la realidad de la inmunoterapia en el tratamiento de 1ª y 2ª línea del cáncer de ... ·...

La realidad de la inmunoterapia en el

tratamiento de 1ª y 2ª línea

del cáncer de vejiga

• Daniel Castellano • Oncología Médica. Unidad de Tumores Genito-Urinarios

• Hospital Universitario 12 de Octubre. • I + 12 Research Institute

Outline

Rationale for immunotherapy in urothelial cancer

PD-L1/PD-1 inhibitors in urothelial cancer

Bladder cancer

Antoni et al. Eur Urol 2017;71:96–108. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30.

Major cause of morbidity and mortality worldwide

430,000 new cases and 165,000 deaths per year

First-line randomised trials in

advanced transitional cell carcinoma

Better patient selection, earlier diagnosis and screening, better supportive care (growth factors)

Author Treatment N RR (%) MDS (months) Best arm

Loehrer MVAC CDDP

126 120

39 12

12.5 8.2

MVAC > CDPP

Logothetis MVAC CISCA

65 55

65 46

12.6 10.0

MVAC > CISCA

Von der Maase MVAC GC

202 203

46 49

14.8 13.8

MVAC ~ GC

Sternberg HD-MVAC + G-CSF

MVAC

134 129

62 50

14.5 14.1

HD-MVAC ≥ MVAC

Bamias MVAC + GCSF

DC + GCSF

109 111

54 37

14.2 9.3

MVAC > DC

Dreicer MVAC PC

44 41

36 28

15.4 13.8

MVAC > PC

Bellmunt PCG GC

312 315

57.1 46.4

15.7 12.8

PCG ~ GC

Phase III trial of vinflunine + BSC vs BSC

*The eligible population excludes 13 patients who presented at least one major protocol violation at baseline

Bellmunt et al. J Clin Oncol 2009;27:4454–61; Bellmunt et al. Ann Oncol 2013;24:1466–72

OS in the eligible population*

Time (months)

0

Ove

rall

su

rviv

al (p

rob

ab

ilit

y)

VFL + BSC

BSC

25 10 35 30 20 0 15 5

OS in the ITT population

Time (months)

0

Ove

rall

su

rviv

al (p

rob

ab

ilit

y)

VFL + BSC

BSC

25 10 35 30 20 0 15 5

1.0

0.8

0.6

0.2

0.4

1.0

0.8

0.6

0.2

0.4

Median OS (ITT)

6.9 months with VFL + BSC (n=253)

versus

4.6 months with BSC (n=117)

HR=0.88 (log rank p=0.2868)

Median OS (eligible)

6.9 months with VFL + BSC (n=249)

versus

4.3 months with BSC (n=108)

HR=0.78 (log rank p=0.0403)

ESMO Guidelines for diagnosis, treatment

and follow-up

Bellmunt et al. Ann Oncol 2014;25 Suppl 3:iii40–8

Patients with poor comorbid status

or impaired renal function ‘unfit’

Management of

metastatic disease

PS ≤2 plus

poor renal function

Carboplatin-based regimens

or single-agents: taxane,

gemcitabine

Cisplatin-based

combination chemotherapy

(e.g. MVAC, GC, HDMVAC, PCG)

Clinical trial

Best supportive care

Progression <12 months

Second-line chemotherapy

1. Vinflunine

2. Taxane-based

3. Clinical trial

Progression >12 months

1. Platinum-based

rechallenge

First line

• FIT → CISPLATIN-based combination

• UNFIT → CARBOPLATIN-based regimen

Subsequent lines

• Vinflunine

• Taxane-based

• Platinum rechallenge

0.01

0.1

10

100

1,000

1

High mutational load in bladder cancer

Lawrence et al. Nature 2013;499:214–8

Bladder tumours along with other malignancies such as lung and melanoma display a high number

of somatic mutations rendering these tumours more immunogenic

So

mati

c m

uta

tio

n

freq

uen

cy (

/Mb

)

n=22 20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121

Rhabdoid

tum

our

Ew

ing s

arc

om

a

Th

yro

id

AM

L

Medullo

bla

sto

ma

Carc

inoid

Neuro

bla

sto

ma

Pro

sta

te

CLL

Low

-gra

de g

liom

a

Bre

ast

Pancre

as

Multip

le m

yelo

ma

Kid

ney c

lear

cell

Kid

ney

papill

ary

cell

Ovaria

n

Glio

bla

sto

ma

multiform

e

Cerv

ical

DLB

CL

Head a

nd n

eck

Colo

recta

l

Oesophageal

adenocarc

inom

a

Sto

mach

Bla

dder

Lung a

deno

-

carc

inom

a

Lung s

quam

ous

cell

carc

inom

a

Mela

nom

a

1. Zehir et al. Nat Med 2017;23:703-713

Mutational Burden (13,8 mut./Mb)

So

mati

c m

uta

tio

n b

urd

en

(mu

t/M

b)

1

5

10

50

100

200 300

500

Germ

cell

tum

ou

r

Soft

-tis

sue

sarc

om

a

Pro

sta

te c

an

cer

Thyro

id c

an

cer

Bili

ary

can

cer

Ovari

an

can

cer

Ren

al cell

carc

ino

ma

Pan

cre

atic c

an

cer

Bre

ast carc

ino

ma

He

ad

an

d n

eck

ca

rcin

om

a

Glio

ma

Esop

ha

gogastr

ic

carc

ino

ma

End

om

etr

ial can

cer

Non

-sm

all-

cell

lun

g c

an

cer

Colo

recta

l can

cer

Mela

nom

a

Bla

dd

er

can

cer

High mutational burden in bladder cancer

Immune Response Is Regulated by a Balance of

Co-stimulation and Co-inhibition Acting at Different Steps

Adapted from Mellman I, et al. Nature. 2011;480(7378):480-489.

