AUANEWSassets.auanet.org/SITES/AUAnet/common/pdfs/auanews/AUANEWS… · TF, a 57-year-old electrician, presented in May 2014 with dark urine, 20 lb weight loss, a hemo-globin 7.2

AUANEWS| THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION |

AmericanUrologicalAssociation

Immunotherapy in Urology: The Next FrontierCancer Immunology 101: What You Need to KnowNicholas J. Vogelzang, MD

Immunotherapy for Urological Malignancies: Evolution of End Points and Future DirectionsDaniel P. Petrylak, MD

Intravesical Immunotherapy for Bladder CancerPeter C. Black, MD

Systemic Immunotherapy for Bladder CancerMark Schoenberg, MD

Immunotherapy for Renal Cell CarcinomaMoshe C. Ornstein, MD, MA and Petros Grivas, MD, PhD

Immunotherapy for Prostate CancerSusan F. Slovin, MD, PhD

AUANews EditorManoj Monga, MD, FACS

PublisherAmerican Urological Association1000 Corporate BoulevardLinthicum, MD 21090

Copyright © 2017 by American Urological AssociationNone of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or “off-label” uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions and of possible contraindications or dangers in use, review of any applicable manufacturers’ product information and comparison with the recommendations of the authorities.

Immunotherapy in Urology: The Next Frontier

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SUPPLEMENT ON IMMUNOTHERAPY 1

▼ Continued on page 2

Immunotherapy is a concept familiar to urologists. From renal cancer to blad-der cancer, we have been on the fore-front of identifying and adapting oppor-tunities that offer

our patients novel approaches to battle disease. In this special supplement to AUANews we provide insight to the lat-est developments in immunotherapy for urological oncology.

Manoj Monga, MD, FACSEditor, AUANews

Cancer Immunology 101: What You Need to KnowNicholas J. Vogelzang, MD,* Vice Chair, SWOG GU Committee, Research Medical Director, US Oncology Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada

Case Report

TF, a 57-year-old electrician, presented in May 2014 with dark urine, 20 lb weight loss, a hemo-

globin 7.2 gm/dl and chest pain. He was found to have a small right coronary artery myocardial infarct but a chest radiograph showed multiple pulmonary nodules. Followup computerized tomog-raphy showed innumerable lung nodules and a right renal mass. Aspiration biopsy revealed clear cell carcinoma. The patient was treated with transfu-sions, aspirin and atorvastin. Anesthesiol-ogy refused to clear him for cytoreductive nephrectomy. Therefore, pazopanib was begun1 and 2 months later, after the iron deficiency anemia resolved, he under-went an uncomplicated coronary artery bypass. Four months after diagnosis and due to persistent gross hematuria with clot retention, cytoreductive nephrecto-my was performed (11.7 cm mass), which was complicated by bleeding requiring 6 units of red blood cells. Two months later hypercalcemia developed and posi-tron emission tomography showed mod-est regression of lung nodules but new lesions in the liver, skin and nodes as well as a lytic lesion in the femur.

The patient underwent orthopedic stabilization of the femur, and received denosumab and radiation to the skin lesion and femur followed by everoli-mus as second line systemic therapy. Disease progressed in 4 months and he was entered in a clinical trial receiving bezacizumab. Disease again progressed in 2 months with increasing liver and lung lesions, and he was given fourth line axitinib. The patient experienced a 2-month response with reduced pain and stable liver lesions but disease soon rapidly progressed, and new brain metastases developed. While completing whole brain radio-therapy and with increasing liver lesions, in September 2015 he was started on a new agent, cabozantinib,2 to which was added after 2 months another new agent, the immune checkpoint inhibi-

tor nivolumab3 intravenously every 2 weeks. Although the cabozantinib was withheld due to osteonecrosis of the jaw after 11 months, nivolumab continues after 27 doses. All liver lesions have regressed and the lung lesions are sig-nificantly smaller (fig. 1). At 2½ years after diagnosis the patient completed a motorcycle trip to South Dakota. While this case is atypical and adminis-tration of the 2 new agents, cabozantinib and nivolumab, in combination was done in desperation, the success for the last 1 year is undeniable.

