. JAMA. 2016.
Efficacy in 611 Patients in KEYNOTE 001
Pembrolizumab provided an ORR of 25% to 52% in the initial melanoma expansion cohorts of KEYNOTE-001,irrespective of dosing schedule or prior ipilimumab status.
Pembrolizumab Treatment-related AEs with Incidence >5%
Similar safety profiles in IPI-N and IPI-T patients
Adverse Event, %
TotalN=411
Any Grade Grade 3/4
Fatigue 36 2
Pruritus 24 <1
Rash 20 <1
Diarrhea 16 <1
Arthralgia 16 0
Nausea 12 <1
Vitiligo 11 0
Asthenia 9 0
Cough 9 0
Adverse Event, n (%)
TotalN=411
Any Grade Grade 3/4
Myalgia 9 0
Headache 8 <1
Hypothyroidism 8 <1
Decreased appetite 7 <1
Dyspnea 7 <1
Chills 6 0
Pyrexia 6 0
ALT increased 5 <1
Total 83 12
Analysis cut-off date: October 18, 2013.
Ribas A, et al. JAMA. 2016
Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone
N=314
CheckMate-067: Study Design
N=316
N=315
NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4 then
NIVO 3 mg/kg Q2W
Previously untreated,
unresectable or metastatic melanoma
N=945
Randomize 1:1:1
NIVO 3 mg/kg Q2W + IPI-matched placebo
IPI 3 mg/kg Q3W x4 + NIVO-matched placebo
Treat until progression**
or unacceptable
toxicity
*Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses.
**Patients could have been treated beyond progression under protocol-defined circumstances.
Wolchok JD, et al. ASCO. 2015.
Stratify by:
• BRAF status
• AJCC M stage
• Tumor PD-L1 expression <5% vs ≥5%*
The study was not powered for a comparison between NIVO and NIVO+IPI
Overall Survival Results From a Phase III Trial of Nivolumab Combined with Ipilimumab in Treatment-naïve Patients with Advanced Melanoma
CheckMate 067
• NIVO+IPI and NIVO significantly improved OS and PFS vs. IPI alone in patients with untreated advanced melanoma
• In descriptive analyses, NIVO+IPI resulted in
numerically higher OS, PFS and ORR vs. NIVO alone
• For NIVO+IPI, median DOR and time to subsequent therapy are still not reached
Larkin J, et al. AACR 2017. Abstract CT075.
• The trial isn’t combined vs. sequential
• Just combo vs. single agents with crossover outside the study
• Study not designed or powered for comparison between nivo monotherapy vs. combination
• Number of events at this first OS analysis less then anticipated
112
Dr. Larkin’s Comments about KEYNOTE-067
• With an additional 19 months of follow-up, safety was consistent with the initial report
• Most select AEs were managed and resolved within 3-4 weeks (85–100% across organ categories)
• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached
Combination ICI Safety Summary
NIVO+IPI(N=313)
NIVO
(N=313)IPI
(N=311)
Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4
Treatment-related adverse event (AE)
95.8 58.5 86.3 20.8 86.2 27.7
Treatment-related AE leading to discontinuation
39.6 31.0 11.5 7.7 16.1 14.1
Treatment-related death, n (%) 2 (0.6)a 1 (0.3)b 1 (0.3)b
aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment.bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).
Larkin J, et al. New Engl J Med 2015.
Progression-Free Survival (Intent-to-Treat)
Wolchok JD, et al. ASCO. 2015.
In the randomized phase III KEYNOTE-006 study, pembrolizumabhad fewer toxicities and significantly improved overall survival compared with ipilimumab.
Robert C, et al. N Engl J Med. 2015.
Checkmate 016: Phase 1b Trial of Nivolumab + Ipilimumab in Metastatic RCC
Stopped due to toxicity
*Estimated study enrollment including arm that terminated due to toxicity. There are 47 patients continuing in each remaining arm. †One prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed provided recurrence occurred ≥6 months after the last dose of the adjuvant or neoadjuvant therapy. Only prior cytokine-based treatment for metastatic RCC (eg, interferon-alpha [IFN-α] or interleukin 2 [IL-2]) as prior therapy is allowed. ‡AEs, SAEs, and laboratory abnormalities. §By RECIST v1.1.
www.clinicaltrials.gov. NCT01472081; Hammers HJ, et al. Poster presentation at ESMO 2016. Abstract 1062P.
Primary Outcome Measures: Safety and tolerability‡
Secondary Outcome Measures: ORR, DOR§
N=175*
Key Eligibility Criteria• Advanced or metastatic clear cell
RCC
• KPS ≥80%
• No active CNS metastases
• Available tumor tissue (archival or recent acquisition)
• For NIVO3 + IPI1 and NIVO1 + IPI3 expansion arms and NIVO3 + IPI3 addition arm:
• Treatment naïve†
Nivolumab3 mg/kg (IV)
Q2W
Nivolumab 3 mg/kg (IV) +ipilimumab 1 mg kg (IV)
Q3W x 4
Nivolumab 1 mg/kg (IV) + ipilimumab 3 mg/kg (IV)
Q3W x 4
Nivolumab 3 mg/kg (IV) + ipilimumab 3 mg/kg (IV)
Q3W x 4
Overall Survival of Nivolumab + Ipilimumab in Advanced/Metastatic RCC (Checkmate 016)
Median OS, months (95% CI)NIVO3 + IPI1 NRNIVO1 + IPI3 32.6 (25.99–NR)
0 3 6 129 15
Time (months)
18 21 24 27 360.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
30
Ove
rall
Surv
ival
(P
rob
abili
ty)
33
Number of patients at riskNIVO3 + IPI1 14 13 0NIVO1 + IPI3 15 12 0
67
1717
2729
3537
3538
3839
4141
4443
4745
4747
Adapted from Hammers HJ, et al. Poster presentation at ESMO 2016. Abstract 1062P.