T cell

CTLA-4

PD-1

TIM-3 BTLA VISTA LAG-3

CD28

OX40

GITR CD137 CD27 HVEM

T-cell activation or

inhibition

Inhibitory

receptors

Activating

receptors +

CD8 T cell Tumour cell

MHC

PD-L1

- - -

PD-L2 PD-1

- - -

Tumor antigen

TCR

PD-1

+ + +

Expression of PDL-1 on tumour cells

and macrophages suppresses

immune surveillance and

permits neoplastic growth

Programed cell death receptor 1 (PD-1)

is a negative co stimulatory receptor

expressed primarily on activated T cells

PD-L/PD-1 binding prevents inhibits effector

T cell function: T cell break

Melanoma4

Ovarian5

Lung cancer3

SCCHN3

Bladder2 Breast1

PD-L1 Is Expressed in a Range of Tumor Types

Reprinted from J Transl Med. 14:173. Sun WY, Lee KY, Koo JS, Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies, © Sun WY, Lee KY, Koo JS 2016.

Adapted by permission from Macmillan Publishers Ltd: Nature Rev Cancer Topalian SL, et al. Nat Rev Cancer. 2016; 16:275-287, Copyright 2016.

1. Sun WY, et al. J Transl Med. 2016;14:173. 2. Massard C, et al. J Clin Oncol. 2016;34(suppl): Abstract 4502. 3. Rebelatto MC, et al. J Clin Oncol.

2015;33(suppl): Abstract 8033. 4. Topalian SL, et al. Nat Rev Cancer. 2016; 16:275-287. 5. Darb-Esfahani S, et al. Oncotarget. 2015;7:1486-1499.

Examples of tumor types with strong PD-L1 staining (≥10% of cells):

Adapted from Oncotarget 7(2) Darb-Esfahani S, et al.

Prognostic impact of programmed cell death-1 (PD-1)

Pages 1486-1499,2016 Impact Journals, LLC.

1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 1996 2017

Evolution of systemic therapy for urothelial cancer

BLA, Biologics License Application

http://www.accessdata.fda.gaov/scripts/cder/drugsatfda/index.cfm; http://www.ema.europa.eu/ema/

1. Sternberg et al. Cancer 1989;64:2448–58; 2. McCaffrey et al. J Clin Oncol 1997;15:1853–7

3. von der Maase et al. J Clin Oncol 2005;23:4602–8; 4. Sternberg et al. J Clin Oncol 2001;19:2638–46

5. Vaughn et al. J Clin Oncol 2002;20:937–40; 6. Bellmunt et al. J Clin Oncol 2009;27:4454–61

7. Rosenberg et al. Lancet 2016;387:1909–20; 8. Balar et al. Lancet 2017;389:67–76

9. Sharma et al. Lancet Oncol 2017; doi: 10.1016/S1470-2045(17)30065-7

10. Bellmunt et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1613683

11. Balar et al. J Clin Oncol 2017;35(suppl 6S):Abstract 284

Pu

blic

ati

on

s

Re

gu

lato

ry s

tatu

s Cisplatin

FDA

approval

1978

Gemcitabine

EU approval

Vinflunine

EU approval

Atezolizumab

FDA approval prior platinum

18 May 2016

Atezolizumab

FDA BLA 1L cis-ineligible

09 January 2017

Docetaxel2

Standard MVAC1

1989

HD-MVAC4

Paclitaxel5

Vinflunine6

Atezolizumab

(prior platinum)7

Gemcitabine

+ cisplatin3

Pembrolizumab

(prior platinum)10

Nivolumab

(prior platinum)9

Atezolizumab

(1L cis-ineligible)8

Durvalumab

FDA BLA prior platinum

09 December 2016

Nivolumab

FDA approval prior platinum

02 February 2017

Pembrolizumab

FDA BLA 1L cis-ineligible

AND prior platinum

03 February 2017

Avelumab

FDA BLA prior platinum

28 February 2017

Pembrolizumab

(1L cis-ineligible)11

Immunotherapy in urothelial cancer:

what compounds?

PD-L1 inhibitors

Atezolizumab

Durvalumab

Avelumab

PD-1 inhibitors

Nivolumab

Pembrolizumab


what compounds?

Prior platinum 1L cis-ineligible

PD-L1 inhibitors

Atezolizumab N=932 (phase III) N=119

Durvalumab N=103

Avelumab N=153

PD-1 inhibitors

Nivolumab N=270

Pembrolizumab N=542 (phase III) N=370

1. Rosenberg et al. Lancet 2016;387:1909–20; 2. Powles et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 286

3. Patel et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 330; 4. Sharma et al. Lancet Oncol 2017; doi: 10.1016/S1470-2045(17)30065-7

5. Bellmunt et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1613683; 6. Balar et al. Lancet 2017;389:67–76


Powles T, et al. Nature. 2014;515(7528):558-562.

