BLADDER CANCERSystemic treatment

Carlos Vallejos, MD.Medical Oncologist.

Founding Director – Oncosalud AUNA.

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Bladder Cancer: Spectrum of Disease

Metastatic: ~ 5%NMIBC: 70%

CIS, Ta, T1

MIBC: 30%T2-T4

The Past

Humphrey PA, Eur Urol. 2016 Jul;70(1):106-119. 2. Matulay J, Version 1. F1000Res. 2018; 7: F1000 Faculty Rev-1137. 3. American Cancer Society; Mungan, Urology 2000; 55: 876-880

Localized: ~ 95%

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FIRST-LINE SYSTEMIC TREATMENT FOR METASTATIC UROTHELIAL CARCINOMA OF THE BLADDER

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Standard MVAC1989

Cisplatin FDA approved

20181997 2000 2003 2006 2009 2012 2015

Docetaxel1997

GC 2000

Accelerated MVAC 2001

Paclitaxel2002

Vinflunine2009

Gemcitabine EMA approved

2008

Vinflunine

EMA approved

2009

Pu

blic

atio

nA

gen

cy A

ctio

n 1974

1978

Doxorubicin

FDA approved

Atezolizumab

FDA approved

2016

Evolution of Systemic Therapy for UrothelialCarcinoma

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Identifying Patients Who Are Cisplatin-Ineligeble

Chemotherapy ineligible? : Poorly controled type 2 diabetes, vascular or coronary disease, high risk of myelosuppression

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Cisplatin-Eligible

Gemcitabine Cisplatin

ORR: 49%CR: 12% mOS: 14 mo

1. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077. 2. Sternberg CN, et al.

Eur J Cancer. 2006;42:50-54. 3. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.

ddMVAC

ORR: 72%CR: 25% mOS: 15.1 mo

CarboplatinGemcitabine

ORR: 36%CR: 3%mOS: 9.3 mo

Cisplatin-Ineligible

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Durable Responses With Cisplatin-Based CT in UC

Cisplatin Eligible Cisplatin Ineligible

Gemcitabine + Cisplatin[1,2]

ORR: 49%CR: 12%Median OS: 14.0 mos

Dose Dense MVAC[3]

ORR: 72%CR: 25%Median OS: 15.1 mos

Gemcitabine + Carboplatin[4]

ORR: 36%CR: 3%Median OS: 9.3 mos

1. von der Maase H, et al. J Clin Oncol. 2005;23:4602-4608. 2. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077. 3. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54. 4. De Santis M, et al. J Clin Oncol. 2012;30:191-199.

Pro

po

rtio

n S

urv

ivin

g 1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84

MosPatients at Risk, n

203202

118125

5062

3640

3034

2329

79

01

GCMVAC

GC: median 14.0 mos (12.3-15.5 mos)MVAC: median 15.2 mos (13.2-17.3 mos)HR: 1.09 (0.88-1.34)Log-rank P = .44, Walds P = .66

GCMVAC

100

80

60

40

20

00 2 4 6 8 10 12

YrsPatients at Risk, nN

129134

3245

1529

1123

48

20

Median5 yrs, %(95% CI)

M-VACHD M-VAC

O112101

M-VACHD M-VAC

HD M-VAC15.1 mos

21.8 (14.5-21.9)

M-VAC14.9 mos

13.5 (7.4-19.6)

Log-rank P = .042HR: 0.76 (95% CI: 0.58- 0.99)

100

80

60

40

20

00 1 2 3 4 5 6

YrsPatients at Risk, nN

119119

3744

1315

75

32

12

M-CAVIGC

O108110

Surv

ival

(%

)

7

Log-rank test P = .64

M-CAVIGC

11

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Cisplatin but Not Carboplatin Can Yield Durable and Complete Responses in the Frontline

1. De Santis M, et al. J Clin Oncol. 2012;30:191-199. 2. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54.

mOS: 9.3 mos

OS

(%

)

100

80

60

40

20

00 1 2 3 4 5 6 7

Yrs

MCAVI

Gem/carbo

Log-rank test P = .64

Patients at Risk, n

MCAVI (n = 119)

Gem/carbo (n = 119)

37

44

13

15

7

5

3

2

1

2

1

1

mOS: 15.1 mos

OS

(%

)

100

80

60

40

20

00 2 4 6 8 10 12

Yrs

32

45

15

29

11

23

4

8

2

0

DD MVACHR: 0.76

P = .042

mOS, mos

DD MVAC

15.1

MVAC

14.9

Patients at Risk, n

MVAC (n = 129)

DD MVAC (n = 134)