In Select Nivo-treated Pts, Median Survival Not Reached; How Much Crossover After Nivo?
Escudier B, et al. Eur Urol. 2017.Motzer RJ, et al. N Engl J Med. 2015.
Phase II Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell
Carcinoma. HCRN: GU16-260
PR or CR – Part AContinue nivolumab 360 mg IV Q3W
until PD, toxicity or 84 weeks
Nivolumab 360 mg Q3W starting week 13-19
Nivolumab 240 mg IV Q2W x 6 then initial disease assessment
www.clinicaltrials.gov; NCT03117309.
Toxicity that requires discontinuation of
study drug or 84 weeks of treatment
completed – continue being followed per
protocol
PDEvaluate for Part B
PD or SD @ 12 months – Part BRe-induce nivolumab 3 mg/kg and
ipilimumab 1 mg/kg Q3W x 4 (must complete by week 16)
PR, CR or SDContinue nivolumab until PD, toxicity or 48 weeks
PDOff study
www.clinicaltrials.gov; NCT02516241.
DANUBE (Durvalumab +/- Tremelimumab) in 1st Line UBC
• TCC of the urothelium(renal pelvis, ureters, urinary bladder and urethra)
• Treatment-naïve patients
• Unresectable/stage IV
Randomization Stratification Factors1. Cisplatin eligibility (eligible vs. ineligible)2. PD-L1 status (positive vs. negative)3. Visceral metastasis (presence or absence; i.e., bone, lung or liver)
RandomizationN=650
Estimated TimelinesEstimated Completion: September 2019Estimated Primary Data: March 2018
Durvalumab + tremelimumab
N=217
DurvalumabMonotherapy
N=217
SOCN=217
Primary Endpoints
PFS & OS (Combo vs. SOC)
Secondary Endpoints• PFS & OS (Single agents vs. SOC)• PFS (PD-L1+ and PD-L1-)• OS (Combo vs. SOC)• ORR (Combo vs. SOC)• FACT-BL• Immunogenicity• PK (Cmax and Ctrough)
Checkmate 032: Phase 1/2 Trial of Nivolumab vs Nivolumab + Ipilimumab in mUC: Overall Survival and Progression-Free Survival
Median follow-up times for NIVO 3 + IPI 1 arm is 16.7 months, and NIVO 1 + IPI 3 arm is 7.8 monthsDiamonds are censored patients.
Sharma P, et al. Oral presentation at SITC 2016. Abstract 449.
Overa
ll S
urv
ival
(Pro
ba
bil
ity)
Time (months)
0.0
0.1
0.2
0.3
0.4
0.6
0.5
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27
No. at riskNIVO 1 + IPI 3
NIVO 3 + IPI 1
26 21 17 7 3 3 3 2 1 0
104 84 59 45 38 27 8 0 0 0
Median OS, months (95% CI)
NIVO 3 + IPI 1 7.3 (5.6–11.4)
NIVO 1 + IPI 3 10.2 (4.5–NR)
Pro
gre
ssio
n-F
ree
Su
rviv
al
(Pro
ba
bil
ity)
0.0
0.1
0.2
0.3
0.4
0.6
0.5
0.7
0.8
0.91.0
0 3 6 9 12 15 18 21 24 27Time (months)
No. at riskNIVO 1 + IPI 3NIVO 3 + IPI 1
26 15 6 1 1 1 1 1 0 0
104 41 27 20 19 8 4 0 0 0
Median PFS, months (95% CI)
NIVO 3 + IPI 1 2.6 (1.4–3.9)
NIVO 1 + IPI 3 4.3 (1.6–8.2)
Bellmunt J, et al. N Engl J Med. 2017.
43.9%30.7%
KEYNOTE-045 Study (NCT02256436) Overall Survival: Total
Median (95% CI)10.3 mo (8.0-11.8) 7.4 mo (6.1-8.3)
270 226 194 169 147 131 87 54 27 13 4 0 0
272 232 171 138 109 89 55 27 14 3 0 0 0
No. at risk
Events, n HR (95% CI) P
Pembro 155 0.73 (0.59-0.91) .0022
Chemo 179
Pembrolizumab
Chemotherapy
Can We Select Patients More Likely to Respond to PD-1/L1 Blockade?
1. Pre-existing T cell infiltration and adaptive PD-L1 expression
Tumeh, et al. Nature. 2014.
Herbst, et al. Nature. 2014.
2. TCR clonality
Tumeh, et al. Nature. 2014.
3. IFN signature by expression profiling
Nonresponder Responder
0.81.01.21.41.61.82.02.22.4
Best Overall Response, RECISTv1.1
Ribas, et al. ASCO. 2015.
4. Mutational load
Le, et al. NEJM. 2015.
Rizvi, et al. Science. 2015.
5. Transcriptome
Hugo, et al. Cell. 2016.
• PD-1/PD-L1 blockade therapy should be used as single agent in patients who have a chance of responding to this therapy
• Combination therapies with PD-1/PD-L1 blockade should only be used in patients with a low likelihood of a tumor response to single agent therapy
Conclusions
Should PD-1 blockade be used alone or in combination?