IMvigor210 Cohort 2: study design

• Co-primary endpoints

‒ ORR (confirmed) per RECIST v.1.1 (central independent review)

‒ Investigator-assessed ORR per modified RECIST

‒ Primary endpoints met if null hypothesis (ORR of 10%) rejected at significance level

(α) of 5%

• Key secondary endpoints

‒ PFS, DOR, OS, safety

• Data previously published in The Lancet1, longer follow-up presented at ESMO 20162

(21.0 months vs 11.7 months)

IRF, independent review facility. ClinicalTrials.gov ID: NCT02108652 aPD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded bCockcroft-Gault formula

1. Rosenberg et al. Lancet 2016;387:1909–20; 2. Loriot et al. Ann Oncol 2016;27(suppl_6):783P

Cohort 2 (N=310):

Platinum-treated mUC

Atezolizumab 1,200mg IV q3w

until loss of clinical benefit

Cohort 1 (N=119):

1L cisplatin ineligible


until RECIST v1.1 progression

• Inoperable locally advanced

or metastatic urothelial

carcinoma

• Predominantly UC histology

• Tumour tissue evaluable for

PD-L1 testinga

IMvigor210 Cohort 2: ORR

IRF, independent review facility

Median follow-up: 21.0 months; data cut-off: July 4, 2016

Loriot et al. Ann Oncol 2016;27(suppl_6):783P

• Median treatment duration was 12 weeks (range, 0 to 104)

– 137 patients were treated beyond RECIST v1.1 progression

• Durable clinical benefit also observed

– Disease control rate (IRF RECIST v1.1 CR + PR + SD ≥24 weeks) of 21%

(95% CI, 17% to 26%) in all patients

IC2/3

(n=100)

IC1/2/3

(n=207)

All

patients

(N=310)

IC1

(n=107)

IC0

(n=103)

ORR per IRF RECIST v1.1a, %

(95% CI)

28

(19, 38)

19

(14, 25)

16

(12, 20)

11

(6, 19)

9

(4, 16)

CR rate per IRF RECIST v1.1, %

(95% CI)

14

(8, 22)

8

(5, 13)

6

(4, 9)

3

(1, 8)

2

(0, 7)

ORR per immune-modified

RECISTb, % (95% CI)

29

(20, 39)

24

(18, 30)

20

(15, 25)

19

(12, 27)

12

(6, 19)

IMvigor210 Cohort 2: overall survival

Median follow-up: 21.0 months; data cut-off: July 4, 2016

Loriot et al. Ann Oncol 2016;27(suppl_6):783P

0

20

40

60

80

100

Ove

rall

su

rviv

al (%

)

0 4 8 12

Time (months)

16 20 24

IC0/1

(n=210)

IC2/3

(n=100)

All

patients

(N=310)

Median OS, months

(95% CI) 6.7

(5.4, 8.0)

11.9

(9.0, NE)

7.9

(6.7, 9.3)

12-month OS rate, %

(95% CI) 31

(24, 37)

50

(40, 60)

37

(31, 42)

Number at risk

All patients 310 265 203 176 146 126 110 99 91 79 70 23 2

CheckMate 275: study design and objectives

NCT02387996

Sharma et al. Lancet Oncol 2017; doi: 10.1016/S1470-2045(17)30065-7

• Primary endpoint: ORR based on blinded independent review committee (BIRC)

(RECIST v1.1) evaluation in all patients and in patients with tumour PD-L1 expression

≥1% and ≥5%

Open-label, single-arm, phase II study

• Metastatic or locally

advanced mUC

• Disease progression on a

prior platinum-based

therapy

• Evaluable PD-L1 tumor

tissue sample

Treat until progression

or

unacceptable toxicity

Nivolumab

3mg/kg IV q2w

N=270

Blinded independent review committee

(BIRC) assessment of response using

RECIST v1.1

Treatment Patients

CheckMate 275: overall survival

*Similar results were seen using the 5% PD-L1 tumour expression cut-off

Sharma et al. Lancet Oncol 2017; doi: 10.1016/S1470-2045(17)30065-7

Time (months)

OS

es

tim

ate

1.0

0.8

0.4

0.0 0 3 15 6 9

0.6

0.2

Median OS, months (95% CI)*

All treated 8.74 (6.05–NR)

PD-L1 <1% 5.95 (4.30–8.08)

PD-L1 ≥1% 11.30 (8.74–NR)

12

ORR and median OS in all patients were 19.6% and 8.7 months

Number at risk

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

• Co-primary endpoints: OS and PFS in total and PD-L1 CPS ≥10% populations

• Secondary endpoints: ORR and DOR in total and PD-L1 CPS ≥10% populations;

safety in total population

• Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra

• Transitional cell predominant

• PD after 1–2 lines of platinum-based chemotherapy or recurrence within 12 months of perioperative platinum-based therapy

