Disclosures Consulting fees from: Bristol Myers Squibb, Genentech, - - PDF document

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Winship Cancer Institute of Emory University

Immune‐Based Therapeutic Approaches in Genitourinary Malignancies

Michael B. Atkins, MD Professor of Medicine Deputy Director Georgetown‐Lombardi Comprehensive Cancer Center

Disclosures

• Consulting fees from: Bristol Myers‐Squibb,

Genentech, GlaxoSmithKline, Merck, Novartis, and Pfizer

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Immunotherapy for GU Cancer

RCC

• High Dose IL-2:

– Contemporary clinical experience – Patient Selection opportunities

• Vaccine Approaches
• Checkpoint inhibitors

– Anti-CTLA4 – PD1 pathway blockade Bladder Cancer

RCC: Eight Years of Impressive Progress

Setting Phase III Alternative 1st-Line Therapy Good or intermediate risk* Sunitinib Pazopanib HD IL-2 Bevacizumab + IFN Poor risk* Temsirolimus Sunitinib 2nd-Line Therapy Prior cytokine Sorafenib Sunitinib or bevacizumab Prior VEGFR inhibitor Everolimus Axitinib Clinical Trials Prior mTOR inhibitor Clinical Trials

Does Immunotherapy have any role?

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RR 15% (37/255); 7% CR Durable Responses in almost 50% of responding patients Median Response Duration –54 months Median Survival 16 mos

High-Dose IL-2 Therapy: RCC Response Durations-255

36 48 60 72

CWG Phase III RCC: PFS

Median PFS

IL-2/IFN 3.1 mos HD IL-2 3.1 mos Time from randomization (months) Proportion alive and free from progression

0.0 0.2 0.4 0.6 0.8 1.0 12 24 HD IL-2 IL-2 and IFN 36 48 60 72

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Combined UCLA/DFHCC Model

+

High Low CA-9 Staining Poor Intermed Good Pathology Risk Group Intermed

Poor Good

Atkins, et al Clin Can Res, 2005

Activity of IL-2 is greater than package Insert

Response* %

Historical rate 14 IL-2 Select Trial (all pts n=120)* 28

p=0.0016 95% CI=20.5-37.3%

*Using WHO Criteria

Likely explanations for improved RR include: 1) Enhanced “pre-screening”

• smaller non-clear cell population

2) Impact of alternative therapies on IL-2 referral patterns 3) Application of debulking nephrectomy

• fewer patients treated with primary in place

McDermott et al ASCO 2010

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24% (15%-35%) Intermediate (n= 83)

P-value* RR (95% CI) Tumor risk group

0.89 27% (6%-61%) Good (n=11) 28% (12%-49%) Poor (n=25)

Response by Tumor Features

0.19 22% (13%-33%) High (>85% n=77) 33% (19%-50%) Low (<85% n=39)

CA-9 Score Combined Score

0.39 23% (14%-34%) Good (n=74) 30% (17%-46%) Poor (n=42)

IL-2 Select Trial: Commentary

• Potential explanations for this result:

– Tumor factors are important but markers other than CA-9 will be more predictive – Samples analyzed are not “representative” given the lack of standards for tumor processing at community centers – Host factors (e.g. patient immune response, tumor microenvironment) may play are larger role in determining response

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Response to IL-2 may be associated with tumor expression of PD-L1/B7H3

RR p-value*

PD-L1 Tumor Negative (n=95) 19% 0.012 Positive (n=18) 50% B7H3 Tumor Negative (n=28) 10.7% 0.075 Positive (n=85) 29.4%

IHC performed at Mayo Clinic by Kwon, Leibovich, et al.

Vaccines for RCC

IMA-901 phase 2 study

Cyclophosphamide (300 mg/m2 single infusion) + IMA-901 + GM-CSF IMA-901 + GM-CSF N  68

• Advanced RCC
• HLA-A*02+
• Prior cytokine or

TKI therapy

• Measurable

lesion(s)

• Documented

progression IMA-901 delivered via 17 intradermal vaccinations over 9 months.

