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Clinical Application of Immune Checkpoint Inhibitors in Bladder Cancer
This program is supported by educational grants from Genentech and Merck.
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Key Issues and Controversies in Immunotherapy for Advanced Bladder Cancer: Quiz Round 4
Elizabeth R. Plimack, MD, MS Director, Genitourinary Clinical Research Associate Professor Hematology/Oncology Fox Chase Cancer Center Temple Health Philadelphia, Pennsylvania
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About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
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Faculty Program Director:
Daniel P. Petrylak, MD Professor of Medicine Medical Oncology Director, Prostate and GU Medical Oncology Director, Prostate Cancer Translational Research Group Yale Cancer Center New Haven, Connecticut Elizabeth R. Plimack, MD, MS Director, Genitourinary Clinical Research Associate Professor, Department of Hematology/Oncology Fox Chase Cancer Center Temple Health Philadelphia, Pennsylvania David I. Quinn, MBBS, PhD, FRACP, FACP Associate Professor of Medicine Division of Cancer Medicine and Blood Diseases The University of Southern California Medical Director USC Norris Cancer Hospital and Clinics Los Angeles, California Jonathan E. Rosenberg, MD Associate Attending Physician Genitourinary Oncology Service Division of Solid Tumor Oncology Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York This slide lists the faculty who were involved in the production of these slides.
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Faculty Disclosures Daniel P. Petrylak, MD, has disclosed that he has received consulting fees from Bayer, Bellicum, Dendreon, Exelixis, Ferring, Johnson & Johnson, Medivation, Millennium, Pfizer, Roche Laboratories, sanofi-aventis, and Tyme; has received funds for research support from Agensys, Celgene, Dendreon, Eli Lilly, Johnson & Johnson, Millennium, Oncogenex, Progenics, sanofi- aventis; and has ownership interest in Bellicum and Tyme. Elizabeth R. Plimack, MD, MS, has disclosed that she has received consulting fees from Acceleron, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Pfizer, Roche, and Synergene and funds for research support from AstraZeneca, Bristol-Myers Squibb, and Merck. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.
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Faculty Disclosures David I. Quinn, MBBS, PhD, FRACP, FACP, has disclosed that he has received consulting fees from Astellas, AstraZeneca, Bayer, Exelixis, Genentech, Merck, Novartis, Peloton, Pfizer, Sanofi, Serono, and Vertex. Jonathan E. Rosenberg, MD, has disclosed that he has intellectual property rights/patents from Somatic ERCC2 mutation and platinum sensitivity; has received consulting fees from Agensys, Eli Lilly, Genentech/Roche, OncoGeneX, and sanofi- aventis; and has ownership interest in Illumina and Merck. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.
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Evolution of Systemic Therapy for Urothelial Cancer
Docetaxel Gemcitabine + cisplatin Atezolizumab Accelerated MVAC Standard MVAC 1989 Paclitaxel Vinflunine Today 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2016 EMA, European Medicines Agency; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin. Cisplatin FDA approved 1978 Gemcitabine EMA approved Atezolizumab FDA approved 5/18/2016 Vinflunine EMA approved Durvalumab breakthrough therapy designation 2/17/2016 Sternberg CN, Yagoda A, et al. Cancer 1989;64: McCaffrey JA, et al. J Clin Oncol 1997;15: von der Maase H, et al. J Clin Oncol 2005;23: Sternberg CN, et al. J Clin Oncol 2001;19: Vaughn DJ, et al. J Clin Oncol 2002;20: Bellmunt J, et al. J Clin Oncol 2009;27: Rosenberg JE, et al. Lancet. 2016;387: Slide credit: clinicaloptions.com
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Systemic Therapy for UBC Before 2016
