Yohann Loriot - BiennaleCancerologieIMvigor 210, a Phase II trial of Atezolizumab (MPDL3280A) in...
Transcript of Yohann Loriot - BiennaleCancerologieIMvigor 210, a Phase II trial of Atezolizumab (MPDL3280A) in...
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.
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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
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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
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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