Immunotherapy and urothelial carcinoma. Yohann Loriot

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1 Immunotherapy and urothelial carcinoma Yohann Loriot

2 Immunothérapie en clinique : Cancers de vessie Où en sommes nous? Données phase I/II FDA «breakthrough designation» Prochaines étapes?

3 Immunothérapie en clinique : Cancers de vessie Où en sommes nous? Données phase I/II FDA «breakthrough designation» Prochaines étapes?

4 Phase I Atezolizumab - Bladder Cancer

5 Phase I Atezolizumab - Bladder Cancer 1. Activité clinique 2. Potentiel biomarqueur IHC 3. Profil de tolérance

6 Pembrolizumab - Bladder Cancer 1. Activité clinique 2. Potentiel biomarqueur IHC 3. Profil de tolérance

7 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. Rosenberg 18 1 Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 2 Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 3 Netherlands Cancer Institute, Amsterdam, Netherlands; 4 Division of Hematology/Oncology, University of Virginia, Charlottesville VA USA; 5 Gustave Roussy, Villejuif, France; 6 Urologische Klinik und Poliklinik, Technische Universität München, Munich, Germany; 7 US Oncology Research/Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 8 Clinica Universidad de Navarra, Pamplona, Spain; 9 Norton Cancer Institute, Louisville, KY, USA; 10 USL8 Ospedale San Donato, Arezzo, Italy; 11 University of Washington and Seattle Cancer Care Alliance, Seattle, WA, USA; 12 Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA; 13 Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA; 14 USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 15 Yale Cancer Center, New Haven, CT, USA; 16 University of Liverpool, Clatterbridge Cancer Centre, Liverpool, UK; 17 Genentech, Inc, South San Francisco, CA, USA; 18 Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7

8 Phase II IMvigor 210 Study of Atezolizumab in muc IMvigor 210 muc Tumor sample for PD-L1 testing a Cohort 1 UNFIT N = 119 Cohort 2 N = 310 Progression during/ following platinum (no restrictions on # prior lines of therapy) ECOG PS 0-1 CrCl 30 ml/min Atezolizumab 1200 mg IV q3w until loss of benefit 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: NCT Hoffman-Censits et al. IMvigor 210, 2016

9 IMvigor 210 Cohort 2: Patient Flowchart Screened (n = 486) Enrolled a (n = 316) Excluded (n = 170) b Brain metastasis (n = 26) ECOG PS2 (n = 22) Inadequate hematologic and end-organ function (n = 18) Other (n = 104) Received treatment (N = 311) a 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) Treated patients: c Europe 26% United States/Canada 73% Safety/efficacy evaluable: N = 310 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 reassessments 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

10 IMvigor 210 Cohort 2: Patient Population 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 sites a 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% Hoffman-Censits et al. IMvigor 210, 2016

11 IMvigor 210: Responses to Atezolizumab IC2/3 (n = 100) IC1/2/3 (n = 207) All (N = 310) IC1 (n = 107) IC0 (n = 103) ORR (95% CI) per confirmed IRF RECIST v1.1 26% (18, 36) 18% (13, 24) 15% (11, 19) 10% (5, 18) 8% (3, 15) Higher ORR was associated with higher PD-L1 IHC status, but responses were seen in all PD-L1 subgroups 11

12 IMvigor 210: Responses to Atezolizumab IC2/3 (n = 100) IC1/2/3 (n = 207) All (N = 310) IC1 (n = 107) IC0 (n = 103) ORR (95% CI) per confirmed IRF RECIST v1.1 26% (18, 36) 18% (13, 24) 15% (11, 19) 10% (5, 18) 8% (3, 15) ORR (95% CI) per investigator mrecist 27% (19, 37) 22% (16, 28) 19% (15, 24) 17% (10, 25) 13% (7, 21) Higher ORR was associated with higher PD-L1 IHC status, but responses were seen in all PD-L1 subgroups 12