Discussion

Renal cancer has long been known to be immunologically “sensitive,” begin-ning with numerous case reports of spontaneous regression followed by the use of interferon and then interleukin-2,

Introduction

*Financial and/or other relationship with Bayer, Pfizer, Novartis, Sanofi Aventis, Bristol-Myers Squibb, Roche/Genentech, Eisai, Vogelzang and Connelly, Caris, Dendreon, Medivation/Astellas, Janssen, Amgen, Heron, Klast Consulting, Exelexis, Cuerulean, US Oncology and Dava Oncology-Per.

Figure 1. CT of chest before start of nivolumab and cabo-zatinib (A) and after 6 months of therapy (B).

A B

2 SUPPLEMENT ON IMMUNOTHERAPY


which was approved by the FDA (U.S. Food and Drug Administration) in 1991. In 2011 Brahmer et al reported the dramatic results of the immune checkpoint inhibiting agent nivolumab against lung and other solid tumors.4 Prior to that, the immune agent ipilu-mumab (CTLA-4 [cytotoxic T lympho-cyte antigen 4]) revolutionized the treat-ment of metastatic melanoma, inducing cure in 10% to 20% of patients, leading to FDA approval.5 When nivolumab was added to ipilumumab, the poten-tial cure rate increased to nearly 40%.6 Nivolumab is now approved for mela-noma, lung cancer (second line), kid-ney cancer (second line and beyond) and Hodgkin lymphoma. Meanwhile the 2 other immune checkpoint inhibi-tors that have been FDA approved are atezolizumab for refractory bladder can-cer and pembrolizumab for nonsmall cell lung cancer, melanoma, and head and neck cancer. Two other immune checkpoint inhibitors, durvalumab and avelumab, are in phase 3 testing as well. Specifically for renal cancer there are 5 phase 3 trials in treatment naïve patients (see Appendix). How has this explosion of new drugs and treatment options for renal and bladder cancer come about, and why has it bypassed prostate cancer? Let’s begin with a few basic points about immunol-ogy.7 The 2 branches of the immune system are the innate (composed of macrophages, NK cells and dendritic cells) and the adaptive (composed of B and T cells). The innate side is an immediate response, needs no antigens and has no memory, while the adaptive is a delayed response, requires antigens and has memory. The adaptive immune response has 5 phases that begin with 1) recognition followed in turn by 2) activation and amplification, 3) elimi-nation, 4) contraction and 5) memory. The recognition phase is the responsi-bility of the macrophages and dendritic/APCs (antigen presenting cells) that present the foreign antigens to the T cells. The activation and amplification

phase represents T-cell activation and amplification which is carefully regu-lated to prevent inappropriate activa-tion. Such T cells can be differentiated

into fully activated effector cells. Phase 3 is elimination of the target by the T cells that target the antigens on foreign cells via binding to the MHC complex leading to cell mediated cytotoxicity. Phase 4 is contraction during which the activated T cells are eliminated to protect healthy cells. All T cells express PD-1 (programmed death-1 receptor) and other such receptors so they can be induced into cell death by other immune cells such as dendritic cells that carry PDL-1 (programmed death ligand-1 receptor). These receptors and their ligands are called immune check-point inhibitors. A few effector cells survive at low levels to provide long-lasting memory. In the case of cancer this same pro-cess, called the cancer immunity cycle,8 occurs but is dysregulated at numer-ous points. In its simplest form tumor antigens are released and engulfed/

phagocytized by dendritic cells (fig. 2, 1-2). This activates the dendritic cells to become APCs which present the antigens to T cells. The T cells in turn

need to enter the tumor via blood and lymphatic vessels, cause inflammation and theoretically lyse the tumor cells. Within the tumor microenvironment many factors conspire to inactivate the T cells but most notably many tumor cells up-regulate PDL-1 to activate and kill the invading T cells. Some T cells express B7.1 which also binds to PDL-1, and B7.1 may also inactivate the T cell. A third checkpoint inhibitor is PDL-2 found on normal epithelial cells and APCs. In the tumor microenvi-ronment other immune cells such as macrophages and dendritic cells may (mistakenly?) inactivate T cells. Tumor cells also express cytokines which may further up-regulate PDL-1 to protect against T-cell attack. In turn T cells counterattack with gamma interferon which can kill tumor cells. Thus, antibodies to PD-1 and PDL-1 strip the tumor cells of a major defense

