Immunotherapy In Advanced Urothelial Cancer

Robert Dreicer, M.D., M.S., MACP, FASCOHead, Medical Oncology Section

Deputy Director University of Virginia Cancer CenterAssociate Director for Clinical Research

Co-Director Paul Mellon Urologic Oncology CenterProfessor of Medicine and Urology

University of Virginia School of Medicine

Disclosures

• Consultant: Orion, Astra Zeneca, Genentech/Roche, Sanofi-Genzyme, Janssen, Astellas, Bristol Myers Squibb, EMD Serono/Pfizer

• Research Funding: Genentech, Asana, Lilly, Bayer

Management Advanced Urothelial Cancer: Issues/Challenges

• A nasty aggressive epithelial cancer

• “Moderately” chemotherapy responsive, but few CR’s

• Impacts an “older” patient population

• Relatively high rate of patients with compromised performance status and/or renal function : The unfit patient

State of the Art Therapy in Advanced Urothelial Cancer Circa Spring 2016

1Loehrer JCO 1992; 2Von der Maase JCO 2000; 3 Bellmunt et al JCO 20124De Santis ASCO 2010; 5Linardou Urology 2004 6Nogué-Aliguer Cancer 2003; 7Rosenberg et al Lancet 2016

Setting Regimen Response RateMedian Survival

1st line CisplatinEligible

MVAC1

Gemcitabine +Cisplatin2

PGC3

40-50%12-15 months

Cisplatin Ineligible

Gemcitabine +Carboplatin4-6 36-56% 7-9 months

2nd line Single Agent Chemotherapy

~10% 5-8 months

Management of Metastatic Urothelial Cancer: Summary of Current Evidence

• Cisplatin-based combination chemotherapy provides the potential to cure in the range of 5-15%, primarily in good PS pts with low volume nodal disease

• Non-cisplatin based chemotherapy appears to be primarily palliative, may impact slightly on PFS

• A small group of highly selected patients may benefit from an integrated chemotherapy/surgical approach

Second Line Chemotherapy for Advanced Urothelial Cancer

• To date no level 1 evidence supporting improvement in survival from chemotherapy

• There is no current evidence for the superiority of salvage combination chemotherapy compared to monotherapy, or precise delineation of non-cross resistant regimens

PD-L1 Expression in Metastatic Bladder Cancer

Powles T et al. Nature. 2014;515:558-562.

IHC Score(N = 205)

Tumor-Infiltrating Immune Cells, n (%)

Tumor Cells, n (%)

IHC 3 18 (9) 14 (7)

IHC 2 37 (18) 8 (4)

IHC 1 89 (43) 37 (18)

IHC 0 61 (30) 146 (71)

PD-L1 Positivity in UBC Tumors by IHC

Tumor Response With Atezolizumab Anti–PD-L1 Therapy in Metastatic Bladder Cancer

Powles T et al. Nature. 2014;515:558-562.

a Patients with CRs who had ≤100% reduction of target lesions due to lymph node target lesions; all lymph nodes returned to normal size per RECIST v1.1.

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80

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

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

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Expression characteristics of bladder cancer. Integrated analysis of mRNA, miRNA and protein data led to identification of distinct subsets of urothelial carcinoma

MARCH 2014 | VOL 507 | NATURE | 315

IMvigor 210: Phase 2 Atezolizumab in Metastatic UC

1. Rosenberg JE et al. Lancet. 2016;387:1909-1920.

Treatment

Patients

Cohort 1 (N = 119)1st-line cisplatin

ineligible

Atezolizumab 1,200 mg IV every 3 wk

until RECIST v1.1 progression

IMvigor 210

• Inoperable locally advanced or metastatic urothelial carcinoma

• Predominantly UC histology

• Tumor tissue evaluable for PD-L1 testinga

Atezolizumab 1,200 mg IV every 3 wk

until loss of clinical benefit

Cohort 2 (N = 310)Platinum-treated mUC

Co-primary endpoints: (1) Confirmed ORR by RECIST v1.1 and central IRF

(2) ORR by investigator-assessed modified RECIST

Key secondary endpoints: DOR, PFS, OS, safety

Dreicer R, et al. IMvigor210: atezolizumab in platinum-treated mUC. ASCO 2016

KEYNOTE-045 Phase 3 Trial (NCT02256436)1

1. Bellmunt J et al. Society for Immunotherapy of Cancer 2016 Annual Meeting (SITC 2016). Abstract 470.

Key Eligibility Criteria• Urothelial carcinoma of the renal pelvis,

ureter, bladder, or urethra• Transitional cell predominant• PD after 1-2 lines of platinum-based

chemo or recurrence within 12 mo of perioperative platinum-based therapy

• ECOG PS 0-2• Provision of tumor sample for biomarker

assessment

Stratification Factors• ECOG PS (0/1 vs 2)• Hemoglobin level (<10 vs ≥10 g/dL)• Liver metastases (yes vs no)• Time from last chemotherapy dose