1:1

Primary endpoint: Disease control rate Secondary endpoints: ORR, DoR, TTP, PFS, OS, safety

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Vaccines for RCC

IMA-901 phase 2 study

Cy, cyclophosphamide.

2 6 8 4 10 40 60 20 80 100

Time, mo

Percentage Progression-free Survival

+Cy

• Cy
• Trend for prolonged OS in +Cy arm

20 30 10 40 40 60 20 80 100

Time, mo

Percentage Survival

+Cy

• Cy

OS: 23.5 mo for +Cy vs 14.8 mo for −Cy; HR = 0.57; P = .090

• PFS was comparable in the 2 arms

Walter S, et al. Nat Med. 2012;18:1254-1261.

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 Normals MTSS Pre‐ Treatment MTSS C1D28 MTSS C2D28 MTSS C4D28 Positive by FACS (%) CD15+CD14‐ CD33+HLADR‐

N = 10 N = 23 N = 30 N = 34 N = 20 b

ap = < .05 (compared to normal) bp = < .001 (compared to normal) cp = < .05 (compared to pre-treatment) dp = < .001 (compared to pre-treatment)

b c c d d d

Ko et al, 2009.

Myeloid Derived Suppressor Cells in RCC Pts on Sunitinib

a

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Vaccines for RCC

IMA-901 phase 3 study

Cyclophosphamide (300 mg/m2 single infusion) + Sunitinib + IMA-901 + GM-CSF Sunitinib Sunitinib (1 cycle)

3:2

Primary endpoint: OS Secondary endpoints: OS in patients with defined biomarker signature, PFS, best tumor response, safety, immune cell populations

Rini BI, et al. ASCO 2011. Abstract TPS183.

N  330

IMA-901 delivered with GM-CSF via 10 intradermal vaccinations over 4 months Stratification Risk group (low vs intermediate) Region (WEE vs CEE vs US) Nephrectomy (yes vs no) Initial OS and immune response results expected soon, final data in 2015

Vaccines for RCC

AGS-003

Phase I/II AGS-003 Monotherapy (n = 20)1 Phase II AGS-003 + Sunitinib (n = 21)2

Median PFS: 5.6 months (95% CI, 5.0–10.8) Median PFS 11.9 months >2.5 months, poor MSKCC risk 6.0 months, poor MSKCC risk >5.1 months, intermediate MSKCC risk 14.9 months, intermediate MSKCC risk Median OS: 18.5 months (95% CI, 9.3–NR) Median OS: Not reached 7.9 months, poor MSKCC risk No grade 3/4 AEs were observed No grade 3/4 AEs were observed Logan T, et al. ASCO GU 2010. Abstract 379. Figlin RA, et al. ASCO GU 2012. Abstract 348.

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Phase II Trial of AGS-003 + Sunitinib: Overall Survival Results: 21 pts (Figlin et al)

• Estimated median OS = 29.3 months per Kaplan Meier method
• Encouraging OS compared to expected sunitinib OS in similar

risk mRCC subjects

Vaccines for RCC

AGS-003 phase 3 study

AGS-003 (8 doses) + standard treatment n = 300 Standard treatment n = 150 Diagnosis, nephrectomy, screening ↓ Registration, leukapheresis (AGS-003 arm only) Stratification based upon number of Heng risk factors (1, 2, 3, or 4). AGS-003 quarterly + standard treatment until PD Standard treatment until PD Pretreatment Induction (48 weeks) Booster ≥ SD ≥ SD

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 Co-stimulation regulates naive and activated T cells  There are positive and negative co-stimulatory signals  Many of the negative checkpoint pathways promote tolerance and turn off T-cells (e.g. CTLA-4, PD-1/PD-L1)

+

• Co-stimulation 2014:

Immune Checkpoints

CTLA-4 Blockade in mRCC

• Ipilimumab Phase II trial

– Single institution (NCI) * – Major response rate = 9% – Max dose tested 3 mg/kg

