Immunotherapy and urothelial carcinoma

Yohann Loriot

Immunothérapie en clinique : Cancers de vessie

• Où en sommes nous?

– Données phase I/II

FDA « breakthrough designation »

• Prochaines étapes?

Immunothérapie en clinique : Cancers de vessie

• Où en sommes nous?

– Données phase I/II

FDA « breakthrough designation »

• Prochaines étapes?

Phase I Atezolizumab - Bladder Cancer

Phase I Atezolizumab - Bladder Cancer

1. Activité clinique 2. Potentiel biomarqueur IHC 3. Profil de tolérance

Pembrolizumab - Bladder Cancer

1. Activité clinique 2. Potentiel biomarqueur IHC 3. Profil de tolérance

IMvigor 210, a Phase II trial of Atezolizumab (MPDL3280A) in Platinum-treated Locally

Advanced or Metastatic Urothelial Carcinoma (mUC)

Jean Hoffman-Censits,1 Petros Grivas,2 Michiel S. van der Heijden,3 Robert Dreicer,4 Yohann Loriot,5 Margitta Retz,6 Nicholas J. Vogelzang,7 Jose Luis Perez-Gracia,8

Arash Rezazadeh Kalebasty,9 Sergio Bracarda,10 Evan Y. Yu,11 Christopher Hoimes,12 Joaquim Bellmunt,13 David I. Quinn,14 Daniel P. Petrylak,15 Syed A. Hussain,16 Na Cui,17 Sanjeev

Mariathasan,17 Oyewale Abidoye,17 Jonathan E. Rosenberg18

1Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 2Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 3Netherlands Cancer Institute, Amsterdam, Netherlands; 4Division of Hematology/Oncology, University of Virginia, Charlottesville VA USA; 5Gustave Roussy, Villejuif, France; 6Urologische Klinik und Poliklinik, Technische Universität München, Munich, Germany; 7 US Oncology Research/Comprehensive Cancer Centers of Nevada,

Las Vegas, NV, USA; 8Clinica Universidad de Navarra, Pamplona, Spain; 9Norton Cancer Institute, Louisville, KY, USA; 10USL8 Ospedale San Donato, Arezzo, Italy; 11University of Washington and Seattle Cancer Care Alliance, Seattle, WA, USA; 12Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA;

13Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA; 14USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA;

15Yale Cancer Center, New Haven, CT, USA; 16University of Liverpool, Clatterbridge Cancer Centre, Liverpool, UK; 17Genentech, Inc, South San Francisco, CA, USA; 18Memorial Sloan Kettering Cancer Center, New York, NY, USA.

7

Phase II IMvigor 210 Study of Atezolizumab in mUC

• Co-primary endpoints: (1) ORR per confirmed RECIST v1.1 and central IRF (2) ORR per investigator-assessed modified RECIST

• Key secondary endpoints: DOR, PFS, OS, safety

IC, tumor-infiltrating immune cell; IRF, independent review facility. a Patients and investigators blinded to PD-L1 IHC status. Trial enrolled an all-comer population with a minimum of 100 IC2/3 patients. Trial Identifier: NCT02108652

Hoffman-Censits et al. IMvigor 210, 2016

Cohort 1 UNFIT N = 119

Atezolizumab 1200 mg IV q3w

until loss of benefit

• Progression during/ following platinum (no restrictions on # prior lines of therapy)

• ECOG PS 0-1

• CrCl ≥ 30 mL/min

Cohort 2 N = 310

IMvigor 210

•mUC

•Tumor sample for PD-L1 testinga

IMvigor 210 Cohort 2: Patient Flowchart

a Based on May 5, 2015 data cut. Two cohort 2 patients and one cohort 1 patient were re-assigned to the alternate cohort based on eligibility reassess- ments between the May 5 and September 14, 2015 data cuts (enrolled and treated n’s based on September data cut are 315 and 310, respectively).

b Includes rescreened patients. c Excludes 1 patient with unknown site.