Nonmuscle Invasive Neoadjuvant Adjuvant First-line Metastatic Next-line Metastatic No systemic therapy Gem + cisplatin A-MVAC (cisplatin) Gem + cisplatin A-MVAC (cisplatin) or Gem + carbo Paclitaxel Docetaxel Vinflunine* Cisplatin ORR 50% to 60%; median OS: 15 mos; 1-yr OS: 60% Carboplatin ORR: 36%; median OS: 9 mos; 1-yr OS: 37% A-MVAC, accelerated methotrexate, vinblastine, doxorubicin, and cisplatin; Carbo, carboplatin; Gem, gemcitabine; UBC, urothelial bladder cancer ORR: 12% median; OS: 7 mos; *1-yr OS: 26% Slide credit: clinicaloptions.com NCCN Guidelines. Bladder cancer. v
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Systemic Therapy for UBC Now
Nonmuscle Invasive[1] Neoadjuvant Adjuvant[1] First-line Metastatic[1] Second-line Metastatic[2] Next-line Metastatic[1] No systemic therapy Gem + cisplatin A-MVAC (cisplatin) Gem + cisplatin A-MVAC (Cisplatin) or Gem + carbo Atezolizumab Paclitaxel Docetaxel Vinflunine* Cisplatin ORR 50% to 60%; median OS: 15 mos; 1-yr OS: 60% Carboplatin ORR: 36%; median OS: 9 mos; 1-yr OS: 37% AMVAC, accelerated methotrexate, vinblastine, doxorubicin, and cisplatin; Carbo, carboplatin; Gem, gemcitabine; UBC, urothelial bladder cancer ORR: 15%; median OS: 8 mos; 1-yr: OS 37% ORR: 12% median; OS: 7 mos; *1-yr OS: 26% 1. NCCN Guidelines. Bladder cancer. v Dreicer R, et al. ASCO Abstract 4515.
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Testing for PD-L1: How Does It Fit Into Clinical Practice?
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PD-L1 Testing: No Standardized Assay
V ATEZOLIZUMAB[1,2]: Immune Cells Only PEMBROLIZUMAB[3] IC, immune cells. Tumor cells Tumor + inflammatory cells 1. Rosenberg JE, et al. Lancet. 2016;387: Rosenberg JE, et al. European Cancer Conference Abstract 21LBA. 3. Plimack ER, et al. ASCO Abstract 4502. Slide credit: clinicaloptions.com
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PD-L1 and Response in the Postplatinum Therapy Setting
Atezolizumab[1] Phase II PD-L1, n (%) ORR CR PR SD PD IC1/2/3 (n = 207) 37 (18) 13 (6) 24 (12) 34 (16) 107 (52) All pts (n = 310) 45 (15) 15 (5) 30 (10) 59 (19) 159 (51) IC0 (n = 103) 8 (8) 2 (2) 6 (6) 25 (24) 52 (50) Pembrolizumab[2] Phase I basket (n = 33) PD-L1+ defined as ≥ 1% PDL1 in tumor or stroma by IHC; 100% were positive Response rate: 28% in PD-L1–positive group, and overall Nivolumab[3] Phase I basket (n = 78) PD-L1+ defined as ≥ 1% expression; 37% were positive Response rate: 24% in PD-L1–positive group, and overall IC, immune cell; GU, genitourinary; PD, progressive disease; SD, stable disease; TC, T cell. Durvalumab[4] Phase I basket (n = 42) PD-L1+ defined as ≥ 25% of TC or IC staining for PD-L1; 66% were positive Response rate: 46% in PD-L1–positive group; 31% overall 1. Rosenberg JE, et al. Lancet. 2016;387: Plimack ER, et al. ASCO Abstract Sharma P, et al. ASCO Abstract Massard C, et al. ASCO Abstract 4502. Slide credit: clinicaloptions.com
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High PD-L1 Level Loses Relevance Across Atezolizumab Studies
Response Rate 0.60 0.50 0.40 0.30 0.20 0.10 Phase I[1] Phase II (postplatinum)[2] PD-L1 high (IC 2/3) PD-L1 low (IC 0/1) GU, genitourinary; IC, immune cell. 1. Petrylak DP, et al. ASCO Abstract Dreicer R, et al. ASCO Abstract 4515. Slide credit: clinicaloptions.com
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PDL1 Low (IC 0/1) Pts Still Respond to Atezolizumab
Response Rate 0.60 0.50 0.40 0.30 0.20 0.10 Phase I[1] Phase II (postplatinum)[2] PD-L1 high (IC 2/3) PD-L1 low (IC 0/1) Historical response rate with second-line chemotherapy ~ 12% GU, genitourinary; IC, immune cell. 1. Petrylak DP, et al. ASCO Abstract Dreicer R, et al. ASCO Abstract 4515. Slide credit: clinicaloptions.com
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What Is FDA “Breakthrough Status,” and What Does It Mean for the Future of PD-L1 Inhibitors in Bladder Cancer?