• (dose response in melanoma)
• Survival effect in melanoma despite low response rate
• Additional studies warranted

– CTLA-4 Blockade + Bev (Hodi et al, DFHCC Melanoma Phase I, 2014, in press)

*Yang, JIT 2007

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Dendritic cell T cell

MHC TCR CD28 B7 CTLA4 RCC Cell

Activation (cytokines, lysis, proliferation, migration)

Role of PD-1 in Suppressing Antitumor Immunity

Differences between blocking CTLA4/B7 and blocking PD-1/PD-L1 Dendritic cell

MHC B7 TCR CD28 CTLA4

T cell RCC cell T cell

MHC TCR PD-L1 (B7-H1) PD-1

T cell

MHC TCR

Clinical Development of Inhibitors of PD-1 Immune Checkpoint

Target Antibody Molecule Company Development stage PD-1 Nivolumab- BMS-936558 Fully human IgG4

Bristol-Myers Squibb Phase III multiple tumors

Pidilizumab CT-011 Humanized IgG1 CureTech

Phase II multiple tumors Pembrolizumab MK-3475

Humanized IgG4

Merck Phase I-II

PD-L1 BMS-936559 Fully human IgG4

Bristol-Myers Squibb Phase I

MedI-4736 Engineered human IgG1

MedImmune Phase I

MPDL-3280A Engineered human IgG1

Genentech Phase I-II

MSB0010718C

EMD Serono Phase I

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23

 RR of 29% observed; PFS 7.3 months  Several responses persisted well beyond the duration of therapy

Nivolumab in mRCC- Phase 1 Trial

Drake CG, et al. ASCO 2013. Abstract 4514.

Partial Regression of Metastatic RCC in a Patient Treated with 1 mg/kg BMS-936558

 57-year-old patient had developed progressive disease after receiving sunitinib, temsirolimus, sorafenib, and pazopanib  Currently in cycle 6 with ongoing PR

Pretreatment 6 months

Courtesy of C. Drake, Johns Hopkins Univ

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 44% of patients had ≥ 3 prior therapies  Median OS not yet reached

Nivolumab in mRCC: Phase I Trial

Drake CG, et al. ASCO 2013. Abstract 4514.

Select adverse events (≥1%) occurring in patients with mRCC treated with nivolumab (n=34)

Category Any Grade n (%) Grade 3-4 n (%)

Any treatment-related AE 29 (85.3) 6 (17.6) Skin 12 (35) 1 (3) Endocrinopathies 6 (18) Gastrointestinal 6 (18) Hepatic 4 (12) 1 (3) Infusion reaction 2 (6) Pulmonary 2 (6) 1 (3) Drake, McDermott… Atkins, ASCO 2013

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PD-L1 (+) PD-L1 (-) Proportion of Patients

CR/PR Non-responders P=0.006**

* 2 pts still under evaluation ** Results based on a post-hoc analysis

Patient samples: 18 MEL,10 NSCLC, 7 CRC, 5 RCC, 2 CRPC RCC

*

Correlation of PD-L1 Expression in Pretreatment Tumor Biopsies with Clinical Outcomes

PD-L1 expression by IHC in 61 pretreatment tumor biopsies across tumor types from 42 pts

Topalian et al NEJM, 2012

28

Nivolumab Phase 3 Trial

Motzer R, et al. ASCO 2013. Abstract TPS4592.

Nivolumab 3 mg/kg IV every 2 wks Everolimus 10 mg PO daily Primary endpoint: OS Secondary endpoints: PFS, ORR, OR duration, Safety Accrual completed early 2014 N  822

• mRCC
• ≤ 2 prior anti-angiogenic

therapies

• ≤ 3 total prior systemic

regimens

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ASCO 2014:Nivo RCC Update Single agent Nivolumab in mRCC

# 5009 MOTZER #5012 CHOUEIRI Design Randomized, dose-ranging phase II (N=168) Biomarker-based randomized clinical trial (N=91)

(Baseline and on-therapy fresh tumor biopsies)

