Checkpointinhibitoren in der Uro-Onkologie. Carsten Grüllich

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1 Checkpointinhibitoren in der Uro-Onkologie Carsten Grüllich

2 T-cell Aktivierung und Regulation T cell Costimulation Recognition MHC I Peptide b2m mrna Tumorantigen Tumor Pardoll Nature Rev Cancer 12, 2012

3 PD-1 Rezeptorsättigung Nierenzellkarzinom Phase I Anti-PD-1 Beispiel Ansprechen Rezeptorsättigung vs.dosis Vor Behandlung 6 Monate Dosis Topalian, N Engl J Med 366, 2012

4 % der Patienten Nivolumab Phase I (CA ) Bestes Ansprechen Mario Sznol, zusammengefasste Daten

5 Mittleres Überleben Nierenkarzinomphase I Studie

6 Nivolumab (RCC) Randomize a 1:1:1 CA : Randomized, Dose-Ranging Phase II Trial of Nivolumab for Metastatic Renal Cell Carcinoma (mrcc) Key Criteria mrcc with clear-cell component 1 prior antiangiogenic agent 1 3 prior therapies Disease progression after last therapy and within 6 months of enrollment KPS 70% Adequate organ function Arm 1 0,3 mg/kg nivolumab IV Q3 weeks Arm 2 2 mg/kg nivolumab IV Q3 weeks Arm 3 10 mg/kg nivolumab IV Q3 weeks Treat until progression or intolerable toxicity Treatment arms blinded Primary Objective: To assess whether a dose response relationship exists in the 0,3, 2, and 10 mg/kg arms as measured by PFS (RECIST v1.1) Secondary Objectives: To assess PFS, ORR, OS, and safety Exploratory Objectives: To assess efficacy by PD-L1 expression ClinTrials.gov NCT a Treatment arms stratified by MSKCC prognostic score (0 vs 1 vs 2/3) and number of prior lines of therapy in the metastatic setting (1 vs >1). Motzer et al, Oral presentation at ESMO

7 Responders 7 Nivolumab (RCC) CA : Duration of Response by Dose Objective Response Rates 0,3 mg/kg: 12/60 (20%) 2 mg/kg: 12/54 (22%) 10 mg/kg: 11/54 (20%) 0,3 mg/kg (n = 12) 2 mg/kg (n = 12) 10 mg/kg (n = 11) Time to response Ongoing response Time (months) Based on data cutoff of March 5, 2014.

8 Patients (%) 8 Nivolumab (RCC) CA : Response according to PD-L1 status using a 5% cutoff by IHC PD-L1+ PD-L Responder Non-responder 0 Response Rate: 4/18 (22%) 3/38 (8%) Choueiri et al, Poster presentation at ESMO 2014

9 Overall survival (%) 9 Nivolumab (RCC) CA : Overall Survival by Number of Prior Lines of Therapy prior line of therapy (events: 22/46) 2 prior lines of therapy (events: 75/122) Median OS, months (80% CI) 1 NR (19,8, NR) 2 18,7 (13,4 26,0) Number of patients at risk Time (months) 1 prior therapy >1 prior therapy NR, not reached; Symbols represent censored observations. Motzer et al, Oral presentation at ESMO 2014

10 Nivolumab (RCC) CA : Overall Survival in Phase III Trials and Nivolumab Phase II Study AXIS 1,a INTORSECT 2 RECORD-1 3 GOLD 4 Nivolumab study Drug Axitinib; sorafenib Temsirolimus; sorafenib Everolimus; placebo Dovitinib; sorafenib Nivolumab; 0,3; 2; 10 mg/kg Patients, n Risk group, % b Favorable Intermediate Not stated Poor Prior therapy Sunitinib Sunitinib VEGF VEGF + mtor VEGF ± mtor Line of therapy 2nd 2nd 2nd or higher 3rd or higher 2nd to 4th Median OS, months 15,2; 16,5 12,3; 16,6 14,8; 14,4 11,1; 11,0 18,2; 25,5; 24,7 CI 12,8 18,3 c 13,7 19,2 c 10,1 14,8 c 13,6 18,7 c Not stated 9,5 13,4 c 16,2 24,0d 8,6 13,5 c 19,8 28,8 d 15,3 26,0 d a Post TKI subset. b Total 100% due to rounding. c 95% CI. d 80% CI. 1. Motzer R, et al, Lancet Oncol. 2013;14: Hutson TE, et al, J Clin Oncol. 2014;32: Motzer R, et al, Cancer. 2010;116: Motzer R, et al, Lancet Oncol. 2014;15: ESMO 2014; Motzer et al,oral presentation at ESMO