Hoffman-Censits et al. IMvigor 210, 2016

Screened (n = 486)

Enrolleda (n = 316)

Still on therapy (n = 62) Discontinued treatment (n = 248) • Progression of disease (n = 211) • Adverse event (n = 13) • Withdrawal by subject (n = 9) • Other (n = 15)

Excluded (n = 170)b

• Brain metastasis (n = 26) • ECOG PS2 (n = 22) • Inadequate hematologic and

end-organ function (n = 18) • Other (n = 104)

Treated patients:c

• Europe 26% • United States/Canada 73%

Safety/efficacy evaluable: N = 310

Received treatment (N = 311)a

IMvigor 210 Cohort 2: Patient Population

Hoffman-Censits et al. IMvigor 210, 2016

Baseline Characteristics: Safety- and Efficacy-Evaluable Patients N = 310

Age, median (range) 66 y (32-91 y)

Male 78%

Site of primary tumor: bladder 74%

Creatinine clearance < 60 mL/min 36%

ECOG PS 1 62%

Hb < 10 g/dL 22%

Prior cystectomy 37%

Visceral / liver metastatic sitesa 78% / 31%

Prior platinum:

Cisplatin-based regimen / carboplatin and no other platinum 73% / 26%

Prior systemic regimen setting, (neo)adjuvant / metastatic 19% / 81%

2 regimens for metastatic disease 21%

≥ 3 regimens for metastatic disease 20%

PD-L1 IC status: IC2/3 / IC1 / IC0 32% / 35% / 33%

IMvigor 210: Responses to Atezolizumab

Higher ORR was associated with higher PD-L1 IHC status, but responses were seen in all PD-L1 subgroups

11

IC2/3 (n = 100)

IC1/2/3 (n = 207)

All (N = 310)

ORR (95% CI) per confirmed IRF RECIST v1.1

26% (18, 36)

18% (13, 24)

15% (11, 19)

IC1 (n = 107)

IC0 (n = 103)

10% (5, 18)

8% (3, 15)

IMvigor 210: Responses to Atezolizumab

Higher ORR was associated with higher PD-L1 IHC status, but responses were seen in all PD-L1 subgroups

12

IC2/3 (n = 100)

IC1/2/3 (n = 207)

All (N = 310)

ORR (95% CI) per confirmed IRF RECIST v1.1

26% (18, 36)

18% (13, 24)

15% (11, 19)

ORR (95% CI) per investigator mRECIST

27%

(19, 37)

22%

(16, 28)

19%

(15, 24)

IC1 (n = 107)

IC0 (n = 103)

10% (5, 18)

8% (3, 15)

17%

(10, 25)

13%

(7, 21)

IMvigor 210: Responses to Atezolizumab

IC2/3 (n = 100)

IC1/2/3 (n = 207)

All (N = 310)

ORR (95% CI) per confirmed IRF RECIST v1.1

26% (18, 36)

18% (13, 24)

15% (11, 19)

ORR (95% CI) per investigator mRECIST

27%

(19, 37)

22%

(16, 28)

19%

(15, 24)

Complete response (CR) per confirmed IRF RECIST v1.1

11% 6% 5%

IC1 (n = 107)

IC0 (n = 103)

10% (5, 18)

8% (3, 15)

17%

(10, 25)

13%

(7, 21)

2% 2%

Higher ORR was associated with higher PD-L1 IHC status, but responses were seen in all PD-L1 subgroups

IMvigor 210: Change in Tumor Burden by PD-L1 Subgroup

• Reduction in tumor burden was associated with PD-L1 status

• 117/257 patients with tumor assessments (46%) had SLD reductions

IC2/3

IC1

IC0

52/85 (61%)

40/88 (45%)

PD-L1 status

26%

10%

8%

ORRb

PD SD PR CR Unknown

Response Assessmentsb

aa

a

Mea

n S

LD R

edu

ctio

n F

rom

Bas

elin

e, %

100

0

‒100 aa 100

0

‒100

100

0

‒100

25/84 (30%)

IMvigor 210: Duration of Response to Atezolizumab

• Responses were durable, with mDOR not reached in any PD-L1 subgroup (range, 2.0+ to 13.7+ mo)

• Ongoing responses were seen in 38 of 45 responding patients (84%)