Gemcitabine/Carboplatin[1] DD MVAC (Cisplatin)[2]

MVAC

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Cisplatin FDA approved

Standard MVAC1989

20181997 2000 2003 2006 2009 2012 2015

Docetaxel1997

GC 2000

Accelerated MVAC 2001

Paclitaxel2002

Vinflunine2009

Gemcitabine EMA approved

2008

Vinflunine

EMA approved

2009

Pu

blic

atio

nA

gen

cy A

ctio

n

2018Feb Mar Apr May

Nivolumab 2nd lineFeb

2017

Atezolizumab 1st-line cis ineligible

Apr 2017Durvalumab 2nd line

May 2017

Avelumab 2nd lineMay 2017

Pembrolizumab 1st-line cis ineligible May 2017

Pembrolizumab 2nd line May 2017

1974

1978

Doxorubicin

FDA approved

AtezolizumabFDA approved

2016

Evolution of Systemic Therapy for Urothelial Carcinoma

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Frontline Checkpoint Inhibition in Cisplatin Ineligible UC: Updates from Single-Arm Trials

Pembrolizumab (n = 370)KEYNOTE-52[1]

Atezolizumab (n = 119)IMvigor 210 Cohort 1[2]

Median follow up, mos 11.5 29

ORR, % 29 24

Median OS, mos 11.5 16.3

12 month OS, % 48 58

Pembrolizumab OS Atezolizumab OS100

80

60

40

20

00 4 8 12 16 20 24

MosPatients at Risk, n

370

28 32

283 223 173 147 86 38 11 11

OS

(%)

100

80

60

40

20

00 4 8 12 16 20 24

MosPatients at Risk, n

28 32

OS

(%)

36

1-yr OS: 58% (95% CI: 49-67)

2-yr OS: 41% (95% CI: 32-50)

Median OS: 16.3 mo (95% CI: 10.4-24.5)

1. Vuky J, et al. ASCO 2018. Abstract 4524. 2. Balar AV, et al. ASCO 2018. Abstract 4523.

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Decreased Survival in Patients With Low Levels of PD-L1 Using ICI Monotherapy

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PEMBROLIZUMAB:Clone: 22C3Combined positive score ≥10

the ratio of PD-L1–expressing tumor-infiltrating immune cells relative to the total number of tumor cells

ATEZOLIZUMAB:Clone: SP142staining on tumor-infiltrating immune cells covering at least ≥ 5%

PD-L1 Status Required in the Frontline Setting for Cisplatin Ineligible UC.

IHC PD-L1

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• Cisplatin Is Highly Active In This Space.

• Cisplatin-eligible Patients Should Get Cisplatin.

• Cisplatin-ineligible Patients Should Get Gemcitabine –Carboplatin Unless They Are PD-L1 Positive.

• Patients Inegligible For Any Chemotherapy Can Be Considered For Checkpoint Inhibitor Therapy Regardless Of PD-L1 Status

What We Know About First-line Treatment In Metastatic Bladder Cancer?

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SECOND-LINE (POST-PLATINUM) SYSTEMIC TREATMENT FOR METASTATIC UROTHELIAL CARCINOMA OF THE BLADDER

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FDA-Approved Checkpoint Inhibitors for UC

1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017. 3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018. 5. Pembrolizumab [package insert]. June 2018.

Agent Target Schedule FDA Approval Type by Setting

Post-Platinum Frontline Cisplatin Ineligible

Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated

Avelumab[2] PD-L1 Q2W Accelerated --

Durvalumab[3] PD-L1 Q2W Accelerated --

Nivolumab[4] PD-1 Q4W Accelerated --

Pembrolizumab[5] PD-1 Q3W Level 1 Accelerated

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KEYNOTE-045: Study Design• International, randomized, open-label phase III study

• Primary endpoints: OS, PFS

• Secondary endpoints: ORR, DoR, safety

Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.

Adult patients with predominantly transitional cell UC of the renal pelvis, ureter, bladder, or urethra; PD after

1-2 lines of platinum-based CT or recurrence < 12 mos after

perioperative platinum-based CT; ECOG PS 0-2

(N = 542)

Treatment continued for 2 yrs or until PD,

unacceptable toxicity, or withdrawal of consent

Pembrolizumab 200 mg IV Q3W

(n = 270)

Paclitaxel 175 mg/m2 IV Q3W or Docetaxel 75 mg/m2 IV Q3W orVinflunine 320 mg/m2 IV Q3W

(n = 272)

Stratified by ECOG PS (0/1 vs 2), Hg (< 10 vs ≥ 10 g/dL), liver

mets (yes vs no), and time since last CT (< vs ≥ 3 mos)

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Pembrolizumab

Chemotherapy

KEYNOTE-045: OS

270 194 147 116 98 67 23

272 171 109 73 58 35 13

44.4%30.3% 33.2%

19.7%

Median OS, Mos (95% CI)10.3 (8.0-12.3)

7.4 (6.3-8.3)

0 4 8 12 16 20 24 28 320

20

40

60

80O

S (%

)

Mos

100

Patients at Risk, n

de Wit R, et al. ESMO 2017. Abstract LBA37_PR.