▼ Continued from page 1

Figure 2. Cancer immunity cycle and agents that can disrupt the cycle8


against T-cell attack.9 The infiltrating T cells are not as readily inactivated and can induce cell mediated cytotoxic-ity. Numerous other agents are under development to augment immunologi-cal attack on the tumor (fig. 2). A reason that the patient described in the case report had such a good response may have been that he was on cabozan-tinib, an anti-VEGF agent that enhances T-cell infiltration into tumors (fig. 2, 5). The logic behind the trials listed in the Appendix is in part built on enhancing such T-cell attack. Of course tumors can resist. A recent study showed that melanoma cells resistant to checkpoint inhibitors are deficient in interferon receptor signaling pathways, render-ing them resistant to gamma inter-feron produced by T cells.10 Another study revealed that melanoma cells and tumors resistant to checkpoint inhibi-tors expressed beta catenin.11 Prostate cancer frequently overexpresses WNT/beta catenin,12 which may account for the low level of activity of check-point inhibitors in prostate cancer. In conclusion, there are a host of new antibodies that promise to revolution-ize the care of patients with urological cancers.

Appendix. First line phase 3 trials for patients with clear cell renal cell carci-nomaPhase 3 Design

Sponsor Activity

Atezolizumab plus beva-cizumab vs sunitinib

Roche/Genentech

Completed 2016

Nivolumab plus ipilimum-ab vs sunitinib

Bristol-Myers Squibb

Completed 2015

Pembroli-zumab plus axitinib vs sunitinib

Merck Ongoing

Pembroli-zumab plus lenvatinib vs lenvatinib plus everolimus vs sunitinib

Eisai Ongoing

Avelumab plus axitinib vs sunitinib

Pfizer Ongoing

1. Powles T, Sarwar N, Stockdale A et al: Safety and efficacy of pazopanib therapy prior to planned nephrectomy in metastatic clear cell renal cancer. JAMA Oncol 2016; 2: 1303.

2. Choueiri TK, Escudier B, Powles T et al: Cabo-zantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373: 1814.

3. Motzer RJ, Escudier B, McDermott DF et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373: 1803.

4. Brahmer JR, Tykodi SS, Chow LQ et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455.

5. Hodi FS, O'Day SJ, McDermott DF et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711.

6. Larkin J, Chiarion-Sileni V, Gonzalez R et al: Combined nivolumab and ipilimumab or mono-therapy in untreated melanoma. N Engl J Med 2015; 373: 23.

7. Abbas AK, Lichtman AH and Pillai S: Basic Immunology: Functions and Disorders of the Immune System, 4th ed. Philadelphia, Pennsylva-nia: Saunders Elsevier 2014.

8. Chen DS and Mellman I: Oncology meets immu-nology: the cancer-immunity cycle. Immunity 2013; 39: 1.

9. Sharma P and Allison JP: The future of immune checkpoint therapy. Science 2015; 348: 56.

10. Zaretsky JM, Garcia-Diaz A, Shin DS et al: Muta-tions associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016; 375: 819.

11. Spranger S, Bao R and Gajewski TF: Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015; 523: 231.

12. Ma F, Ye H, He HH et al: SOX9 drives WNT pathway activation in prostate cancer. J Clin Invest 2016; 126: 1745.


Immunotherapy for Urological Malignancies: Evolution of End Points and Future Directions

Daniel P. Petrylak, MD,* Director, Genitourinary Oncology Research Program, Co-Director, Signal Transduction Program, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut

For decades, cancer therapy has focused on administering extrinsic agents and therapeutic modali-ties to treat cancers by directly inducing

cell death (eg chemotherapy, hormonal ablation, radiation therapy). The obser-vation that tumors can spontaneously regress points toward an intrinsic mech-

anism of surveillance and eradication of tumors through the immune system, which plays a crucial role in all stages of tumor development and progression. Initially the immune system is able to eradicate nascent tumors from the epi-thelium. However, as tumors become genetically unstable and more hetero-geneous, the ability to eradicate tumors is lost and equilibrium is established. Tumor growth occurs when these vari-

ant tumors develop the ability to evade the immune system. Immune surveillance and tumor destruction can be simplified into 7 steps of 1) release of cancer cell anti-gens, 2) cancer cell antigen presentation to T cells, 3) priming and activation of T cells, 4) trafficking of T cells to tumors, 5) infiltration of T cells into tumors, 6) recognition of cancer cells by T cells and 7) destruction of cancer