• Median follow-up time: 11.7 mo (range, 0.2+ to 15.2 mo)

50

0

‒100

0 9 18 27 36 45 54 63

Time on Study, weeks

SLD

Ch

ange

Fr

om

Bas

elin

e, %

0 9 18 27 36 45 54 63 0 9 18 27 36 45 54 63

IC2/3 IC0 IC1

♦ Discontinued ▲ New lesion

Patients with CR or PR per IRF RECIST v1.1

IMvigor 210: Subgroup Analysis by Prognostic Factors

• 41% of IMvigor 210 patients had ≥ 2 prior regimens, limiting the comparability to historical 2L chemotherapy trials

• Poor baseline prognostic factors did not preclude responses to atezolizumab

– Responses were durable: mDOR not reached in any pre-defined prognostic subgroup

Data cutoff: September 14, 2015.

Subgroup IC2/3 (n = 100) All (N = 310)

n ORR (95% CI) CR n ORR (95% CI) CR

≥ 4 prior systemic regimens for mUC 10% 20% (3, 56) 10% 8% 8% (1, 27) 4%

Visceral metastatic sites 66% 17% (9, 28) 3% 78% 10% (6, 14) 1%

Liver metastatic sites 27% 11% (2, 29) 0% 31% 5% (2, 12) 0%

Lymph node–only metastatic sites 24% 33% (16, 55) 29% 14% 30% (17, 46) 23%

ECOG PS 1 58% 14% (6, 25) 5% 62% 8% (5, 13) 3%

Hb < 10 g/dL 24% 21% (7, 42) 0% 22% 7% (2, 16) 0%

Hoffman-Censits et al. IMvigor 210, 2016

IRF RECIST v1.1 by baseline characteristic

No. at

Risk:

IC2/3: 100 76 42 30 24 22 8 1

IC0/1: 210 132 55 34 29 20 7 1

IMvigor 210: Progression-free Survival in mUC

Hoffman-Censits et al. IMvigor 210, 2016

IC2/3 n = 100

IC0/1 n = 210

All n = 310

Per confirmed IRF RECIST v1.1

Median PFS (95% CI)

2.1 mo (2.1, 4.1)

2.1 mo (2.0, 2.1)

2.1 mo (2.1, 2.1)

6-month PFS

(95% CI)

30% (21, 39)

At risk: 30

17% (12, 22)

At risk: 34

21% (17, 26)

At risk: 64

Per investigator mRECIST

Median PFS (95% CI)

4.0 mo (2.6, 5.9)

2.2 mo (2.1, 3.2)

2.7 mo (2.1, 3.9)

Median follow-up: 11.7 mo (range, 0.2+ to 15.2 mo)

PFS per IRF RECIST v1.1 100

80

60

40

20

0

6 8 10 2 4

Pro

gres

sio

n-F

ree

Surv

ival

0

Time, months

– IC2/3 – IC0/1 + Censored

12 14

No. at

Risk:

IC2/3: 100 92 74 67 58 50 23 2

IC0/1: 210 173 128 107 87 64 24 2

IMvigor 210: Overall Survival in mUC

Hoffman-Censits et al. IMvigor 210, 2016

• mOS appears longer in pts with higher PD-L1 IC status

• 12-mo OS compares favorably with estimates of ≈ 20% in a 2L-only setting1

– In 124 pts who had only 1 prior line of therapy for mUC and no prior (neo)adjuvant therapy:

• mOS (IC2/3): NE (95% CI: 9.3, NE)

• mOS (entire 2L population): 9.0 months (95% CI: 7.1, 10.9)

IC2/3 n = 100

IC0/1 n = 210

All N = 310

Median OS (95% CI)

11.4 mo (9.0, NE)

6.7 mo (5.4, 8.0)

7.9 mo (6.6, 9.3)

12-mo OS (95% CI)

48% (38, 58)

At risk: 23

30% (23, 36)

At risk: 24

36% (30, 41)