• ECOG PS 0–2

• Provision of tumour sample for biomarker assessment

N=542

Paclitaxel 175mg/m2 IV q3w

or docetaxel 75mg/m2 IV q3w

or vinflunine 320mg/m2 IV q3w

R

Pembrolizumab 200 mg IV q3w

NCT02256436

Bellmunt et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1613683

KEYNOTE-045: study design and objectives

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 months)

Enrollment

Nov 2014-Nov 20151

Data cutoff: Sept 7, 2016

Median duration of

follow-up: 14.1 months

Bellmunt J et al. NEJM 20171

Data cutoff: May 19, 2017

Median duration of

follow-up: 22.5 months

de Wit R et al. ESMO 20173

Q4

2015 2016 2017 2014

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Data cutoff: October 26, 2017

Median follow-up: 27.7 months

1. Bellmunt J et al. N Engl J Med. 2017;376:1015-1026. 2. Bajorin DF et al. J Clin Oncol. 2017;35(suppl 15):4501. 3. de Wit R et al. Ann Oncol. 2017;28(suppl 5):v605-v649.

KEYNOTE-045 Trial Follow-Up Data cutoff: Jan 18, 2017

Median duration of follow-up:

18.5 months

Bajorin DF et al. ASCO 20172

n (%)

Age, median (range), y

Men

Pembro

(N = 270)

67 (29-88)

200 (74.1)

Chemo

(N = 272)

65 (26-84)

202 (74.3)

Upper tract disease 38 (14.1) 37 (13.6)

232 (85.9) 235 (86.4) Lower tract disease

ECOG PSa

0 120 (44.4) 106 (39.0)

1

2

Visceral disease

Disease in lymph

node only

142 (52.6)

3 (1.1)

241 (89.3)

28 (10.4)

158 (58.1)

4 (1.5)

235 (86.4)

37 (13.6)

n (%)

Liver metastases

Hemoglobin <10 g/dLb

Pembro

(N = 270)

91 (33.7)

43 (15.9)

Chemo

(N = 272)

95 (34.9)

44 (16.2)

Time since completion of most recent prior therapy

≥3 months

<3 months

167 (61.9)

103 (38.1)

168 (61.8)

104 (38.2)

Setting of most recent prior therapy

Neoadjuvant

Adjuvant

First line

Second line

Third line

19 (7.0)

12 (4.4)

184 (68.1)

55 (20.4)

0

22 (8.1)

31 (11.4)

158 (58.1)

59 (21.7)

2 (0.7)

Baseline Characteristics

aMissing for 5 patients in the pembrolizumab arm and 4 patients in the chemotherapy arm. bMissing for 7 patients in the pembrolizumab arm and 4 patients in the chemotherapy arm.

Data cutoff date: October 26, 2017.

n (%)

Pembro

(N = 270)

Chemo

(N = 272)

Prior platinum therapy

199 (73.7)

70 (25.9)

1 (0.4)

214 (78.7)

56 (20.6)

2 (0.7)

Cisplatin

Carboplatin

Othera

Smoking statusb

Never Former Current

PD-L1 CPS ≥10%

104 (38.5) 136 (50.4) 29 (10.7)

74 (27.4)

83 (30.5) 148 (54.4) 38 (14.0)

90 (33.1)

n (%)

Pembro

(N = 270)

Chemo

(N = 272)

Risk Factorsc

0

1

2

3-4

54 (20.0)

96 (35.6)

66 (24.4)

45 (16.7)

45 (16.5)

97 (35.7)

80 (29.4)

45 (16.5)

Baseline Characteristics

aOxaliplatin, nedaplatin. bMissing for 1 patient in the pembrolizumab arm and 3 patients in the chemotherapy arm. cIncludes Bellmunt risk factors of ECOG performance status >0,

hemoglobin level <10 g/dL, and liver metastases (J Clin Oncol. 2010;27:1850-1855) + time from prior chemotherapy <3 months (Eur Urol. 2013;63:717-723). Missing for 8 patients in the pembrolizumab arm and 5 patients in the chemotherapy arm. Data cutoff date: October 26, 2017.

OS

, %

Overall Survival: Total 14.1 months of follow-up1

Median (95% CI): 10.3 months (8.0–12.3)

7.3 months (6.1–8.1)

Chemo 272 173 109 73 58 41 33 18 4 0 0 aBased on Cox regression model with treatment as a covariate stratified by ECOG performance status (0/1 vs 2), liver metastases (yes vs no), hemoglobin (<10 vs ≥10 g/dL), and time from completion of chemotherapy (<3 vs ≥3 months). bOne-sided P value based on stratified log-rank test. Data cutoff date: October 26, 2017. 1. Bellmunt J et al. N Engl J Med. 2017;376:1015-1026.

No. at risk

0 4 8 12 28 32 36 40

0

20

100 80 60 40

16 20 24 Time, months

44.4% 29.8%

27.0% 14.3%

Pembro 270 194 147 116 80 67 32 6 0 0 98

Pb

0.0022 Pb

0.00017

Pembro

Chemo Pembro

Chemo

HR (95% CI)a Events, n

155 0.73 (0.59-0.91) 179 27.7 months of follow-up

Events, n HR (95% CI)a

199 0.70

218 (0.57–0.85)

60.6% at 24 months in the chemotherapy arm

received an immunotherapeutic agent,

including those who received pembrolizumab

as part of the cross over.