11 11 Nivolumab (RCC) CA : Schlussfolgerungen Die randomisierte Phase II trial zeigte Aktivität von Nivolumab, auch mit anhaltenden Remissionen Keine Dosis-Wirkungsbeziehung Sicherheit gegeben bei 11% der Patienten mit Grad 3 Toxizität und keiner Grad 4 Toxizität Gute Daten für das Gesamtüberleben Motzer et al, Oral presentation at ESMO 2014

12 Nivolumab+Ipilimumab

13 13 Nivolumab + Ipilimumab (RCC) CA : Design of a Phase I study of Nivolumab in combination with Ipilimumab in metastatic renal cell carcinoma (mrcc) Patients with mrcc: Previously treated or treatment naïve Randomization Arm N3 + I1 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Q3W x4 Arm N1 + I3 Nivolumab 1 mg/kg IV+ Ipilimumab 3 mg/kg IV Q3W x4 Continuous Nivolumab 3 mg/kg IV Q2W Primary endpoint: Safety (AEs, laboratory tests) Secondary endpoint: Efficacy (ORR, duration of response, PFS) Exploratory endpoint: Response by tumor PD-L1 status Study assessments: Tumor response (RECIST v1.1) evaluated at screening, every 6 weeks (first 4 assessments), then every 12 weeks until disease progression ORR, objective response rate; TKI cohort presented by Amin A et al. ASCO 2014, Abstract Hammers et al, Oral presentation at ASCO 2014

14 Change in baseline target lesions (%) 14 Nivolumab + Ipilimumab (RCC) CA : Maximum Tumor Burden Reduction in Baseline Target Lesions N3 + I1 (n = 21) N1 + I3 (n = 22) Patient Positive change in tumor burden indicates tumor growth; negative change indicates tumor reduction.

15 Patient 15 Nivolumab + Ipilimumab (RCC) CA : Time to response and Duration of response N3 + I1 (n=9) N1 + I3 (n=11) Responders at first assessment (6 weeks): N3 + I1 = 4/9 (44,4%) N1 + I3 = 6/11 (54,5%) Ongoing responders: N3 + I1 = 7/9 (77,8%) N1 + I3 = 9/11 (81,8%) Time to response Ongoing response Response following discontinuation of therapy Patients discontinuing treatment (not due to progression) who continued to respond: N3 + I1 = 3/9 (33,3%) N1 + I3 = 5/11 (45,5%) Time on Therapy (weeks) Time on therapy (weeks) Median duration of response (DOR) for N3 + I1 was 31 weeks. Median DOR was not reached in the N1 + I3 arm at 40.1 weeks follow-up Hammers et al, Oral presentation at ASCO 2014

16 Proportion of PFS 16 Nivolumab + Ipilimumab (RCC) CA : Progression-Free Survival Median PFS, weeks (95% CI): N3 + I1: 36.6 (6.0, --) N1 + I3: 38.3 (18.3, --) 0.6 PFS at 24 weeks N3 + I1 = 65% (95% CI: 40 82) N1 + I3 = 64% (95% CI: 41 80) N3 + I1 (n = 21) N1 + I3 (n = 23) Number of patients at risk BL Time since first dose (weeks) N3 + I N1 + I Symbols represent censored observation. Number of patients at risk listed is number at risk before entering the time period.

17 17 Nivolumab + Ipilimumab (RCC) CA : Treatment-related AEs leading to discontinuation N3 + I1 (n=21) N1 + I3 (n=23) All All Patients with an event, n (%) 2 (9,5) 6 (26,1) Event, n (%) Amylase increased 1 (4,8) 0 Lipase increased 1 (4.8) 2 (8,7) ALT increased 0 2 (8,7) Diarrhea 0 1 (4,3) Pneumonitis 0 1 (4,3) Rates of discontinuation appeared higher in the N1 + I3 arm Hammers et al, Oral presentation at ASCO 2014