Dose IV Q3W

0.3mg/kg n =60 2 mg/kg n=54 10 mg/kg n=54 0.3mg/kg n =22 2 mg/kg n=22 10 mg/kg n=23 10 mg/kg n=24 (naïve)

Prior Tx

70% ≥ 2 prior therapies No treatment-naïve pts 74% (1-3) prior therapies 24 (16%) treatment-naïve pts

ORR (%) 20% 22% 20% 9% 23% 22% 13% mPFS (m) 1º endpoint 2.7 4.0 4.2 PFS at 24 weeks: 36% mOS (m) 18.2 25.5 24.7 Not Reported G3/4 TOX 5% 17% 13% 18% Biomarker None reported

• Increased T-cell tumor infiltrates after nivolumab
• Increased serum chemokines post-nivolumab
• Numerically higher (22% vs. 8%) ORR in PD-L1 (+) pts

Activity and Safety of BMS-936559 in the First in Human Phase I trial

Tumor Type Dose (mg/kg) No. Patients (N=160) ORRa No. Patients (%) Duration of Response Range, Months SD>24 Weeks No. Patients (%) Melanoma 0.3-10 52 9 (17)b 2.8-23.5+ 14 (27) NSCLC 1-10 49 5 (10) 2.3+-16.6+ 6 (12) All Squamous 13 1 (8)

• 3 (23)

All Non-squamous 36 4 (11)

• 3 (8)

RCC 10 17 2 (12) 4-17 7 (41) Ovarian 3 and 10 17 1 (6) 1.3+ 3 (18)

Response-evaluable patients who initiated treatment by August 1, 2011

a ORR was assessed using modified RECIST v1.0 criteria b Includes 3 CRs

Safety – Drug related adverse event (AE) rate = 61%

• Grade 1 / 2 = 52%, Grade 3 / 4 = 9%
• Only 6% stopped treatment due to AE, No drug related deaths

Brahmer J et al NEJM 2012

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MPDL3280A Phase 1a Efficacy Summary

Investigator Assessed

RECIST 1.1 Response Rate (ORR) SD of 24 Weeks or Longer 24-Week PFS Overall population (N = 140) 21% 16% 45% RCC* (n = 47) 13% 32% 53% Clear cell (n = 40) 13% 35% 57% Non-clear cell (n = 6) 17% 20%

* 1 patient with unknown histology. Includes sarcomatoid and papillary RCC.

All patients first dosed prior to August 1, 2012; data cutoff February 1, 2013. ORR includes unconfirmed PR/CR and confirmed PR/CR.

Patients, % Complete response Partial response Stable disease

Investigator-Assessed Best Overall Response Rate (ORR*), % (n/n) PD-L1 Positive PD-L1 Negative All† Overall population (N = 140) 36% (13/36) 13% (9/67) 21% (29/140) RCC (N = 47) 20% (2/10) 10% (2/21) 13% (6/47)

Best Response

MPDL3280A Phase 1a in RCC: Summary of Response by PD-L1 IHC Status

* ORR includes investigator-assessed unconfirmed and confirmed PR/CR by RECIST 1.1.

† 16 patients with RCC were of unknown status.

Patients first dosed at 3-20 mg/kg prior to August 1, 2012 with at least 1 post-baseline evaluable tumor assessment; data cutoff Feb 1, 2013.

Cho et al, ASCO 2013

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PD1 Pathway Inhibition in RCC

Anti-PD1 pathway blockade shows considerable anti-tumor activity patients with VEGFR TKI resistant RCC Nivolumab trials show encouraging overall survival Phase III trial of anti-PD1 vs everolimus in VEGFR TKI resistant tumors is fully accrued and pending analysis Tolerability of agents support their use as backbones in combination studies Current data doesn’t support first line single agent Phase III trial

PDL1 Expression as a Biomarker: RCC

• PDL1 expression associated with poor

survival in absence of therapy

• PDL1 expression associated with good
• utcome with anti-PD1

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Months OS 10 20 30 40 0.0 0.2 0.4 0.6 0.8 1.0 Pazopanib Low Pazopanib High Sunitinib Low Sunitinib High

H-Score: Low <= 125, High > 125 Group (N) Median OS months (95% CI) Pazopanib Low (213) 31.6 (26.5, NR) Pazopanib High (8) 5.1 (4.2, NR) Sunitinib Low (225) 27.4 (21.4, 30.5) Sunitinib High (7) 8.9 (2.6, NR) P=0.017

PD-L1 is a prognostic marker of OS in RCC patients treated with VEGR TK inhibitors

Front-line Trial Impact?