Rem

ain

ing

In

Res

po

nse

, %

Pa

tien

ts, %

(9

5%

CI)

10 5 0

15

20

30 25

Pembrolizumab

N = 270

Chemotherapy

N = 272

21.1%

11.0%

9.3%

(7.0%)

11.9%

(14.1%)

2.9%

(3.3%)

8.1%

Objective Response Rates

CR

PR

0 6 12 18 24 30 36

40 20 0

60

100 80

Time, months

Pembro Chemo

57 30

46 8

35 5

32 5

1 0

0 0

13 2

Time to Response, median (range) Duration of Response, median (range)

Pembro Chemo

2.1 mo (1.4-6.3)

2.1 mo

(1.7-4.9)

NR (1.6+ to 30.0+ mo)

4.4 mo

(1.4+ to 29.9+)

Objective Response and Response Duration

Assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: October 26, 2017.

AEs, adverse events

Data cutoff date: October 26, 2017

Patients, %

5 10 15 20 25 30 35 40

Pruritus

Fatigue

Nausea

Decreased appetite

Diarrhea

Asthenia

Anemia

Constipation

Peripheral sensory neuropathy

Peripheral neuropathy

Decreased neutrophils

Neutropenia

Alopecia

Grade 1-2

Grade 3-5

Patients, %

0 0 5 10 15 20 25 30 35 40

Pruritus

Fatigue

Nausea

Decreased appetite

Diarrhea

Asthenia

Anemia

Constipation

Peripheral sensory neuropathy

Peripheral neuropathy

Decreased neutrophils

Neutropenia

Alopecia

Grade 1-2

Grade 3-5

Pembrolizumab Chemotherapy

Treatment-Related AEs Occurring in ≥10% of pts

aOf patients in either treatment arm. 7.5% febrile neutropenia in the chemotherapy arm. Data cutoff date: October 26, 2017.

Atezolizumab

1200 mg q 3 w

Investigator’s Choice

Paclitaxel 175 mg/m2 q 3 w/

Docetaxel 75 mg/m2 q 3 w/

Vinflunine 320 mg/m2 q 3w

IMvigor211: Atezolizumab vs Chemotherapy

for Post-Platinum Advanced UC • An open-label, 2-arm, randomized phase III trial

Treated until PD

unacceptable AE, or investigator decision Treated until PD or

unacceptable AE

Patients with metastatic or locally advanced UC after

recurrence or progression

following platinum-based

chemotherapy;

ECOG PS 0-1; evaluable

tumor tissue for

PD-L1 testing

(N = 932)

▪ Primary endpoints: OS

▪ Secondary endpoints: ORR, PFS, safety, pharmacokinetics UC, urothelial cancer

National Institutes of Health. http://clinicaltrials.gov/ct2/show/ NCT02302807. Accessed November 23, 2017.

IMvigor211: Overall Survival for IC2/3 Population

Atezolizumab Chemotherapy

Events /

Patients 72/116 88/118

Median OS (95% CI) 11.1 months (8.6, 15.5) 10.6 months (8.4, 12.2)

12-Month OS

Rate (95% CI) 46% (37, 56) 41% (32,50)

IC, immune cell

Powles T, et al. Abstract presented at: EACR-AACR-SIC Special Conference 2017; June 24-27, 2017: Florence, Italy. Abstract 606.

IMvigor211: Overall Survival for ITT Population

Atezolizumab Chemotherapy

Events /

Patients 324/467 350/464

Median OS (95% CI) 8.6 months (7.8, 9.6) 8.0 months (7.2, 8.6)

12-Month OS

Rate (95% CI) 39% (35,44) 32% (28, 37)

Median follow-up duration in ITT population:

17.3 months (range, 0 to 24.5 months)


All Cause Treatment-Related

AE, n(%) All Grade AEs Grade 3 or 4 AEs Grade 5 AEs All Grade AESIs Grade 3 or 4 AESIs Grade 5 AESIs SAEs AEs leading to treatment disc AEs leading to dose modification, delay, or intertuption

Atezolizumab (N = 459) 438 (95%) 233 (51%) 17 (4%) 139 (30%) 37 (8%) 0 188 (41%) 34 (7%) 134 (29%)

Chemo (N = 443) 435 (98%) 249 (56%) 18 (4%) 98 (22%) 13 (3%) 1 (<1%) 191 (43%) 78 (18%) 210 (47%)

Atezolizumab (N = 459) 319 (70%) 91 (20%) 1 (1%) - - - 72 (16%) 16 (3%) -

Chemo (N = 443) 395 (89%) 189 (43%) 8 (2%) - - - 110 (25%) 63 (14%) -

• Rates of treatment-related AEs and AEs leading to discontinuation (any cause)

were numerically lower in the atezolizumab arm AESI, adverse event of special interest; SAE, serious adverse event


IMvigor211: Safety Summary

Durvalumab and avelumab in prior platinum urothelial

cancer: summary of antitumour activity

N=103

Confirmed ORR, % (95% CI) 17.8

(13.1, 29.5)

CR, % 3.9

1. Powles et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 286

2. Patel et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 330

Durvalumab1

Median duration of follow-up, 8.4 months

PD-L1-high expression defined as ≥25% of tumour cells (TCs) or immune cells (ICs) staining for PD-L1; PD-L1-low/negative expression

defined as <25% of both TCs and ICs staining for PD-L1

Avelumab2

N=153

Confirmed ORR, % (95% CI) 17.6

(12.0, 24.6)

CR, % 5.9

Clinical cut-off, 19 March 2016. Median duration of follow-up, 7.3 months


what compounds?