18 18 Nivolumab + Ipilimumab (RCC) CA : Nivolumab in combination with Ipilimumab Conclusion Nivolumab + Ipilimumab showed acceptable safety and evidence of antitumor activity in mrcc: Grade 3 4 events were manageable within established treatment guidelines The ORR suggests greater activity than reported previously with Nivolumab or Ipilimumab monotherapy in RCC Responses appear durable even after discontinuation of study drug The encouraging antitumor activity reported with this combination is the basis for a planned phase III combination trial in first-line mrcc Topalian et al, N Engl J Med. 2012; 366: 2443; Motzer et al, ASCO 2014, Abstract 4504; Choueiri et al, ASCO 2014, Abstract 5012; Yang et al, J Immunother. 2007; 30: 825; Hammers et al, Oral presentation at ASCO 2014

19 NIVOLUMAB + SUNITINIB / PAZOPANIB

20 Nivolumab + Sunitinib / Pazopanib (RCC) CA : Design of a phase I Study with Nivolumab in combination with Sunitinib or Pazopanib in patients with metastatic renal cell carcinoma (mrcc) Patients with mrcc: Including patients who received prior Pazopanib a Including patients who received prior Sunitinib a Arm S Escalation Sunitinib 50 mgb + Nivolumab 2 mg/kg IV Q3W (planned escalation to 5 mg/kg Q3W) c Arm P Escalation Pazopanib 800 mg/d + Nivolumab 2 mg/kg IV Q3W (planned escalation to 5 mg/kg Q3W) c M T D Treatmentnaïve patients Arm S Expansion Sunitinib + Nivolumab 5 mg/kg IV Q3W Arm P Expansion Pazopanib + Nivolumab 5 mg/kg IV Q3W Study assessments Tumor response (RECIST v1.1) evaluated at screening, every 6 weeks (first 4 assessments), then every 12 weeks until disease progression Dose escalation Decision rules for Arms S and P utilized the mtpi method. MTD was assessed based on this design For this study, MTD was defined as the dose with the estimated toxicity rate closest to 29% The 3 actions after a toxicity outcome was observed were: E, escalating to the higher dose; S, staying at the same dose; and D, de-escalating to the lower dose a Patients who received prior systemic therapy for mrcc, but not prior pazopanib or sunitinib, were assigned alternately to the 2 dose-escalation arms when both arms were open; b 4 Weeks on, 2 weeks off; c Up to 2 dose levels of nivolumab were studied. mtpi, modified toxicity probability interval; Amin et al, Oral presentation at ASCO

21 Change in baseline target lesions (%) 21 Nivolumab + Sunitinib / Pazopanib (RCC) CA : Maximum tumor burden reduction in baseline target lesions by Nivolumab dose Treatment S + N2 (n=7) S + N5 (n=22) P + N2 (n=19) Patient Positive change in tumor burden indicates tumor growth; negative change indicates tumor change; Amin et al, Oral presentation at ASCO 2014

22 Patient 22 Nivolumab + Sunitinib / Pazopanib (RCC) CA : Time to response and duration of response S + N (n=17) P + N (n=9) Time to response Ongoing response Response following discontinuation of therapy Responders at first assessment (6 weeks): S + N = 7/17 (41,2%) P + N = 5/9 (55,6%) Responders at first assessment (6 weeks): S + N = 7/17 (41.2%) P + N = 5/9 (55.6%) Ongoing responders: S + N = 10/17 (58,8%) P + N = 3/9 (33,3%) Ongoing responders: S + N = 10/17 (58.8%) P + N = 3/9 (33.3%) Patients discontinuing treatment (not due to progression) who continued to respond: S + N = 4/17 (23,5%) Patients discontinuing treatment (not due to progression) who continued to respond: S + N = 4/17 (23.5%) Time on therapy (weeks) Median follow-up: S + N, 54.7 weeks; P + N, 76.5 weeks; Amin et al, Oral presentation at ASCO 2014