Choueiri et al Comparz Data ASCO 2013,

Issues with PDL1 as a Biomarker

PD-L1 neg can’t be relied on

– Assays are technically difficult, imperfect; results may differ depending on the antibody/assay (tumor vs immune cells) – 5% expression, tumor heterogeneity, and inducible gene = sampling error (false negs) – Archived tissue different than recent biopsy

• May be more useful in determining which

tumors rather than which patients to treat

• PDL1 expression may be less relevant for

combination therapies

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Presented by: Prof. Thomas Powles

Maximum SLD Reduction from Baseline, %

* *

MPDL3280A: Summary of Response in UBC Investigator Assessed

IHC (IC) 0 IHC (IC) 1 IHC (IC) 2 IHC (IC) 3 IHC (IC) unknown

BLADDER #5011 Powles Inhibition of PD-L1 by MPDL3280A in pts with metastatic bladder cancer

PD-L1 + PD-L1 -

30 PD-L1 POSITIVE patients

• Median FU: 4.2 mo (1.1+to 8.5)
• ORR = 43%, 2 CR

35 PD-L1 NEGATIVE patients

• Median FU: 2.7 mo (0.7+ to 3.6)
• ORR=11%
• Very short follow up and small # of pts
• PD-L1 (-) patients can still respond

May 31, 2014: MPDL3280 given FDA breakthrough Therapy Designation in Bladder Cancer

Issues with PDL1 as a Biomarker: RCC

• Too few tumors express PDL1 (at most 1/3)
• PDL1 expression might be constitutive (no

immune infiltrate)

• Still biomarkers may be key to front line

single agent anti-PD1 development

• Need to focus on combinations that induce

immune infiltration and PDL1 expression

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Ipi/Nivo- Tumor Response (Melanoma)

Cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab All patients in concurrent cohorts

First occurrence of new lesion

Wolchok et al. ASCO #9012 ORR >80% Tumor Reduction ipilimumab 7% <3% nivolumab 28% <2% combination (cohort 2) 53% 41% Wolchok et al NEJM 2013

#5010 AMIN (Nivo+VEGF TKI) #4504 HAMMERS (Nivo+Ipi)

Arm S Sunitinib 50 mg (4/2) + nivolumab 2mg/kg Q3W (N2) or 5mg/kg Q3W (N5) Arm P Pazopanib 800 mg QD + nivolumab 2mg/kg Q3W (N2)

(N3+I1)

Nivolumab 3mg/kg + ipilimumab 1mg/kg Q3Wx4

(N1+I3)

Nivolumab 1mg/kg + ipilimumab 3mg/kg Q3Wx4 Prior therapy 42% 100% 80% Nb. n=33 n=20 n=21 n=23 MSKCC risk Favorable/Intermediate (94%) Favorable/Intermediate (100%) ORR (%) 52% 45% 43% 48% Median DOR range (wks) 54 18.1-80+ 30 12.1-90.1+ 31.1 4.1+ – 42.1+ NR 12.1+ – 35.1+ Median PFS (wks) ~estimated (mo) 48.9 ~11.4 31.4 ~7.3 36.6 ~8.4 38.3 ~8.9

• Gr. 3/4

Toxicity (%) 81.8% 70% 29% (9.5% d/cd) 61% (26% d/cd)