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FDA “Breakthrough Therapy” Designation
A mechanism of identifying drugs with sufficient early evidence of efficacy to justify a “seamless” development program Allows for: Closer communication with the FDA regarding the drug’s development Review of expansion of “basket” cohorts from phase I or phase II trials for filing consideration Potential approval based on single-arm data Requirements: Serious condition Lack of existing therapies Preliminary clinical evidence demonstrating substantial improvement over available therapies with respect to clinically significant endpoints Subsequent confirmatory data Slide credit: clinicaloptions.com Prowell TM, et al. N Engl J Med. 2016;374:
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“Breakthrough Therapy” Granted to 2 Immunotherapies for Bladder Cancer
Atezolizumab June 2014 Durvalumab February 2016 Slide credit: clinicaloptions.com
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FDA Accelerated Approval
When studying a new drug, it can sometimes take many yrs to learn whether a drug actually provides a real effect Accelerated approval is allowed for drugs for serious conditions that fill an unmet medical need based on effects on a surrogate or an intermediate clinical endpoint The drug company will still need to conduct studies to confirm findings related to definitive endpoints (eg, OS) to maintain continued approval Atezolizumab FDA approved (accelerated) for bladder cancer in May 2016. Surrogate endpoint: response rate Slide credit: clinicaloptions.com
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When Is the Optimal Time to Introduce Immunotherapy in Bladder Cancer?
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Atezolizumab: FDA Approved in May 2016 for Bladder Cancer
The first agent in its class approved to treat bladder cancer Approved for locally advanced or metastatic urothelial carcinoma Disease progression during or following platinum- based chemotherapy or Disease progression within 12 mos of neoadjuvant or adjuvant treatment with platinum-based chemotherapy Accelerated approval may be contingent on confirmatory trials Slide credit: clinicaloptions.com Atezolizumab [package insert]
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FDA Indication for Atezolizumab in Bladder Cancer: Second-line Postplatinum
Agent RR, % Median OS, Mos 12-Mo OS, % Atezolizumab[1] 15 8 37 Docetaxel[2] 13 9 N/A Paclitaxel[3] 10 7 Vinflunine[4] 26 RR, response rate. 1. Dreicer R, et al. ASCO Abstract 4515. 2. McCaffrey JA, et al. J Clin Oncol. 1997;15: 3. Vaughn DJ, et al. J Clin Oncol. 2002;20: 4. Bellmunt J, et al. J Clin Oncol. 2009;27: Slide credit: clinicaloptions.com
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Is Receipt of Chemotherapy Prior to Immunotherapy Important Biologically?