(<3 vs ≥3 mo)

Pembrolizumab 200 mg IV Q3W for 2 y

Paclitaxel 175 mg/m2 Q3W, orDocetaxel 75 mg/m2 Q3W, orVinflunine 320 mg/m2 Q3W

n = 270

n = 272

R 1:1

N = 542

Key Endpoints• Primary: OS and PFS in total and in PD-L1 combined

positive score ≥10% populations• Secondary: ORR and DOR in total and in PD-L1

combined positive score ≥10% populations; safety in total population

Bellmunt J, et al.

published on

February 17 2017,

at NEJM.org.

DOI:

10.1056/NEJMoa1

613683

Bellmunt J, et al. published on February 17 2017, at NEJM.org.

DOI: 10.1056/NEJMoa1613683

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Overall Survival

10.3 mo in P vs 7.4 mo C

Progression Free Survival

IMvigor210, CheckMate 275, STUDY 1108 and JAVELIN: Recent Investigational and Registrational Trials in Pretreated mUC*

Patient number

Study Arms

Key Inclusion Criteria

Primary Endpoints

PD-L1 expressionPD-L1+PD-L1-NE/unknown

*No head-to-head studies have been conducted and direct comparisons cannot be made between these studies. †265 patients were evaluated for efficacy. ‡191 locally advanced/mUC patients enrolled and received treatment; 103 patients were eligible for efficacy analysis..§241 mUC patients were evaluated for safety and 153 mUC patients were evaluated for efficacy.BOR, best overall response; E1Loriot Y et al. Poster presentation at ESMO 2016. 783P; 2Sharma P, et al. Lancet Oncol. 2017; 3Powles T, et al. Poster presentation at ASCO GU. 286. 4Patel M et al. Poster presentation at ASCO GU. 330.

CheckMate 2752

NivolumabPhase 2

270†

Nivolumab 3 mg/kg IV q2w

• ≥1 Platinum-containing or ≤12 months of neoadjuvant/adjuvant treatment

• Tumor tissue for PD-L1 testing

• ECOG PS 0-1

• ORR

1% cut-off on TC• 46%• 54%

Study 11083

DurvalumabPhase 1/2

191‡

Durvalumab10 mg/kg IV q2w

• Histologically confirmed solid tumors

Locally advanced or mUC cohort:• Had progressed, on were

ineligible for, or refused any number of prior therapies

• ECOG PS 0-1

• Safety• ORR

25% cut-off on TC or IC• 51.3%• 41.4%• 7.3%

IMvigor 2101

Atezolizumab Phase 2

310 (Cohort 2)

Atezolizumab 1200 mg (IV) q3w

Cohort 2:• ≥1 Platinum-containing or ≤12

months of neoadjuvant/adjuvant treatment

• Tumor tissue for PD-L1 testing

• ECOG PS 0-1

• ORR

IC1/2/3 (1% cut-off on IC)• 67%• 33%

JAVELIN solid tumor4

AvelumabPhase 1

241§

Avelumab 10 mg/kg q2w

• Solid tumorsmUC cohort:• Had progressed post-platinum

treatment or cisplatin-ineligible• Unselected for PD-L1• ECOG PS 0-1

• BOR• Safety

5% cut-off on TC• 33.6%• 48.5%• 17.8%

Patients “Unfit” for Cisplatin-based Chemotherapy

• Represents 40-60% of patients with advanced urothelial cancer

• Widely accepted definition includes• ECOG 2 or greater

• Creatinine Clearance ≤ 60 ml/min

• Grade 2 or greater peripheral neuropathy/hearing loss

Carboplatin Combinations for Advanced Bladder Cancer Patients: EORTC Study 30986

De Santis M et al. J Clin Oncol. 2012;30:191-199.