23 23 Nivolumab + Sunitinib / Pazopanib (RCC) CA : Grade 3 4 treatment-related AEs in 70% of patients S + N (n=33) P + N2 (n=20) Any grade Grade 3 4 Any grade Grade 3 4 Total patients with an event, n (%) 33 (100) 27 (81,8) 20 (100) 14 (70,0) Hypertension 16 (48,5) 6 (18,2) 5 (25,0) 2 (10,0) Increased ALT 13 (39,4) 6 (18,2) 5 (25,0) 4 (20,0) Hyponatremia 6 (18,2) 5 (15,2) 0 0 Increased lymphocyte count 6 (18,2) 5 (15,2) 1 (5,0) 1 (5,0) Diarrhea 20 (60,6) 3 (9,1) 12 (60,0) 4 (20,0) Increased AST 12 (36,4) 3 (9,1) 6 (30,0) 4 (20,0) Fatigue 27 (81,8) 3 (9,1) 12 (60,0) 3 (15,0) Patients with any event (any grade): 53 (100%) No grade 5 treatment-related AEs were observed Most toxicities were consistent with the known profile of TKIs Amin et al, Oral presentation at ASCO 2014

24 Nivolumab + Sunitinib / Pazopanib (RCC) CA : Nivolumab in combination with Sunitinib or Pazopanib Conclusion Nivolumab + TKI showed encouraging antitumor activity with a manageable toxicity profile Efficacy: ORRs were higher with combination therapy than seen previously with Nivolumab or VEGF-TKI monotherapy in RCC 1 Safety: Renal and hepatic AEs were higher than anticipated based on available data for each single agent 2,3 Combination of PD-1 inhibition and VEGF inhibition warrants further investigation but should be approached with caution 1 Motzer et al. ASCO 2014 ASCO. Abstract 5009; 2 Sutent [prescribing information], 2013, Pfizer Inc, NY, USA; 3 Votrient [prescribing information], 2012, GlaxoSmithKline, NC, USA; ; Amin et al, Oral presentation at ASCO

25 Nivolumab + Sunitinib / Pazopanib (RCC) CA : Toxicity a hurdle for implementation of combined regimen Agent (mg/kg) Grade 3 4 (%) NIVO 0,3 1 5 NIVO NIVO MPDL3280A 2 13 NIVO 3 + IPI NIVO 1 + IPI SU + NIVO 4 82 PAZ + NIVO Motzer ASCO 2014 # 5009; 2 Cho ASCO 2013 (abstr. 4505); 3 Hammers ASCO 2014: # 4504;4 Amin ASCO 2014: # Grünwald, oral presentation at ESMO

26 Urothelkarzinom MPDL3280A Anti-PDL1: MPDL3280A

27 27 MPDL3280A (UBC) Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic urothelial bladder cancer (UBC) MPDL3280A Phase Ia Phase Ia Expansion Ongoing RCC Melanoma NSCLC Other Tumor Types Urothelial Bladder Cancer (UBC) (15 mg/kg) PD-L1 + patients PD-L1 + patients PD-L1 + patients PD-L1 + patients PD-L1 + patients Allcomers Allcomers Allcomers Allcomers Allcomers MPDL3280A administered by IV Q3W for up to 16 cycles Key Eligibility Criteria Measurable disease per RECIST v1.1 ECOG PS 0 or 1 Powles et al, Oral presentation at ASCO 2014

28 MPDL3280A (UBC) MPDL3280A: Summary of ORR in UBC Efficacy-evaluable population with UBC in Phase I expansion a Patients with complete responses. Patients with a CR had < 100% reduction of the target lesion due to lymph node target lesion. All lymph nodes returned to normal size per RECIST v1.1; IC, tumor.infiltrating immune cells. Responses are investigator assessed (unconfirmed). 7 patients are not included due to no post-baseline tumor assessments; PD-L1+: IHC (IC) 2/3; PD-L1-: IHC (IC) 0/1; Patients dosed by Jan 27, 2014 ( 12-wk follow-up) with measurable disease at baseline. Clinical data cutoff was April 21, 2014 Bellmunt et al, Oral presentation at ESMO

29 MPDL3280A (UBC) MPDL3280A: Summary of ORR in UBC PD-L1 IHC (IC) ORR, Best Response % (95% CI) IHC 3 (n=10) 60 (27 85) IHC 2 (n=20) 48 (27 68) IHC 1 (n=24) 17 (6, 37) IHC 0 (n=12) 8 (0, 35) PD-L1+ vs PD-L1 ORR, Best Response % (95% KI) 52 (34, 69) 14 (6, 28) 3 CRs (1 IHC 2, 2 IHC 3) Median follow-up was 6 months (range, 1+ to 12) for PD-L1+ patients and 4 months (range, 1+ to 7) for PD-L1- patients PD-L1+ Tumor-Infiltrating Immune Cells (ICs): Investigator-assessed ORRs unconfirmed per RECIST v1.1; 1 patient with unknown IHC status not included in table; PD-L1+: IHC (IC) 2/3; PD-L1-: IHC (IC) 0/1; Patients dosed by Jan 27, 2014 ( 12-wk follow-up) with measurable disease at baseline. Clinical data cutoff was April 21, 2014 Bellmunt et al, Oral presentation at ESMO