13 IMvigor 210: Responses to Atezolizumab IC2/3 (n = 100) IC1/2/3 (n = 207) All (N = 310) IC1 (n = 107) IC0 (n = 103) ORR (95% CI) per confirmed IRF RECIST v1.1 26% (18, 36) 18% (13, 24) 15% (11, 19) 10% (5, 18) 8% (3, 15) ORR (95% CI) per investigator mrecist 27% (19, 37) 22% (16, 28) 19% (15, 24) 17% (10, 25) 13% (7, 21) Complete response (CR) per confirmed IRF RECIST v1.1 11% 6% 5% 2% 2% Higher ORR was associated with higher PD-L1 IHC status, but responses were seen in all PD-L1 subgroups

PD-L1 status IC2/3 IC1 IC0 ORR b 26% 10% 8% Reduction in tumor burden was associated with

14 Mean SLD Reduction From Baseline, % IMvigor 210: Change in Tumor Burden by PD-L1 Subgroup 100 a aa aa 52/85 (61%) Response Assessments b 40/88 (45%) 25/84 (30%) PD-L1 status IC2/3 IC1 IC0 ORR b 26% 10% 8% Reduction in tumor burden was associated with PD-L1 status 117/257 patients with tumor assessments (46%) had SLD reductions PD SD PR CR Unknown

15 SLD Change From Baseline, % IMvigor 210: Duration of Response to Atezolizumab Patients with CR or PR per IRF RECIST v IC2/3 IC1 IC Time on Study, weeks Discontinued New lesion Responses were durable, with mdor not reached in any PD-L1 subgroup (range, 2.0+ to 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)

16 IMvigor 210: Subgroup Analysis by Prognostic Factors Subgroup IRF RECIST v1.1 by baseline characteristic 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% 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, Hoffman-Censits et al. IMvigor 210, 2016

Progression-Free Survival IMvigor 210: Progression-free Survival in muc 100 80 60 40 20 0 IC2/3 IC0/1 + Censored 0 PFS per IRF RECIST v1.1 2 4 6 8 10 12 14 No.

17 Progression-Free Survival IMvigor 210: Progression-free Survival in muc IC2/3 IC0/1 + Censored 0 PFS per IRF RECIST v No. at Time, months Risk: IC2/3: IC0/1: Median PFS (95% CI) IC2/3 n = 100 IC0/1 n = 210 Per confirmed IRF RECIST v1.1 6-month PFS (95% CI) Median PFS (95% CI) 2.1 mo (2.1, 4.1) 30% (21, 39) At risk: mo (2.0, 2.1) 17% (12, 22) At risk: 34 Per investigator mrecist 4.0 mo (2.6, 5.9) 2.2 mo (2.1, 3.2) All n = mo (2.1, 2.1) 21% (17, 26) At risk: mo (2.1, 3.9) Median follow-up: 11.7 mo (range, 0.2+ to 15.2 mo) Hoffman-Censits et al. IMvigor 210, 2016

Overall Survival IMvigor 210: Overall Survival in muc 100 IC2/3 n = 100 IC0/1 n = 210 All N = 310 80 Median OS (95% CI) 11.4 mo (9.0, NE) 6.7 mo (5.4, 8.0) 7.9 mo (6.6, 9.

2 mo) 20 0 IC2/3 IC0/1 + Censored 0 2 4 6 8 10 12 14 No.

18 Overall Survival IMvigor 210: Overall Survival in muc 100 IC2/3 n = 100 IC0/1 n = 210 All N = Median OS (95% CI) 11.4 mo (9.0, NE) 6.7 mo (5.4, 8.0) 7.9 mo (6.6, 9.3) 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) 20 0 IC2/3 IC0/1 + Censored No. at Time, months Risk: IC2/3: IC0/1: mos appears longer in pts with higher PD-L1 IC status 12-mo OS compares favorably with estimates of 20% in a 2L-only setting 1 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) Hoffman-Censits et al. IMvigor 210, 2016