(N = 238)

Gem/Carbo M-CAVI

9.3 months 8.1 months

Median OS

100

80

60

40

20

0Su

rviv

al, %

0 2 3 4 5 6 7

Time, y

M-CAVI

Gem/Carbo

Log-rank test P = .64

Treatmen

tM-CAVI

Gem/Carb

o

O n No. at Risk

44 15 5 2 2 1

37 13 7 3 1 1

119

119

110

108

1

Pembrolizumab

200 mg every 3 wk

Primary Endpoints

• ORR in all patients

• ORR in patients with

PD-L1–positive tumors

Patients (N = 350)

• Advanced urothelial

cancer

• No prior chemotherapy

for metastatic disease

• ECOG PS 0-2

• Ineligible for cisplatin

based on ≥1 of the

following:

– CrCl <60 mL/min

– ECOG PS 2

– ≥ Grade 2 neuropathy

or hearing loss

– NYHA class III CHF

• Secondary Endpoints: DOR, PFS, OS, and ORR in all

patients, PD-L1–positive and PD-L1–high expressing

patients; safety and tolerability

• First 100 patients included in planned interim analysis

– Determine the PD-L1–high expression cutpoint

KEYNOTE-052: Pembrolizumab as Front-Line Therapy

1. Balar A et al. ESMO 2016. Abstract LBA32_PR.

Patient Characteristics:Keynote-052

Balar A et al. Lancet Oncol 2017Published OnlineSeptember 26, 2017http://dx.doi.org/10.1016/S1470-2045(17)30616-2

KEYNOTE-052: Efficacy

Balar A et al. Lancet Oncol 2017 Published Online September 26, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30616-2

KEYNOTE-052: Efficacy

Balar A et al. Lancet Oncol 2017 Published Online September 26, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30616-2

Response in Total Study Population

KEYNOTE-052 Adverse Events

AE, % (N = 370) Any Grade Grade 3-5

Any 46 16

Fatigue 15 2

Pruritus 14 1

Pyrexia 5 1

Decreased appetite 10 2

Diarrhea 8 1

Rash 9 1

ALT/AST increase 11/13 3/3

Nausea 8 1

Muscle spasms 2 2

Balar A et al. Lancet Oncol 2017 Published Online September 26, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30616-2

Standard Therapy in Advanced Urothelial Cancer

Setting Regimen Response Rate Median Survival

1st line

Cisplatineligible

MVAC1

Gemcitabine + cisplatin2

PGC3

40%-50%12-15 mo

Cisplatin ineligible

Gemcitabine +carboplatin4-6 36%-56% 7-9 mo

Atezolizumab Pembrolizumab

~24%~15.9 months (atezolizumab)

2nd line

Atezolizumab7

Nivolumab, Durvalumab, AvelumabPembrolizumab 15%-19% 7.9-10.3 mo

Single-agent chemotherapy

~10% 5-8 mo

1. Loehrer PJ Sr et al. J Clin Oncol. 1992;10:1066-1073. 2. von der Maase H et al. J Clin Oncol. 2000;18:3068-3077. 3. Bellmunt J et al. J Clin Oncol. 2012;30:1107-1113. 4. De

Santis M et al. J Clin Oncol. 2012;30:191-199. 5. Linardou H et al. Urology. 2004;64:479-484. 6. Nogué-Aliguer M et al. Cancer. 2003;97:2180-2186. 7. Rosenberg JE et al. Lancet.

2016;387:1909-1920.

CheckMate-032: Open-Label, Multicenter Phase 1/2 Study

• Treatment beyond progression was permitted if nivolumab was tolerated and clinical benefit was noted

• Patients in the monotherapy arm could cross over to nivolumab combined with ipilimumab after progression if they met prespecified criteria

Nivolumab3 mg/kg IV Q2W

(n = 78)

Nivolumab 3 mg/kg IV Q2W

Pretreated patients with locally advanced or metastatic urothelial carcinoma

Nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W for 4 cycles

(n = 26)

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV Q3W for 4 cycles

(n = 105)

http://www.clinicaltrials.gov/ct2/show/NCT01928394. Accessed May 15, 2017.

Summary

• Immune checkpoint therapy is a standard of care for patients progressing on front-line therapy platinum-based chemotherapy

• For many “unfit” patients front line checkpoint inhibitor therapy is appropriate, although subsets of patients may benefit from cytotoxic therapy used upfront

• PDL1 expression as a biomarker to decide therapy is not useful in making therapy decisions

• Combinatorial immunomodulatory therapies are being broadly investigated

• For a modest but real subset of patients checkpoint inhibitor therapy has provided a paradigm shifting benefit