30 MPDL3280A (UBC) MPDL3280A: Duration on Study, Treatment and Response in Responding Patients Efficacy-evaluable population with UBC in Phase I expansion 19 of 22 responding patients had ongoing responses at the time of data cutoff Median duration of response has not been reached PD-L1+ patients (n=17): range, 0,1+ to 42+ weeks PD-L1- patients (n=5): range, 6+ to 19+ weeks a IHC 3, 2, 1,0: 10%, < 10% and 5%, < 5% and 1% tumor-infiltrating immune cells positive for PD-L1, respectively. Investigator-assessed ORRs (unconfirmed) per RECIST v1.1. Arrow indicates the status of no PD or no death only and has no implication on the timing. Patients dosed by Jan 27, 2014 ( 12 wk follow-up) with measurable disease at baseline. Clinical data cutoff was April 21, 2014 Bellmunt et al, Oral presentation at ESMO

31 MPDL3280A (UBC) MPDL3280A: Summary of Progression Free Survival Efficacy-evaluable population with UBC in Phase I expansion PD-L1 IHC (IC) Median PFS (range), weeks IHC 3 (n=10) Not reached (5 48+) IHC 2 (n=23) 24 (5 50+) IHC 1 (n=24) 11 (0.1+ to 30+) IHC 0 (n=12) 7 (5 to 24+) PD-L1+ vs PD-L1- Median PFS (range), weeks 24 (5 to 50+) 8 (0.1+ to 30+) Median PFS appears to be associated with PD-L1 expression Investigator-assessed PFS per RECIST v1.1; PD-L1+: IHC (IC) 2/3; PD-L1-: IHC (IC) 0/1; Patients dosed by Jan 27, 2014 ( 12 wk follow-up) with measurable disease at baseline. Clinical data cutoff was April 21, 2014 Bellmunt et al, Oral presentation at ESMO

32 MPDL3280A (Melanoma) MPDL3280A: Treatment-Related AEs Patients With UBC N = 74 All Grade, n (%) Grade 3 4 a, n (%) All 48 (65) 4 (5) Fatigue 11 (15) 0 Decreased appetite 9 (12) 0 Nausea 8 (11) 0 Pruritus 7 (9) 0 Pyrexia 7 (9) 0 Asthenia 5 (7) 1 (1) Chills 3 (4) 0 Dry skin 3 (4) 0 Influenza-like illness 3 (4) 0 Lethargy 3 (4) 0 Rash 3 (4) 0 Median treatment duration 95 days (5,5 cycles) MPDL3280A well tolerated in patients with UBC No discontinuations due to treatment-related AEs No investigator-assessed immunerelated toxicities reported as of the clinical cutoff MPDL3280A not observed to be associated with renal toxicity No treatment-related grade 5 AEs a Additional treatment-related grade 3/4 AEs: One patient experienced an increase in alanine aminotransferase (grade 3), aspartate aminotransferase (grade 3) and gamma-glutamyltransferase (grade 4). Two additional patients (one each) experienced either thrombocytopenia (grade 3) or decreased blood phosphorus (grade 3). Clinical data cutoff was April 21, includes events occurring in 3patients. Bellmunt et al, Oral Presentation at ESMO

33 Prostatakarzinom Ipilimumab

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36 Prostatakarzinom Studie noch nicht veröffentlicht Positive Daten für selektionierte Patienten (niedrig aggressive Erkrankung) Nachfolgestudie rekrutiert (Zweiarmig, Zwei Dosisstufen)

37 Prostata-Karzinom Bispecific Antibody T-cell engager (BITE)

38 Bispecific Antibody T-cell engager (BITE) Technology E X P E R I M E N T A L C E L L R E S E A R C H ( )

39 PSMA-BITE: Proof of Concept, First in Man Advanced metastatic prostate cancer

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41 National Center for Tumor Diseases NCT Heidelberg