Prior platinum 1L cis-ineligible

PD-L1 inhibitors

Atezolizumab N=310 N=119

Durvalumab N=103

Avelumab N=153

PD-1 inhibitors

Nivolumab N=270

Pembrolizumab N=542 (phase III) N=370

1. Rosenberg et al. Lancet 2016;387:1909–20; 2. Powles et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 286

3. Patel et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 330; 4. Sharma et al. Lancet Oncol 2017; doi: 10.1016/S1470-2045(17)30065-7

5. Bellmunt et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1613683; 6. Balar et al. Lancet 2017;389:67–76


Galsky MD, et al. Lancet Oncol. 2011;12(3):211-214.

Patients meeting at least one of the following are considered ‘unfit’

• WHO or ECOG performance status of 2, or Karnofsky performance

status of 60%-70%

• Creatinine clearance (calculated or measured) less than 1 mL/s

• CTCAE version 4, grade 2 or above audiometric hearing loss

• CTCAE version 4, grade 2 or above peripheral neuropathy

• NYHA class III heart failure

30%-50% of metastatic patients are ineligible (‘unfit’) for cisplatin

CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology Group; NYHA, New York Heart Association; WHO, World Health Organization

Consensus Definition of Patients With Metastatic Urothelial Carcinoma Who are Unfit for Cisplatin-Based Chemotherapy

IMvigor210 Cohort 1: study design

Primary endpoint

• Confirmed ORR: RECIST v1.1 (per central IRF)

Key secondary endpoints

• DOR, PFS, OS, safety

IRF, independent review facility. ClinicalTrials.gov ID: NCT02108652. aPD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded bCockcroft-Gault formula

Balar et al. Lancet 2017;389:67–76

Cohort 2 (N=310):

Platinum-treated mUC


until loss of clinical benefit

Cohort 1 (N=119):

1L cisplatin ineligible


until RECIST v1.1 progression

• Inoperable locally advanced

or metastatic urothelial

carcinoma

• Predominantly UC histology

• Tumour tissue evaluable for

PD-L1 testinga

IMvigor210 Cohort 1: efficacy Response to atezolizumab (IRF RECIST v1.1)

• Durable clinical benefit also observed

‒ Disease control rate (CR + PR + SD ≥ 24 weeks) of 30% (95% CI, 22% to 39%)

in all patients

• With a median follow-up of 17.2 months, median DOR was not yet reached in any

PD-L1 subgroup (median DOR range, 3.7 to 21.0 months), and 70% of responses

were ongoing

aIncludes 19 patients with missing/unevaluable responses. All treated patients had measurable

disease at baseline per investigator-assessed RECIST v1.1. PD-L1 IC status: IC2/3 (≥5%),

IC1 (≥1% and <5%), IC0 (<1%). Data cut-off: 14 March 2016


IC2/3

(n=32)

IC1/2/3

(n=80)

All patients

(N=119)

IC1

(n=48)

IC0

(n=39)

ORRa, %

(95% CI)

28

(14, 47)

24

(15, 35)

23

(16, 31)

21

(10, 35)

21

(9, 36)

CR, % 13 10 9 8 8

IMvigor210 Cohort 1: efficacy Overall survival (median and landmark 12-month OS)

Data cut-off: 4 July 2016


0 0

20

40

60

80

100

4 8 12

Time (months)

Ove

rall

su

rviv

al (%

)

16 20 24

Subgroup Median OS (95% Cl) 12-month OS (95%

Cl)

All (N=119) 15.9 months (10.4,

NE)

57% (48–66)

IC0/1

(n=87)

19.1 months (9.8,

NE)

59% (48–70)

IC2/3

(n=32)

12.3 months (6.0,

NE)

52% (35–70)

Number at risk

All patients 310 265 203 176 146 126 110 99 91 79 70 23 2

Pembrolizumab as first-line therapy in eldery patients with poor performance

status with cisplatin-ineligible advanced urothelial cancer: results from

KEYNOTE-052

Daniel Castellano,1 Petros Grivas,

2 Elizabeth Plimack,

3 Arjun V. Balar,

4 Peter H. O’Donnell,

5 Joaquim Bellmunt,

6 Thomas Powles,

7 Noah Hahn,

8

Ronald de Wit,9 Dean Bajorin,

10 Misoo Chung Ellison,

11 Tara Frenkl,

11 Stephen M. Keefe,

11 Jaqueline Vuky

12

1Hospital Universitario 12 de Octubre, Madrid, Spain; 2Cleveland Clinic, Cleveland, OH, USA; 3Fox Chase Cancer Center, Philadelphia, PA, USA; 4Perlmutter Cancer Center,