Data cutoff: May 19, 2017

HR: 0.70 (0.57-0.86; P = .0003)

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Pembrolizumab

Chemotherapy

Median PFS, Mos (95% CI)2.1 (2.0-2.2)3.3 (2.4-3.5)

KEYNOTE-045: PFS

270 86 61 44 39 24 6

272 93 39 19 12 7 2

PFS

(%

)

MosPatients at Risk, n

17.8%9.3% 15.3%

4.8%

0 4

60

80

8 12 16 20 24 280

20

40

100

de Wit R, et al. ESMO 2017. Abstract LBA37_PR.

Data cutoff: May 19, 2017

HR: 0.96 (0.79-1.16; P = .32)

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Phase II Studies of Immune Checkpoint Inhibitors Leading to Accelerated Approval

Nivolumab[1]

Durvalumab[3]Avelumab[2]

OS

(%

)

100

80

60

40

20

00 3 6 9 12 15

Pts at Risk, n

(number censored)

All treated pts 265 (0) 198 (3) 148 (4) 63 (71) 5 (125) 0 (130)

All treated pts (n = 265)

Median OS: 8.74 mos

(95% CI: 6.05 to not reached)

100

80

60

40

20

0

OS

(%

)

0 3 6 9 12 151 2 4 5 7 8 1011 1413 161718

Mos Since Treatment Initiation

Pts at Risk, n 44 43 40 31 30 28 25 25 25 23 22 21 19 17 14 10 6 2 0

Median OS: 13.7 mos

(95% CI: 8.5 to NE)

Pro

ba

bil

ity o

f O

S

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27

Mos From First Dose

PD-L1 HighPD-L1

Low/NegativeTotal

Median OS, mos (95% CI)

20.0 (11.6-NE)

8.1 (3.1-NE)

18.2 (8.1-NE)

12-mo OS rate, % (95% CI)

63 (49-74) 41 (21-60) 55 (44-65)

Total (n = 191)

PD-L1 low/negative (n = 79)

PD-L1 high (n = 98)

1. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124. 3. Powles T, et al.

JAMA Oncol. 2017 Sep 14;3(9):e172411.

Overall population (n = 44)

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Post-Platinum Urothelial Carcinoma: ORR

CT: ~ 10%

1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124. 3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322.5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.

Atezolizumab[1]

OR

R (

%, 9

5%

CI)

Data from separate studies. Not head-to-head comparisons.

13.4 18.2 17.8 19.6 21.1

0

10

20

30

40

50

60

70

Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]

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Post-Platinum Urothelial Carcinoma: OS at 12 Mos

1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124. 3. O’Donnell P, et al. AACR 2018. Abstract CT031. 4. Sharma P, et al. AACR 2018. Abstract CT178. 5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.

CT: ~ 26%

Atezolizumab[1]

OS

(%, 9

5%

CI)

Data from separate studies. Not head-to-head comparisons.

39.2 54.3 46.6 40.3 43.9

0

10

20

30

40

50

60

70

Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]

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FIRST LINE(MANDATORY PD-L1 TESTING)

SECOND LINE(NO PD-L1 TESTING)

SETTING

REGIMEN

Cisplatin-eligible

Cisplatin-based CT

Cisplatin-ineligible

(PD-L1 high)

PD-1/PD-L1 blockadeCarboplatin-

based CT

Cisplatin-ineligible (PD-L1

low)CT-ineligible

Evolving Treatment in Advance Urothelial Carcinoma

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Post-Platinum Urothelial Carcinoma: Safety

1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124.3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.

Agent Phase Median F/U, Mos

Patients, n

Treatment-Related AEs, %

Any Grade 3/4 Death None

Atezolizumab[1] III 17.3 459 70 20 < 1 30

Avelumab[2] Ib 16.5 44 66 7 0 34

Durvalumab[3] I/II 5.78 191 61 7 1 39

Nivolumab[4] II 7.0 270 64 18 1 36

Pembrolizumab[5] III 14.1 266 61 15* 2 39

*Reported as grade 3-5.