ALT elevation 18% Hypertension 18% Hyponatremia 15%

4 DLTs (stopped) (LFTs n=3, 20%)

ALT elevation 0% Diarrhea 5% Fatigue 0% ALT elevation 26% Diarrhea 13% Fatigue 8% Highlights of the Day - Genitourinary (Non prostate) Cancer T.K. Choueiri

ASCO 2014 Nivo RCC Update Phase I Nivolumab-based combination studies

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SUNITINIB + N2 (n=7) SUNITINIB + N5 (n=26) PAZOPANIB + N (n=20)

1st occurrence of new lesion 100 Change in baseline (%) Time since first dose (weeks) 80 60 40 20

• 20
• 40
• 60
• 80
• 100

12 36 48 60 72 84 24 12 36 42 48 54 60 24 66 30 18 6 12 36 48 60 96 24 72 84

Amin #5010 New combination studies in mRCC : VEGFR-TKI + Nivolumab

80 100 60 40 20

• 20
• 40
• 60
• 80
• 100

Change in baseline target lesions (%)

Treatment S + N (n=29) P + N (n=19)

1st occurrence of new lesion Time since first dose (weeks)

Hammers #4504 New combination studies in mRCC : Nivolumab + Ipilimumab Nivo3 + Ipi1 (n=20)

Time since first dose (weeks)

6 12 18 24 30 36 42 48 54

Time since first dose (weeks)

6 12 18 24 30 36 42

Nivo1 + Ipi3 (n=22)

100 Change in baseline (%) 80 60 40 20

• 20
• 40
• 60
• 80
• 100

100 80 60 40 20

• 20
• 40
• 60
• 80
• 100

120 120

80.00 100.00 120.00 60.00 40.00 20.00 0.00

• 20.00
• 40.00
• 60.00
• 80.00
• 100.00

Change in baseline target lesions (%) N3 + I1 (n=20) N1 + I3 (n=22)

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Nivolumab Front Line Phase 3 Trial

Ipi 1/ Nivo 3 IV every 3 wks Sunitinib 50 mg po QD x 4 weeks q 6 weeks

• mRCC
• Treatment Naive

Trial anticipated to start in 2014

Novel Immunotherapy: Combinations

– Combination with anti-VEGF therapy TKIs, bevacizumab – With other checkpoint inhibitor CTLA4 inhibitors, LAG-3, TIM3, etc – Combinations with other immunotherapies IL-2 ,IFN, anti-41BB, Peg IFN, etc – Combination with vaccines

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Agent Structure Ongoing studies in metastatic RCC

PD-1 i

MK-3475

Humanized IgG 4 PD-1 monoclonal Ab

Phase I/II – mRCC Combination with pazopanib NCT02014636 Phase I – mRCC Combination with axitinib NCT02133742 Phase I/II – mRCC Combination with Peg IFN or ipilimumab NCT02089685

PD-L1i

MPDL3280A

PD-L1 monoclonal Ab

Randomized Phase II – mRCC Alone or in Combination in mRCC with bevacizumab

• vs. sunitinib

NCT01984242

PD1/PDL1 Blockade Combination Trials in RCC Exhausted TIL express Multiple Immunoinhibitory Receptors: These are druggable targets for tumor immunotherapy

46

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Synergistic Anti-Tumor Efficacy By Blocking PD-1 and LAG-3

Control Ab (0/10 TF) Anti-LAG-3 (0/10 TF) Anti-PD-1 (4/10 TF) 1 2 3 4 5 500 1000 1500 2000 Anti-LAG-3 + Anti-PD-1 (8/10 TF)

Days Post-Treatment Initiation Tumor Volume (mm3)

Day 7 Staged MC38 – Similar Results in Staged SA1N

Woo, Goldberg, Drake and Vignali. Cancer Research 2013

Conclusions

Immune therapies continue to play a role in the treatment of RCC The availability of checkpoint inhibitors enables higher therapeutic index, potentially rational treatment selection and synergistic combinations PD1 pathway blockade may play a role in other cancers – particularly bladder Moving novel immunotherapy to first line may

• bviate the need for additional therapy in a

substantial percentage of patients.