NYU Langone Medical Center, New York, NY, USA; 5The University of Chicago Medical Center, Chicago, IL, USA; 6Dana-Farber Cancer Institute, Boston, MA, USA; 7Barts

Cancer Institute, Queen Mary University of London, London, United Kingdom; 8Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; 9Erasmus MC Cancer Institute, Rotterdam, Netherlands; 10Memorial Sloan Kettering Cancer Center, New York, NY, USA; 11Merck & Co., Inc., Kenilworth, NJ, USA; 12Oregon

Health & Science University, Portland, OR, USA

Results, Safety, and Conclusions

Age Age/ECOG PS 2

n (%)

≥65

n =

302

≥75

n =

179

≥65

ECOG

2

n =

119

≥75

ECOG

2

n = 78

Total

Populati

on

n = 370

Treatment-

related AE,

any grade

204

(68)

122

(68) 70 (59) 50 (64) 243 (66)

Treatment-

related AE,

grades 3-5

59

(20)

33

(18) 24 (20) 15 (19) 70 (19)

7%

22%

0

5

10

15

20

25

30

35

40

45

50

CR

PR

29%

7%

22%

27%

5%

22%

29%

6%

24%

32%

6%

26%

29%

OR

R,

% (

95

% C

I)

≥65 years

(n=302)

≥65 years

ECOG PS 2

(n=119)

≥75 years

(n=179)

≥75 years

ECOG PS 2

(n=78)

Age/ECOG PS 2

Subgroups

Age Subgroups

Total

Population

(N=370)

• First-line pembrolizumab elicits clinically meaningful responses in

cisplatin-ineligible, senior patients with advanced urothelial cancer

consistent with those of the overall study population

• No new safety signals for pembrolizumab were identified, and the

safety profile was consistent in senior patients, including those with

poor performance status

• Pembrolizumab provides a new treatment option for patients with

advanced urothelial cancer who may not tolerate any chemotherapy

Objective Response Rate Safety

Conclusions

Open Questions

• How to identify responders?

• When and how long should we treat patients?

• How should we give ICI for frail patients?

• How to explain resistance and to overcome resistance?

ICI, immune checkpoint inhibitor

Biomarker PD-L1 on IC PD-L1 on TC T CD8 infiltration

CD8 expression

CXCL9 / CXCL10

expression Mutational load

Assay

IHC dako kit (22C3 clone)

IHC Ventana (SP263) IHC dako kit (22C3 clone)

IHC dako kit (28-8)

IHC Ventana (SP263) IHC

Gene expression Gene expression Exome sequencing

Endpoint 1% of cell stained

25% of cell stained 1% of cell stained

1% vs 5% of cell s.

25% of cell stained High vs low High vs low Number of

mutations/megabase

Drug Pembrolizumab

durvalumab Pembrolizumab

Nivolumab

durvalumab Atezolizumab

Nivolumab Nivolumab atezolizumab

Results Higher expression associated with response

Higher expression associated with response Higher expression associated with response

Higher expression associated with response

Higher expression associated with response High T CD8 infiltration associated with response

High CD8 expression associated with response High expression associated with response High mutation load associated with response

TCGA classification Gene expression Luminal vs basal

Atezolizumab

nivolumab

Luminal 2 associated with better response to

atezolizumab

Basal 1 associated with better response to nivolumab

INF-ɣ signature TCR sequencing

25 gene expression

DNA sequencing of the

CDR3 region of the TCR

beta chain

High vs low

Clonal dominance, clonal

expansion and T-cell

fraction

nivolumab atezolizumab

Better response to nivolumab

high T cell infiltration and clonality in the tumor plus

peripheral expansion of dominant tumor-resident TCR

clones associated with response

No biomarker validated so far

Key Biomarkers Currently Assessed in UC to

Predict Response to PD-1 or PD-L1 Blockade

Ongoing First-Line Trials

IMvigor130 (NCT02807636) • 1L cisplatin-ineligible, locally

advanced/metastatic

• ECOG PS ≤2 N = 1200 Co-primary endpoints: PFS and OS DANUBE (NCT02516241) • 1L unresectable stage IV

• Eligible / ineligible for

cisplatin-based chemotherapy N = 1004 Primary endpoint: OS KEYNOTE-361 (NCT02853305)

• 1L unresectable or metastatic

• ECOG PS ≤2 N = 990 Co-primary endpoints: PFS and OS

R R R

Atezolizumab Platinum based chemo +

atezolizumab

Cisplatin + gemcitabine or

carboplatin + gemcitabine Durvalumab + tremelimumab Durvalumab Cisplatin + gemcitabine or

carboplatin + gemcitabine Pembrolizumab + cisplatin/gemcitabine or

Pembrolizumab + carboplatin/gemcitabine Pembrolizumab Cisplatin + gemcitabine or

carboplatin + gemcitabine

Ongoing First-Line Trials

R

CHECKMATE 901 (NCT03036098) • Metastatic urothelial cancer

• Unfit or fit patients

• No chemotherapy in metastatic setting

N = 897

• Metastatic urothelial cancer

• CR, PR, SD upon 4-6 platinum-based

chemotherapy

N = 668

Primary endpoint: OS; secondary endpoints: PFS, ORR, DOR, Safety

R

Nivolumab Nivolumab + chemotherapy SOC Platinum-based chemotherapy

Avelumab SOC: BSC

Primary endpoint: OS and PFS in unfit patients; secondary endpoints: OS in all patients, ORR, safety JAVELIN (NCT002603432)

