your debaters for the eveningd2qrtshcpf0x30.cloudfront.net/nodes/188/asco io final onsite.pdf ·...

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


ESMO 16


Lancet Oncol 17


ASCO GU 17

AvelumabN=153Patel

ASCO GU 17

PembrolizumabN=270


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)


Lancet Oncol 17


ASCO GU 17

AvelumabN=153Patel

ASCO GU 17

PembrolizumabN=270



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


• 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


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


SP142 ≥5%

The proportion of tumour area occupied by PD-L1 expressing tumour-infiltrating immune cells of any intensity

Tumour Area


Definition

https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160002c.pdf

UC: 22C3 Uses Combined Proportion ScorePembrolizumab

+


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


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


• 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



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


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


PD-L1 Expression <1%

Treatment ArmMedian OS, mo

(95% CI)HR

(95% CI)

Nivolumab (n=73) 5.7 (4.4–12.7)0.89


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


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



Nivolumab

Nivolumab


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.


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


*By RECISTv1.1; NR, not reached

PFS by PD-L1 Expression Level (1%)


*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, %


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


36.4 29.4 7.7 5.1 14.8 13.2

Treatment-relateddeath*

0 0.3 0.3


*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


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


• 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.


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


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)


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


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?

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