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Immune-Related Toxicities

Organ System Reported Toxicities

Integumentary Hives, eczema, vitiligo, pemphigus, lichenoid reactions

Gastrointestinal Enterocolitis, pancreatitis, gastritis, celiac disease

Hepatic Autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis

Renal Interstitial nephritis, nephrotic syndrome, autoimmune nephropathy

Pulmonary Pneumonitis, interstitial lung disease, pleuritis

Cardiac Myocarditis, pericarditis, cardiomyopathy

Endocrine Hypo/hyperthyroidism, hypophysitis, adrenal insufficiency

NeurologicEncephalitis, Guillain-Barre syndrome, myasthenia gravis, mononeuritis, autoimmune

inner ear disease

HematologicHemolytic anemia, immune thrombocytopenic purpura, thrombotic thrombocytopenic

purpura, hemophilia, Evans syndrome

Rheumatologic Polyarthritis, systemic lupus erythematosus, antiphospholipid syndrome5th

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Select Any-Grade, Treatment-Related AEs Over Time

Weber JS, et al. J Clin Oncol. 2017;35:785-792.

SkinGIEndocrineHepaticPulmonaryRenal

Patients at Risk, nStill in studyStill receiving treatmentTotal with new eventStill in study with new event, %

45329823953

2811723412

1387643

26115

19

10300

9000

160

No

. of

Pati

ents

140

120

100

80

60

40

20

0

Wks Since Initiation of Nivolumab≤ 16 ≤ 32 ≤ 48 ≤ 64 ≤ 80 ≤ 96

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Most Immune-Related AEs Are Reversible With Immunosuppression/Steroids

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Wks

86420

Toxi

city

Gra

de

Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis

10 18 14

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PERIOPERATIVE SYSTEMIC THERAPY IN BLADDER CANCER

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Bladder Cancer: Spectrum of Disease

MedicalOncology

Localized: ~ 95% Metastatic: ~ 5%

NMIBC: 70%CIS, Ta, T1

MIBC: 30%T2-T4

Urology

The Past

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Bladder Cancer: Spectrum of Disease

MedicalOncology

Localized: ~ 95%

NMIBC: 70%CIS, Ta, T1

MIBC: 30%T2-T4

Urology

The Present

Metastatic: ~ 5%

RadiationOncology5t

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EORTC 30994: Immediate vs Deferred Adjuvant CT

• Improved PFS with immediate vs deferred adjuvant CT

Sternberg CN, et al. Lancet Oncol. 2015;16:76-86.

HR: 0.54 (95% CI: 0.40-0.73)P < .0001

Yrs Since Randomization

PFS

(%

)

DeferredImmediate

100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12

Patients at Risk, nDeferredImmediate

143141

5171

4557

3140

1821

435t

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EORTC 30994: No Impact in Overall Survival

• No difference in OS between arms

Sternberg CN, et al. Lancet Oncol. 2015;16:76-86.

HR: 0.78 (adjusted 95% CI: 0.56-1.08)P = .13

Yrs Since Randomization

OS

(%)

DeferredImmediate

100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12

Number at riskDeferredImmediate

143141

8395

6770

4244

2125

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Meta-analysis of Cisplatin-Based Adjuvant CT vs Surgery

Leow JJ, et al. Eur Urol. 2014;66:42-54.

OSStudy ID % WeightES (95 % CI)

9.838.61

12.3714.2210.576.35

61.95

11.0911.09

14.8312.1329.96

100

0.65 (0.34-1.25)0.74 (0.36-1.53)0.82 (0.48-1.39)0.75 (0.48-1.18)0.57 (0.31-1.05)1.11 (0.45-2.73)0.74 (0.58-0.94)

1.02 (0.57-1.83)1.02 (0.57-1.83)

1.29 (0.84-1.99)0.38 (0.22-0.65)0.71 (0.22-2.35)

0.77 (0.59-1.00)

Cisplatin-based combinations:BonoFreihaOttoSkinnerLehmannStadlerSubtotal (I2 = 0%; P = .880)Single agent cisplatin:StruderSubtotal (I2 = .%; P = .)Gemcitabine-cisplatin combinations:ItalianSpanishSubtotal (I2 = 91.8%; P = 0)

Overall (I2 = 46.5%; P = .060)

Favors Surgery AloneFavors Adjuvant Chemotherapy 1

NOTE: Weights are from random-effects analysis.

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SWOG-8710: Neoadjuvant CT Is Standard of Care for Muscle-Invasive Bladder Cancer

Grossman HB, et al. N Engl J Med. 2003;349:859-866.