*Financial and/or other relationship with Egenix, Bellicum, Ferring, Astra Zeneca, Johnson & Johnson, Dendreon, Boehringer Ingelheim, Medi-vation, Millineum, Prostate Cancer Education Council, Progenic, Celgene and Pfizer.


cells by the immune system. Thus, the immune mediated destruction of tumor cells involves infiltration of inflamma-tory cells into the tumor milieu, and so simple measurements of lesions on com-puterized tomography may not truly reflect the efficacy of an immune treat-ment, as it is impossible to distinguish tumor from immune cells with our current imaging technology. This is an important concept that urologists and oncologists will need to incorporate into patient care. Each of the 7 steps in tumor immune surveillance is mediated by a series of immune checkpoints and cytokines, which regulate immune activity to pre-vent excessive or prolonged activation. Thus, a mechanism is provided through which excessive or prolonged T-cell activation is avoided and normal tissue is preserved, which may result in tis-sue destruction and/or autoimmunity. T cells are regulated by a variety of co-stimulatory molecules (CD28 that binds to CD80 or CD86) as well as inhibi-tory molecules (CTLA-4 that binds to CD80 and CD86), PD-1 and PDL-1. However, up-regulation of PD-1/PDL-1 expression by tumor cells is thought to be a mechanism by which solid tumors evade or develop tolerance to immune regulation. A multitude of other stimu-latory and inhibitory ligands and recep-tors have been identified but to date the CTLA-4 and PD-1/PDL-1 path-ways have been the most extensively evaluated in genitourinary malignan-cies. Humanized monoclonal antibodies (mAbs) that block CTLA-4 (ipilimum-ab, tremelimumab), PD-1 (nivolumab, pembrolizumab) and PDL-1 (atezoli-zumab, durvalumab, avelumab) have all demonstrated antitumor responses in patients with bladder and kidney cancer. Activity has been demonstrated with PD-1 and PDL-1 antibodies in patient with metastatic urothelial cancer who had previously been treated with cispla-tin based therapy. Atezolizumab, pem-brolizumab, nivolumab and durvalum-

ab demonstrate response rates of 16.0%, 27.6%, 24.4% and 31%, respectively, in patients with urothelial cancer regard-less of expression of PDL-1 on tumor or immune cells. An update of the IMvigor 210 trial by Dreicer et al indicates caution when terminating treatment with checkpoint inhibitors too soon.1 In 310 patients with platinum treated metastatic urothe-lial carcinoma 1,200 mg atezolizumab was administered intravenously every 3 weeks until loss of clinical benefit. The overall objective response rate using RECIST (Response Evaluation Criteria in Solid Tumors) criteria was 16%, with 28% of patients with moderately or strongly positive stains for PDL-1 in the immune cells demonstrating objective response. What was particularly inter-esting about this update was the fact that in IMVigor 210 patients were permitted to be treated past progression if the investigator determined that they were gaining clinical benefit from treatment. Of 134 patients who met this criterion at least a 30% reduction in the target lesion was seen on the next radiographic evalu-ation in 28 (19%). A similar observation has been made in patients treated with checkpoint inhibition therapy for metastatic renal cancer. Motzer et al randomized 821 patients with metastatic clear cell renal cancer previously treated with a tyrosine kinase inhibitor to 3 mg/kg nivolumab intravenously every 2 weeks or 10 mg everolimus orally once a day.2 The hazard ratio for death from any cause with nivolumab vs everolimus was HR 0.73 (p=0.002) and objective response rates were nearly fivefold higher with nivolumab (25% vs 5%, p <0.0001). The issue of continued treatment past progression was addressed in this study, as well as in report by Escudier et al.3 In an ad hoc sensitivity analysis among patients who did not experience disease progression or death by 6 months (35% nivolumab and 31% everolimus) by Motzer et al median progression-free

survival (PFS) was 15.6 months with nivolumab vs 11.7 months with evero-limus (HR 0.64).2 The observation that the curves diverged after the median was reached suggests a potential delayed treatment effect with immunotherapy. In the study by Escudier et al overall median duration of treatment was 8.8 months in 38% of 406 patients given nivolumab who were treated past pro-gression and 2.3 months for those who were not treated past progression.3 From randomization to progression, objec-tive response rate was 20% and 14%, median time to response was 1.9 and 3.7 months, and duration of response was 5.6 and 7.0 months for those who were and were not treated past progression, respectively. Of 140 patients treated past progression with tumor measurements before and after progression 14% had ≥30% tumor burden reduction since first progression. The percentage of patients who had tumor burden reduction past progression is similar to that seen with atezolizumab in bladder cancer. In conclusion, the classic definitions of response and PFS do not fully cap-ture the efficacy of anti-PD-1 or PDL-1 therapy for urothelial and renal malig-nancies. This is an important concept for the urologist and the oncologist who may be administering checkpoint inhibition therapy. Careful evaluation of tumor related symptoms, radiographic data, and new imaging techniques are necessary to help better define response and distinguish between true disease progression and pseudo-progression.