19 AE (N = 310) IMvigor 210: Safety Summary All Cause Treatment Related Any Grade 97% 69% Serious AEs 48% 11% Grade % 16% Grade 5 a 1% 0% Immune-mediated AEs 7% AEs leading to withdrawal from atezolizumab AEs leading to dose modification/interruption 4% N/A 30% N/A 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 Hoffman-Censits et al. IMvigor 210, 2016

20 Immunothérapie en clinique : Cancers de vessie Où en sommes nous? Données phase I/II FDA «breakthrough designation» PHASE III vs Chimiothérapie en >2 e ligne

21 Immunothérapie en clinique : Cancers de vessie Où en sommes nous? Données phase I/II FDA «breakthrough designation» PHASE III vs Chimiotherapie en >2 e ligne Prochaines étapes?

$Réfractaire au BCG 2 nde line Pembrolizumab/BCG Platinum-resistant Pembrolizumab (Phase III) MDPL3280A (Phase III) MEDI4736 AMP-514$

22 Current/futur clinical trials in UC Non-Muscle Invasive Bladder Cancer Localised Muscle invasive Bladder Cancer Metastatic Bladder Cancer 1 ère ligne Low Grade High Grade neoadjuvant Adjuvant fit unfit Pembrolizumab/BCG MPDL3280A Maintenance Pembrolizumab MDPL3280A Réfractaire au BCG 2 nde line Pembrolizumab/BCG Platinum-resistant Pembrolizumab (Phase III) MDPL3280A (Phase III) MEDI4736 AMP-514 MSB C MGA271 Nivolumab ± ipilimumab Nivolumab/cabozatinib ± ipilimumab Pembrozilumab/radiation MDPL280A + Bevacisumab MEDI MEDI4730

$fit unfit Pembrolizumab/BCG MPDL3280A Maintenance Pembrolizumab MDPL3280A Réfractaire au BCG 2 nde line Pembrolizumab/BCG Platinum-resistant Pembrolizumab (Phase III) MDPL3280A (Phase III) MEDI4736$

23 Current/futur clinical trials in UC Non-Muscle Invasive Bladder Cancer Localised Muscle invasive Bladder Cancer Cancer de la vessie métastatique 1 ère ligne Low Grade High Grade neoadjuvant Adjuvant fit unfit Pembrolizumab/BCG MPDL3280A Maintenance Pembrolizumab MDPL3280A Réfractaire au BCG 2 nde line Pembrolizumab/BCG Platinum-resistant Pembrolizumab (Phase III) MDPL3280A (Phase III) MEDI4736 AMP-514 MSB C MGA271 Nivolumab ± ipilimumab Nivolumab/cabozatinib ± ipilimumab Pembrozilumab/radiation MDPL280A + Bevacisumab MEDI MEDI4730

24 Current/futur clinical trials in UC Non-Muscle Invasive Bladder Cancer Localised Muscle invasive Bladder Cancer Cancer de la vessie métastatique 1 ère ligne Low Grade High Grade neoadjuvant Adjuvant fit unfit Pembrolizumab/BCG MPDL3280A Maintenance Pembrolizumab MDPL3280A Réfractaire au BCG 2 nde line Pembrolizumab/BCG Platinum-resistant Pembrolizumab (Phase III) MDPL3280A (Phase III) MEDI4736 AMP-514 MSB C MGA271 Nivolumab ± ipilimumab Nivolumab/cabozatinib ± ipilimumab Pembrozilumab/radiation MDPL280A + Bevacisumab MEDI MEDI4730

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:

25 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)

26 Gustave Roussy Genito-Urinary Group

Disclosure. Astellas. Research funding. Advisory board (to institute) Roche/Genentech Astra Zeneca/Medimmune Astellas

Disclosure. Astellas. Research funding. Advisory board (to institute) Roche/Genentech Astra Zeneca/Medimmune Astellas Disclosure Activity Company Research funding Advisory board (to institute) Astellas Roche/Genentech Astra Zeneca/Medimmune Astellas Immunotherapy for urothelial cell carcinoma A NEW HOPE Michiel van der