At risk: 47

Median follow-up: 11.7 mo (range, 0.2+ to 15.2 mo) Ove

rall

Surv

ival

– IC2/3 – IC0/1 + Censored

6 8 10 2 4 0 12 14

100

80

60

40

20

0

Time, months

IMvigor 210: Safety Summary

• Median treatment duration 12 wks (range, 0 to 66 wks)

– Median of 5 doses (range, 1 to 23 doses)

• Atezolizumab was well tolerated with no treatment-related deaths

– AE profile was consistent across IC populations

AE (N = 310) All

Cause

Treatment Related

Any Grade 97% 69%

Serious AEs 48% 11%

Grade 3-4 55% 16%

Grade 5a 1% 0%

Immune-mediated AEs 7% —

AEs leading to withdrawal from atezolizumab

4% N/A

AEs leading to dose modification/interruption

30% N/A

Hoffman-Censits et al. IMvigor 210, 2016

Immunothérapie en clinique : Cancers de vessie

• Où en sommes nous?

– Données phase I/II

FDA « breakthrough designation »

PHASE III vs Chimiothérapie en >2e ligne

Immunothérapie en clinique : Cancers de vessie

• Où en sommes nous? – Données phase I/II

FDA « breakthrough designation »

PHASE III vs Chimiotherapie en >2e ligne

• Prochaines étapes?

Non-Muscle Invasive Bladder Cancer

Localised Muscle invasive Bladder Cancer

Metastatic Bladder Cancer

Low Grade High Grade

Réfractaire au BCG

Pembrolizumab/BCG

Pembrolizumab/BCG

neoadjuvant Adjuvant fit unfit

Maintenance

Platinum-resistant

• Pembrolizumab • MDPL3280A

• Pembrolizumab (Phase III) • MDPL3280A (Phase III) • MEDI4736 • AMP-514 • MSB0010718C • MGA271

• Nivolumab ± ipilimumab • Nivolumab/cabozatinib ±

ipilimumab • Pembrozilumab/radiation • MDPL280A + Bevacisumab • MEDI0680 + MEDI4730

2nde line

1ère ligne

Current/futur clinical trials in UC

MPDL3280A

Cancer de la vessie métastatique

Low Grade High Grade

Réfractaire au BCG

Pembrolizumab/BCG

Pembrolizumab/BCG

neoadjuvant Adjuvant fit unfit

Maintenance

Platinum-resistant

• Pembrolizumab • MDPL3280A

• Pembrolizumab (Phase III) • MDPL3280A (Phase III) • MEDI4736 • AMP-514 • MSB0010718C • MGA271

• Nivolumab ± ipilimumab • Nivolumab/cabozatinib ±

ipilimumab • Pembrozilumab/radiation • MDPL280A + Bevacisumab • MEDI0680 + MEDI4730

2nde line

1ère ligne

Current/futur clinical trials in UC

MPDL3280A

Non-Muscle Invasive Bladder Cancer

Localised Muscle invasive Bladder Cancer

Cancer de la vessie métastatique

Low Grade High Grade

Réfractaire au BCG

Pembrolizumab/BCG

Pembrolizumab/BCG

neoadjuvant Adjuvant fit unfit

Maintenance

Platinum-resistant

• Pembrolizumab • MDPL3280A

• Pembrolizumab (Phase III) • MDPL3280A (Phase III) • MEDI4736 • AMP-514 • MSB0010718C • MGA271

• Nivolumab ± ipilimumab • Nivolumab/cabozatinib ±

ipilimumab • Pembrozilumab/radiation • MDPL280A + Bevacisumab • MEDI0680 + MEDI4730

2nde line

1ère ligne

Current/futur clinical trials in UC

MPDL3280A

Non-Muscle Invasive Bladder Cancer

Localised Muscle invasive Bladder Cancer

Vessie

PD1/PD-L1 va devenir le traitement standard de seconde ligne prochainement

L’expression de PD-L1 expression est predictive de l’efficacité

Future étapes:

• Première ligne

• Combinaison à la chimio

• Place en péri opératoire:

• Adjuvant: Phase III

• Neoadjuvant: phase II

• Place dans les TVNIM (tumeurs de vessie non infiltrant le muscle)

Gustave Roussy Genito-Urinary Group