1. Dreicer R, Hoffman-Censits J, Flaig T et al: Updated efficacy and > 1-y follow up from IMvigor210: atezolizumab (atezo) in platinum (plat) treated locally advanced/metastatic urothelial carcinoma (mUC). J Clin Oncol, suppl., 2016; 34: abstract 4515.


3. Escudier BJ, Motzer RJ, Sharma P et al: Treat-ment beyond progression with nivolumab (nivo) in patients (pts) with advanced renal cell carci-noma (aRCC) in the phase III CheckMate 025 study. J Clin Oncol, suppl., 2016; 34: abstract 4509.



Intravesical Immunotherapy for Bladder Cancer

Peter C. Black, MD,* Department of Urology, University of British Columbia, Vancouver, BC, Canada

Intravesical immu-notherapy in the form of bacillus Calmette-Guérin (BCG) has been the standard of care for patients with inter-mediate and high

risk nonmuscle invasive bladder can-cer (NMIBC) since its introduction by Morales in 1976.1 On the 40th anni-versary of this milestone discovery, sys-temic immunotherapy in the form of immune checkpoint inhibitors has taken the field of bladder cancer by storm. These agents have proven benefit as sec-ond line therapy for advanced urothelial carcinoma2 but they are being tested in all disease states, including NMIBC. In parallel to this intravesical immu-notherapy continues to evolve also on other fronts.

Enhancing BCG

Several new developments in intravesi-cal immunotherapy build on the suc-cess of BCG as an active therapeutic agent. Rentsch et al demonstrated in a prospective randomized trial that the Connaught strain of BCG was superior to the Tice strain in 142 patients with high risk NMIBC with respect to 5-year recurrence-free survival (74% vs 48%, p=0.01).3 Progression-free (94% vs 88%, p=0.34), disease specific and overall survival (OS) did not differ between groups. This trial has been criticized because no maintenance therapy was administered. Two subsequent retrospective analy-ses have addressed this same question. Witjes et al compiled 2,099 cases of high grade T1 bladder cancer from 23 centers treated with either Con-naught or Tice strains of BCG.4 They confirmed the findings of Rentsch et al

in patients who did not receive main-tenance therapy but the opposite was observed in 36% of the patients who did receive maintenance therapy with a better time to first recurrence with the Tice strain (HR 0.66, 95% CI 0.47–0.93, p=0.019). Steinberg et al reanalyzed the prospective phase II trial testing BCG vs BCG with interferon-α2b in a mixed population of 901 BCG naïve and BCG recurrent cases.5 Patients in both arms

received 15 months of maintenance therapy. The 2-year recurrence-free sur-vival was 44% for Tice and 47% for Connaught (p=0.53), indicating no dif-ference between strains. Unfortunately for our patients with NMIBC, Sanofi Pasteur announced on November 17, 2016 that they will per-manently discontinue production of the Connaught strain of BCG. The question of differences between strains, however, remains important. A clinical trial will be launched before the end of 2016 under the leadership of SWOG (trial S1602) to test the Tokyo strain of BCG against the Tice strain in patients with high risk NMIBC. If the Tokyo strain proves noninferior, it may facilitate entry of this strain into the North American market. The S1602 trial from SWOG will ask a second critical question. Preliminary evidence from preclinical models and population studies indicates that vac-

cination with BCG before intravesical BCG therapy may enhance treatment efficacy.6 In animal models the benefit of priming with vaccination is observed for the Tokyo but not the Tice strain. In the 3 study arms of S1602 patients receive Tice BCG, Tokyo BCG or Tokyo BCG after intradermal BCG vaccination (fig. 1). Vaccination could be a remarkably simple method to improve outcomes.

