Immunotherapy for Genitourinary Cancers. Douglas McNeel, MD PhD Professor of Medicine University of Wisconsin Carbone Cancer Center Madison, WI

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1 Immunotherapy for Genitourinary Cancers Douglas McNeel, MD PhD Professor of Medicine University of Wisconsin Carbone Cancer Center Madison, WI

2 Disclosures Madison Vaccines Inc co-founder, IP, consultant There will be discussion about the use of products for non-fda approved indications in this presentation

3 Objectives To recognize the role and mechanisms of action of approved immunotherapies for GU cancers Bladder cancer Renal cancer Prostate cancer To recognize other emerging immunological therapies for these diseases To recognize challenges specific to immunebased therapies for the care provider

4 Immunotherapy = The use of cells, molecules, and genes of the immune system for the therapy of infectious disease, autoimmunity, neoplastic diseases, graft-versus-host disease (GVHD), and to prevent the rejection of organ transplants.

5 Case #1 Bladder Cancer You are seeing a 60 y/o man who was diagnosed with superficial bladder cancer 5 years ago. After several courses of resection and intravesical BCG therapy, he developed muscle-invasive disease 2 years ago and underwent radical cystoprostatectomy. He then did well until 4 months ago when he was found to have lung and liver metastases. He started treatment with gemcitabine and cisplatin chemotherapy, but unfortunately had progressive disease after 3 cycles of therapy. You are considering salvage approaches and clinical trials.

6 Bladder Cancer Mucosa confined Recurrent Muscle-invasive Metastatic

7 Bladder Carcinoma in situ BCG First report of intravesical administration of BCG for the treatment of superficial bladder cancer Morales (1976) J. Urol. 116:180 6-week treatment of CIS 43 patients, 84% CR, 62% recurrence free at 5 years Mugiya (2005) Jap J Clin Onc. 35:395

8 Bladder Cancer Ta/T1 - BCG Superior to mitomycin C in reducing risk of recurrence in Ta/T1 tumors 1901 patients from 7 randomized trials (Shelley (2004) BJU 93:485) Mechanism not completely understood Questions remain regarding dose/schedule, strain, use as maintenance therapy Despite treatment, ~50% experience progression to MIBC Adverse effects: nausea, vomiting, weight loss, anorexia, dysuria, polyuria, hematuria, UTI

9 Bladder Cancer Mucosa confined Recurrent Muscle-invasive Metastatic

10 Metastatic Urothelial Cancer Current Chemotherapy Standard Overall survival Time to Progression Median: 7.4 months Median: 13.8 vs months Time to Treatment Failure Median: 5.8 vs. 4.6 months von der Maase (2000) J Clin Onc 18:3068

11 Metastatic Urothelial Cancer 2 nd Line Chemotherapy Phase II docetaxel 100 mg/m 2 every 21d 30 patients 13% PR Duration of response 3-8 months Median survival 9 months Dose reductions necessary for 60% due to AE Phase II weekly docetaxel Median PFS: 1.4 months Median OS: 8.3 months McCaffrey (1997) J Clin Oncol 15:1853 Kim (2016) Clin Genitourin Cancer 14:76

12 T-cell Checkpoint Blockade Drake 10 Nat Rev Imm 10:580

92% previously treated with platinum-based chemotherapy 27%

13 Metastatic Urothelial Cancer PD Pathway Inhibitors MPDL3280a IgG1 mab specific for PD-L1 67 patients with metastatic disease 92% previously treated with platinum-based chemotherapy 27% tumors/infiltrating cells express PD-L1 Powles (2014) Nature 515:558

14 Metastatic Urothelial Cancer PD Pathway Inhibitors MPDL3280a administered 15 mg/kg q 3 wks Well tolerated 57% reported treatment related AE 4% grade 3 No grade 4 or 5 events Objective RR after 6 weeks of treatment: 43% for IHC 2/3 tumors (7% CR) 11% for IHC 0/1 tumors Median duration of response not reached Granted breakthrough designation status by FDA in June 2014

15 Metastatic Urothelial Cancer Other PD Pathway Inhibitors Pembrolizumab (anti-pd-1) 10 mg/kg q 2 wk 33 patients with metastatic urothelial cancers 52% > 2 prior therapies; 21% had liver metastases Median follow-up 11 months ORR 24%, 10% CR Response duration weeks (median not reached) Median OS 9.3 months Plimack ESMO 2014 Abstract LBA23

16 Case #2 Renal Cancer You are seeing a 65 y/o woman, in otherwise good health, who underwent nephrectomy 1 year ago for what was found to be a T2 renal cell cancer, Fuhrman grade 2. Staging studies completed prior to hospital discharge at that time showed multiple small pulmonary nodules suspicious for metastatic disease. She entered radiographic surveillance, and 1 month ago was found to have increase in the size of one of the pulmonary nodules. Biopsy confirmed the presence of metastatic renal cell cancer. What are potential treatment options for her at this time?