Potential immunogenic effects of chemotherapy Release of tumor antigens Translocate CRT to surface of tumor cell, an “eat me” signal to DCs phagocytosis Cause secretion of ATP “find me” signal to DCs Release dsRNA autonomous secretion of type I interferons “revving” the immune response Deplete regulatory T cells and/or myeloid-derived suppressor cells ATP, adenosine triphosphate; CRT, calreticulin; CRTR, calreticulin receptor; DC, dendritic cells; dsRNA, double-stranded RNA. Slide credit: clinicaloptions.com Emens LA, et al. Cancer Immunol Res 2015;3:
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Survival with First-line Gem/Cis vs MVAC in Bladder Cancer (Phase III)
1.0 Gemcitabine + Cisplatin 5-yr PFS 9.8% 5-yr OS 13.0% 0.9 Median OS, Mos Gem/cis: 14.0 (95% CI: ) MVAC: 15.2 (95% CI: ) HR: 1.09 (P = .44) 0.8 0.7 0.6 Gem/cis MVAC Proportion Surviving 0.5 0.4 0.3 0.2 0.1 Cis, cisplatin; Gem, gemcitabine; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; 12 24 36 48 60 72 84 Mos Pts at Risk, n 50 62 36 40 30 34 23 29 7 9 0 1 Gem/cis MVAC Slide credit: clinicaloptions.com Von der Maase H, et al. J Clin Oncol. 2005;
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High-Dose MVAC/G-CSF vs MVAC as First-line Therapy for UC: Survival
7-yr update of phase III EORTC study in advanced TCC (N = 263) Progression-Free Survival Overall Survival HD MVAC ( ) MVAC ( ) 100 HD MVAC ( ) MVAC ( ) 100 Median, mos 5-yr, % (95% CI) Median, mos 5-yr, % (95% CI) 80 80 60 60 HR: log-rank P = .017 HR: 0.76 log-rank P = .042 Alive Without Progression (%) Alive (%) 40 40 Treatment MVAC HD MVAC Treatment MVAC HD MVAC 20 20 MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; GSCF, granulocyte-stimulating colony factor; HD, high dose; UC, urothelial carcinoma. 2 4 6 8 10 12 2 4 6 8 10 12 Yrs Yrs O N Pts at Risk, n 14 32 O N Pts at Risk, n 32 45 11 22 7 18 4 6 2 0 15 29 11 23 4 8 2 0 5-yr PFS (HD MVAC): ~ 17% 5-yr OS (HD MVAC): 22% Slide credit: clinicaloptions.com Sternberg CN, et al. Eur J Cancer. 2006;42:50-54.
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First-line Gem/Carbo vs M-CAVI in Cisplatin-Ineligible Bladder Cancer: OS
EORTC 30986: randomized phase II/II trial in advanced urothelial cancer (N = 238) Treatment MCAVI Gem/carbo First-line Gem/Carbo ORR: 36% Median OS: 9.3 mos 1-yr OS: 37% 5-yr OS: close to zero 100 80 Log-rank test P = .64 60 Survival (%) 40 20 Carbo, carboplatin; Gem, gemcitabine; MCAVI, methotrexate plus carboplatin plus vinblastine 1 2 3 4 5 6 7 Yrs Treatment MCAVI Gem/carbo O N Pt at Risk, n 37 44 13 15 7 5 3 2 1 2 1 1 Slide credit: clinicaloptions.com De Santis M, et al. J Clin Oncol. 2012;30:
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IMVigor210: First-line Atezolizumab in Cisplatin-Ineligible Advanced Bladder Cancer
Cohort 1 of single-arm phase II trial Primary endpoint: response Secondary endpoints: duration of response, PFS, OS, safety, antitherapeutic antibodies, Cmax of atezolizumab ORR: 24% overall; 28% in PD-L1 IC2/3 group Median OS: 14.8 mos; 1-yr OS: 57% Treatment continued until loss of clinical benefit or unmanageable toxicity Treatment-naive and cisplatin- eligible pts with locally advanced or metastatic UC (N = 429) Atezolizumab 1200 mg IV Q3W Historical comparator: First-line gem/carbo (ORR: 36%; median OS: 9.3 mos; 1-yr OS: 37%) Carbo, carboplatin; Carbo, carboplatin; Cmax, maximum serum concentration; GU, genitourinary; UC, urothelial carcinoma. Slide credit: clinicaloptions.com Balar AV, et al. ASCO Abstract LBA4500.