Median OS Benefit: 2.6 yrs

MVAC + cystectomyCystectomy alone

Patients at Risk, nMVAC + cystectomyCystectomy alone

Survival EventMVAC +

Cystectomy(n = 153)

Cystectomy Alone

(n = 154)

Deaths, n 90 100

Median OS, mos

77 46

Surv

ival

(%

)

Mos After Randomization

0

20

40

60

80

100

0 24 48 72 96 120 144 168

153154

11288

9267

7550

4637

2318

675

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SO-E

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NCCN Guidelines: NAC ± RT is The SOC in Stage II-IIIA UC

Stage II and IIIA

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Cisplatin-Based Neoadjuvant CT

1. Dash A, et al. Cancer. 2008;113:2471-2477. 2. Tully CM, et al. ASCO GU 2014. Abstract 355. 3. Anari F, et al. Eur Urol Oncol. 2018;1:54-60. 4. Iyer G, et al. J Clin Oncol. 2018;36:1949-1956.5. Blick C, et al. Cancer. 2012;118:3920-3927. 6. Plimack ER, et al. J Clin Oncol. 2014;32:1895-1901.7. Choueiri TK, et al. J Clin Oncol. 2014;32:1889-1894.

CharacteristicGem/Cis[1]

(n = 42)Gem/Cis[2]

(n = 154)DD Gem/Cis[3]

(n = 31)DD Gem/Cis[4]

(n = 46)AMVAC[5]

(n = 80)AMVAC[6]

(n = 40)DD MVAC[7]

(n = 39)

Study type Retrospective Retrospective Prospective Prospective Retrospective Prospective Prospective

Cycles, n 4 4 3 6 3-4 3 4

Wks, n 12 12 6 12 6-8 6 8

pCR (pT0), % 26 21 32 15 43 38 26

PR (< pT2), % 36 46 45 57 ~ 61 53 49

Median days from CT start to surgery

138 120 65 ~ 114+ 75 68 ~ 98

Grade 3/4 AEs, % NR NR 35 37 27 18 10

Progression free at 2 yrs, %

64 ~ 68 ~ 68 ~ 76 65 78 ~ 47

Alive at 2 yrs,* % 73 ~ 75 ~ 77 ~ 87 77 83 ≤ 80

*vs 58% with cystectomy alone.

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CharacteristicPembrolizumab

(n = 43)[1]Atezolizumab

(n = 68)[2]

Eligibility criteria T2-T3b; N1 allowed T2-T4a; N0 only

Cisplatin eligible, % 100 0

Received neoadjuvant CT, %

12 0

Duration of neoadjuvant checkpoint inhibition

3 cycles (9 wks) 2 cycles (6 wks)

Safe Yes Yes

Pathological CR (pT0), % 40 29

Available biomarker data Yes Yes

Neoadjuvant Checkpoint Inhibition in Bladder Cancer: Early Results of Phase II Trials

1. Necchi A, et al. ASCO 2018. Abstract 4507. 2. Powles T, et al. ASCO 2018. Abstract 4506.

Encouraging results; long-term outcomes needed before clinical use

pT0 Rates With CT:

Gem/Cis,15% to 32%

DD MVAC,26% to 43%

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RETAIN BLADDER: Risk-Adapted Treatment After Neoadjuvant CT for Bladder Cancer

• Single-arm, open-label phase II trial

• Primary endpoint: metastasis-free survival at Yr 2

Geynisman DM, et al. ASCO GU 2018. Abstract TPS537. ClinicalTrials.gov. NCT02710734.

Adult patients with primary urothelial or

predominantly urothelial

carcinoma of the bladder, cT2-4a N0M0 disease,

ECOG PS 0-2(N = 38)

TURBT 1

AMVAC x 3

TURBT 2

*Any alteration in ATM, RB1, FANCC, ERCC2.†Patient and physician choice.

No residual tumor/cT0 AND

mutation* positive

≥ cT3

cT2

Activesurveillance

Intravesicle txor chemo-RT

or cystectomy†

Cystectomy

Chemo-RTor cystectomy†

cTa or cTis or cT1 or positive cytology

OR cT0 and mutation* negative

Immunotherapy

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CONCLUSIONS• Urothelial Carcinoma is a Chemosensitive Disease.

• Cisplatin-Ineligible Patients Represents a Poor-Risk Prognostic Group: InmuneCheckpoint Inhibitors (hopefully) Can Change The Natural History of The Disease.

• Neoadjuvant Chemotherapy ± RT is the Standard of Care in Stage II and IIIA bladder cancer.

• ICI are Moving from Second-Line/Post-Platinum Systemic Treatment to NeoadjuvantSetting.

• Better Biomarkers for Response to ICI and Chemotherapy are needed.5th E

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THANKS FOR YOUR ATTENTION!

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