17 Renal Cancer Surgically resectable Oligo-metastatic Metastatic reemakeup.blogspot.com

18 Renal Cell Cancer IL-2 Early observations of TIL and spontaneous regressions led to exploration of immune therapies IFNα and IL-2 were standard of care for mrcc for ~ 20 years before approval of molecularly targeted agents beginning in 2005 Pooled analysis of 7 phase II trials 255 patients receiving 2 cycles HD IL-2 14% objective responses, 5% CR Median duration 54 months 4% treatment-related mortality rate Fyfe (1995) J Clin Oncol 13:688

19 Renal Cell Cancer PD-pathway inhibitors Phase III CheckMate 025 trial 821 patients with previously treated mrcc (1-2 VEGF tki): Nivolumab (anti-pd-1) 3 mg/kg q 2 wk versus everolimus 10 mg per day Median OS: 25m vs 19.6m ORR: 25% vs 5% Median PFS: 4.6m vs 4.4m Median duration: 23m vs 13.7m Grade 3/4 AE: 19% vs 37% Most common AE with nivolumab was fatigue (2%) Approved by FDA in 2015 Motzer (2015) N Engl J Med 373:1803

20 Renal Cell Cancer Nivolumab Approval indications: Patients with metastatic renal cell cancer who have received prior anti-angiogenic therapy Dosing: 3 mg/kg every 2 weeks Common adverse reactions: Asthenia, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, arthralgia Warnings: Immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, rash, encephalitis, others

21 Renal Cell Cancer PD-pathway inhibitors Other Trials and Combinations Phase III Nivolumab + Ipilimumab vs. Sunitinib Previously untreated mrcc (CheckMate 214) Phase III Atezolizumab (anti-pd-l1) + Bevacizumab vs. Sunitinib Previously untreated mrcc Phase II Nivolumab pre-surgical resection for mrcc (ADAPTeR) Phase I Nivolumab + Sunitinib or Pazopanib or Ipilimumab Previously untreated mrcc (CheckMate 016) Different combinations with chemotherapy, IFNα, etc Multiple combinations with pembolizumab

22 Renal Cell Cancer Other Immune Therapies Anti-CTLA-4 (ipilimumab) Phase II trial 6/61 with PR 33% with grade 3/4 immune-related toxicities Yang (2007) J Immunoth 30:825 Vaccine (MVA-5T4, TroVax) Phase III trial 733 patients first line mrcc randomized to vaccine vs placebo No difference in OS (median 20.1m vs 19.2m) Magnitude of immune response associated with longer OS Amato (2010) Clin Cancer Res 16:5539

23 Case #3 Prostate Cancer You are seeing a 68 y/o man who was diagnosed with a Gleason 5+4 prostate cancer 5 years ago. He had evidence of metastases to the bone and retroperitoneal lymph nodes, and was started on treatment with leuprolide and bicalutamide. His PSA initially declined, but then began rising two years ago, and the bicalutamide was discontinued. His PSA continued to rise, and he developed pain in his back and ribs, associated with lesions noted on bone scan performed at the same time. He started on docetaxel chemotherapy and completed 9 cycles of therapy 6 months ago. His pain initially resolved, but in the last 2 months has been increasing. His serum PSA has risen from 250 ng/ml to 350 ng/ml in the last month. What are appropriate immunotherapy treatment options for him?

24 Prostate Cancer Clinical Stages Androgen Deprivation Organ Confined Metastatic Disease (D2) Rising PSA Hormone Naïve (D0) Metastatic CR Asymptomatic (D3) Metastatic CR Symptomatic Locally Advanced Rising PSA Castrate- Resistant (D0.5) Timeline

25 Prostate Cancer History of Immunotherapy Animal studies Ab to autologous prostate tissue Cryotherapy - Ab to prostate IL-2 and GM-CSF transfected tumor vaccines (ultimately Cell Genesys) Ab to PSA in D3 patients Primates immunized with vaccinia-psa (ultimately Therion) RNA-loaded DC vaccines DNA vaccines Phase I trial - PSMA peptides on DC (NW Biotherapeutics) PAP-GMCSF vaccine trials started (Dendreon) Phase I trials - carbohydrate vaccines (MSKCC)

26 Prostate Cancer Sipuleucel-T Drake (2010) Nat Rev Immunol. 10:580

27 Prostate Cancer: Sipuleucel-T Phase III IMPACT trial 512 patients with asymptomatic mcrpc randomized to sipuleucel-t vs placebo Median OS: 25.8m vs 21.7m 36-month survival: 31.7% vs 23% No difference in TTP Antibody responses associated with longer survival Most common AE included chills, fever, headache Approved by FDA in 2010 Kantoff (2010) N Engl J Med 363:411

28 Prostate Cancer Sipuleucel-T Approval indications: Patients with asymptomatic to minimally symptomatic castration-resistant metastatic prostate cancer Dosing: Collection and infusion every 2 weeks x 3 Common adverse reactions: Chills, fatigue, fever, back pain, nausea, joint aches, headache Warnings: Infusion reactions, not tested for transmissible infectious diseases, syncope/hypotension, myocardial infarction, thromboembolic events