Estimated completion: 2020

SOC, standard of care

Future Strategies for Immunotherapy

• Targeting several immune checkpoints

• Enhancing neoantigen expression

• Combination with targeted therapies, chemo, or IR

• Targeting T-cell metabolism and microenvironnement

• Reprogramming host microbiome

• Use earlier

IR, ionizing radiation

• Immune checkpoint inhibitors approved in both first- and second-line therapy

• Level 1 evidence for pembrolizumab in second-line

• No data from randomized trials in first-line to date

• ~20% achieved response with PD-1/PD-L1 inhibitors

• Many combinations currently investigated

Conclusions

• BACKUP

Ph

ase

I/II

Durvalumab + tremelimumab

Ongoing Second-Line Trials D4190C00010 (NCT02261220) • Progression or recurrence of urothelial

cancer following a first-line platinum-

containing regimen

Durvalumab

N = 167

Primary endpoints: Safety; Secondary Endpoints: ORR, PFS, DOR, and OS STRONG (NCT03084471) • Progression or recurrence of urothelial

cancer following At least one first-line

platinum-containing regimen R

Durvalumab + tremelimumab Durvalumab

urothelial cancer following a first-

line platinum-containing regimen

• PD-1 and PD-L1–naive

N = 110

Durvalumab + AZD4547 Durvalumab + olaparib

Primary endpoints: Safety; secondary endpoints ORR and PFS

R

• Urothelial and non-urothelial N = 1200 Primary endpoint: Safety; Secondary endpoint: OS

BISCAY (NCT03084471) •Progression or recurrence of

Control

FGFR3 mut DDR+

Somatic DNA

Sequence

Ph

ase

I/II

Ongoing Second-Line Trials CHECKMATE-032 (NCT01928394)1

Ipilimumab 1 mg/kg

Nivolumab 3 mg/kg

R

• Progression or recurrence of urothelial cancer following a first-line

platinum-containing regimen

N = 196

• or recurrence


• No more than 2 prior lines of systemic chemotherapy

N = 1500

R

Primary endpoint: Safety; secondary endpoints: ORR, OS, PFS, and quality of life MK3475-698 (NCT03084471)

Pembrolizumab Pembrolizumab + epacadostat

• Progression or recurrence of urothelial cancer following a first-line


• PD-1 and PD-L1 naive

N = 1200

R

Nivolumab 1 mg/kg

Ipilimumab 3 mg/kg

Nivolumab 3 mg/kg

ORR = 26.5%

ORR = 38.5%

mPFS = 4.3m

mOS = 10.2m ORR = 26%

mPFS = 2.6m mOS = 7.3

1. Sharma P, et al. Presented at: SITC 2016; November 9-13,

2016: National Harbor, Maryland, United States. Abstract 449.

n = 78

n = 26 n = 104

Atezolizumab Estimated timelines

Estimated completion: May 2022

Primary endpoint: OS; Secondary endpoints: PFS and safety

Primary endpoint: ORR; secondary endpoints PFS and safety

SAUL Study Design (NCT02256436)

Progression (NCT02516241) of urothelial

cancer following a first-line

Baseline 08/2014

PS 1

Back pain

PR 11/2014

PS 0 PR 01/2015 CR 03/2015

Hospital 12 de Octubre: IMvigor 210 STUDY

MB: 62-year-old male with Stage IV TCC and extensive RP

lymph node mts after adjuvant GC, paclitaxel-carbo,

vinflunine, gemcitabine alone and anthracycline based-CT.

Atezolizumab 1.200mg q3w initiated on study on September 2014

(> 40 cycles)

Excellent tolerance

Adverse events: G1 flu-like syndrome, and G1-2 asthenia.

CM: 68-year-old female with metastatic TCC after

GC and vinflunine

Courtesy C. Sternberg/ San Camilo Hospital: CheckMate 275

Nivolumab 3mg/kg q2w initiated on study on July 2015

July 2015 September 2015 April 2016

MB: 62-year-old female with Stage IV TCC with lung

and liver and bladder cancer after GC

Courtesy C. Sternberg/ San Camilo Hospital: KEYNOTE-045

Pembrolizumab 200mg q3w initiated on study on 30 June 2015

June 2015 December 2016 October 2015

MB: 62-year-old female with Stage IV TCC with lung

and liver and bladder cancer after GC

San Camilo Hospital: KEYNOTE-045

Pembrolizumab 200mg q3w initiated on study on 30 June 2015

June 2015 December 2016 October 2015

75-year-old male with upper tract UCC and bone, liver and

LN mts after nephroureterectomy + lymphadenectomy

Hospital 12 de Octubre: KEYNOTE-052

Pembrolizumab 200mg q3w initiated on study on September 2015

Baseline 09/2015

PS 2

Cis-inelegible

CR 09/2016

PS 0

24 cycles

Excellent

tolerance

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