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Should PD-1 Pathway Inhibition Be Moved Up to First Line?
For pts eligible for cisplatin: no No data yet in this setting Cisplatin provides durable benefit for some, remains standard of care until randomized trials show superiority of PD-1 inhibition For pts not eligible for cisplatin: not yet FDA indication for atezolizumab is postplatinum (cisplatin or carboplatin) Data from cisplatin-ineligible cohort of IMvigor 210 show encouraging median OS of mos and 1-yr OS of 57% vs historical median and 1-yr OS of 9.3 mos and 37% with gemcitabine/carboplatin Important considerations when evaluating frontline cis-ineligible data What is efficacy compared to historic controls with gem/carbo? Is there a toxicity advantage to atezolizumab over gem/carbo? Is there a longer tail to the OS curve with atezolizumab? GU, genitourinary; gem, gemcitabine; carbo, carboplatin. Slide credit: clinicaloptions.com Balar AV, et al. ASCO Abstract LBA4500.
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Important Unanswered Questions
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Ongoing Trials of PD-1 Pathway Inhibitors in Bladder Cancer
Nonmuscle-invasive bladder cancer Muscle-invasive bladder cancer Metastatic urothelial cancer Low grade High grade Neoadjuvant Adjuvant Cisplatin eligible Cisplatin ineligible Atezolizumab pembro + chemo Atezolizumab* nivolumab* Durvalumab + tremelimumab* Pembrolizumab In development Pembrolizumab + BCG First Line Trimodality Maintenance Pembrolizumab + RT Avelumab* pembrolizumab Second Line and Beyond BCG, Bacillus Calmette-Guérin; pembro, pembrolizumab; RT, radiation therapy. BCG-unresponsive Platinum refractory Pembrolizumab Pembrolizumab vs chemo* atezolizumab vs chemo* *Phase III Slide credit: clinicaloptions.com Schema adapted from Fakhrejahani F, et al. Curr Opin Urol. 2015;25:
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Actively Accruing Second-line (and Beyond) Clinical Trials in Metastatic UC
IT No prior immunotherapy Chemo Prior immunotherapy allowed Non IT combination Targeted therapy UC, urothelial carcinoma; IT, immunotherapy. Unmet need: Trials specifically tailored to pts who relapse after or are refractory to immunotherapy Slide credit: clinicaloptions.com ClinicalTrials.gov.
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Clinical Issues in Immunotherapy for Bladder Cancer: Conclusions
Checkpoint inhibitors are changing therapeutic landscape for metastatic/advanced UBC Currently only one approved in platinum-refractory setting outside of a clinical trial Questionable utility of testing for PD-L1 expression. No standardized assay New USFDA pathways allow for early review of single- arm data to determine breakthrough status and potentially accelerated approval of these agents BCG, Bacillus Calmette-Guérin. Slide credit: clinicaloptions.com
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Clinical Issues in Immunotherapy for Bladder Cancer: Conclusions
What is the most appropriate setting for checkpoint inhibition in urothelial carcinoma? Current indication is postplatinum metastatic Trials ongoing in frontline for cis-ineligible pts, maintenance for cis-eligible, and nonmetastatic UC For pts refractory to PD-1 pathway inhibition or who relapse after treatment, few immunotherapy trials exist Does prior immunotherapy with one agent preclude response to a different agent or combination regimen? What is the best approach in this setting? BCG, Bacillus Calmette-Guérin. Slide credit: clinicaloptions.com
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Go Online for More CCO Coverage of Bladder Cancer!
Downloadable slidesets on the clinical application of immunotherapy in bladder cancer On-demand Webcast from the live symposium CME-certified Expert Analysis of key ASCO 2016 abstracts on GU and other malignancies clinicaloptions.com/oncology
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