29 Prostate Cancer: Viral Vaccines Rilimogene galvacirepvec Drake (2010) Nat Rev Immunol. 10:580

30 Prostate Cancer: Viral Vaccines Rilimogene galvacirepvec Randomized phase II trial 125 patients with minimally symptomatic mcrpc Primary endpoint PFS International, randomized phase III trial currently underway Kantoff (2010) J Clin Onc 28:1099

31 Prostate Cancer: T-cell Checkpoint Inhibitors Phase III trial 799 patients with mcrpc after docetaxel therapy randomized to ipilimumab vs placebo + bone-directed XRT (CA ) Primary endpoint OS Time to Progression Median: 11.2 vs. 10 months Kwon (2014) Lancet 15:700

32 Prostate Cancer PD-pathway inhibitors Other Trials and Combinations Phase III Ipilimumab vs placebo in chemotherapynaïve mcrpc Phase I trials with nivolumab or pembrolizumab No evidence of single-agent activity in mcrpc Multiple combinations with ipilimumab or PD-pathway inhibitors with vaccines (including sipuleucel-t), chemotherapy, androgen deprivation, and radiation therapy

33 Summary Approved Immune Therapies Disease Class Agent Bladder/ Urothelial cancer Immunomodulation BCG Renal cell cancer Cytokines IFNα IL-2 T-cell checkpoint inhibitor Nivolumab Prostate cancer Vaccine Sipuleucel-T

34 Summary Approved and Emerging Immune Therapies Disease Class Agent Bladder/ Urothelial cancer Immunomodulation T-cell checkpoint inhibitors Combinations BCG Renal cell cancer Cytokines IFNα IL-2 T-cell checkpoint inhibitor Combinations Atezolizumab (anti-pd-l1) Pembrolizumab (anti-pd1) Nivolumab Pembrolizumab Atezolizumab Prostate cancer Vaccine Sipuleucel-T Rilimogene galvacirepvec Combinations

35 Objectives To recognize the role and mechanisms of action of approved immunotherapies for GU cancers Bladder cancer Renal cancer Prostate cancer To recognize other emerging immunological therapies for these diseases To recognize challenges specific to immunebased therapies for the care provider

36 Opportunities for Patients and Providers Several first in class newer therapies Few adverse events notably fewer in comparison with traditional chemotherapies Survival benefit and/or time to progression at least as great as seen with other approved therapies Tail of the curve durable responses after therapy discontinued (Probably) easily integrated with other therapies

37 Treatment Challenges Cost vs. benefit Different types of AE few, but serious, and can be delayed onset Different types of radiographic response (progression before response or continued (slower?) progression If responses can be durable, how long should one continue treatment? Is there a role for re-treatment? Are there predictors for patients who respond or don t respond? How does one best use these therapies in combination or sequence with other available therapies?

38 Treatment Challenges Unconventional Radiographic Responses 34 patients with previously-treated mrcc, treated with 1 or 10 mg/kg nivolumab every 2 weeks McDermott 2015 J Clin Oncol 33:2013

39 Treatment Challenges For Vaccines How Do We Measure Response? Radiographic responses and PSA responses are not frequent Is long-term stable disease valid? No detection of difference in TTP in two separate trials Probability of non-progression APC8015 (n=82) Placebo (n=45) P = (log-rank) HR = 1.43 (95% CI: 0.98, 2.09) Time from randomization to progression (weeks) Small (2006) J Clin Onc 24:3089 Kantoff (2010) J Clin Onc 28:1099

40 Model of Treatment Effect Arising from Multiple Vaccine Trials Death from tumor Disease Burden Time Adapted from: Madan (2010) Oncologist 15:969

41 Treatment Challenges Predictors of Benefit? PD-L1 expression as predictor of response to PD-pathway blockade Different antibodies and metrics used across trials PD-L1 on tumor versus infiltrating immune cells PD-L1 expression is dynamic and patients with no expression can have response to therapies Will these be useful tests for combination therapies? Others? Are predictive biomarkers even necessary? For sipuleucel-t, and potentially other emerging vaccines, how can we tell if it has worked?

42 Treatment Challenges Sequence with Available Therapies Bladder / Urothelial cancer Will PD-pathway inhibitors replace chemotherapy for firstline treatment of metastatic disease? Renal cell cancer Is there a role for HD IL-2? With PD-pathway inhibitors, VEGF targeted therapies, and mtor inhibitors, what is optimal sequence for mrcc? Role for adjuvant therapy? What about debulking neprectomy? Prostate cancer How do we sequence sipuleucel-t and emerging therapies with AR-targeted therapies?

43 Conclusions Several first in class newer immune-based therapies are available for the treatment of genitourinary cancers Several other novel immune-based therapies are in advanced stages of clinical testing To date, there has been a favorable safety-to-benefit ratio compared with traditional chemotherapies These therapies provide different considerations for the treating physician with respect to identification of benefit, duration of therapy, and sequence with other available treatment agents

The Role of Immunotherapy in Prostate Cancer: What s Trending?

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