Another approach to improve BCG is through genetic engineering. BCG acts primarily after uptake into the phago-somes of antigen presenting cells such as macrophages and dendritic cells. The BCG is processed and presented in this manner through the MHC II path-way, which activates primarily CD4 T cells. Better immunogenicity would require presentation with MHC I to CD8 T cells. VPM1002BC is a BCG derived from the Prague subtype of the Danish BCG strain that has been engineered to express the listeria toxin listeriolysin. This pore forming toxin enhances antigen presentation by dis-rupting lysosomal and cell membranes, and inducing apoptosis in infected cells, thereby leading to better stimulation of CD8 T cells.7 This recombinant BCG has been tested intravesically in a dose escalation phase I trial that revealed no dose limiting toxicity.8 A phase II trial


*Financial and/or other relationship with GenomeDx Biosciences, Janssen, Astellas, Amgen, Sitka, Ferring, New B Innovation, Biosyent, Merck, iProgen, Bayer, AbbVie,, RedLeaf Medical, Biocancell and Roche/Genentech.

Figure 1. S1602 clinical trial scheme


(NCT02371447) is currently under way through the Swiss Group for Clinical Cancer Research. The development of MCNA (Myco-bacterium phlei cell wall-nucleic acid complex) by Bioniche Life Sciences, Endo Pharmaceuticals and Telesta Therapeutics was an attempt to take advantage of the immunomodulato-ry mechanisms of BCG while reduc-ing the associated toxicity. MCNA is an agent that contains mycobacte-rial cell wall fragments and nucleic acid derived from the nonpathogenic Mycobacterium phlei. Although clini-cal trials have demonstrated activity of MCNA9 they have not been con-ducted in a manner that has enabled this agent to obtain FDA (U.S. Food and Drug Administration) approval at this time. Heat Biologics is developing HS410, also known as Vesigenurtacel-L, as an intradermal vaccine to enhance the effects of intravesical BCG, although it is also being tested as a single agent immunotherapy. HS410 consists of a cancer cell line that has been selected for high expression of some bladder cancer antigens. The cells have been engineered to express high levels of the heat shock protein gp96, which after secretion, delivers the tumor antigens to the antigen presenting cells, which in turn activate a specific antitumor cytotoxic T-cell response (fig. 2). Results of a phase II trial (NCT02010203) of this agent with and without BCG in a mixed population of BCG naïve and BCG recurrent, intermediate and high risk NMIBC cases have been encourag-ing, and further clinical trials are antici-pated.10

Novel Intravesical Immunotherapies

Two intravesical viral therapies have entered clinical trials on NMIBC. The efficacy of each depends, at least in part, on immunomodulation. Dinney et al from MD Anderson Cancer Cen-ter in Houston, Texas developed an adenovirus that expresses recombinant

interferon-α2b (rAd-IFN).11 Interferon is a cytokine that is released by host cells in response to exposure to patho-gens but it can also induce tumor cell death through multiple mechanisms. rAd-IFN has been coupled with Syn3, a novel excipient that enhances viral uptake in the bladder wall and transfec-tion into target cells. Transfected cells secrete the interferon-α2b protein. After a single intravesical dose of the agent, therapeutic levels of interferon-α2b can be measured in the bladder for 7 days, which far exceeds what can be achieved with bolus intravesical administration of interferon. A phase I trial of an intravesical-ly delivered single dose rAd-IFN with Syn3 demonstrated an excellent safety profile and showed early signs of drug activity.11 A subsequent phase II trial in 40 patients with BCG unresponsive high risk NMIBC revealed a complete response (CR) rate of 50% and a durable 21-month CR rate of 30%.12 rAd-IFN was re-dosed at 3-month intervals up to 9 months in patients with a CR. A single arm registration trial in the same disease state is currently under way through the Society of Urologic Oncology-Clinical Trials Consortium. Preliminary molecu-lar analyses suggest that combination

with a checkpoint inhibitor would be worthy of further study. The other viral therapy that is current-ly in clinical trials is the CG0070 virus (Cold Genesys). The genes required for replication of this adenovirus are under the control of the human E2F-1 promot-er, which is activated only in cells that have defects in the Rb pathway. Loss of Rb signaling is particularly common in high risk bladder cancer. The virus replicates selectively in these tumors cells and causes cell lysis with release of virus that can further transfect adjacent cells. The virus is able to spread through the tumor but is incapable of replication outside the tumor. As an oncolytic virus, the immedi-ate effects of this agent are not strict-ly dependent on the immune system but the release of tumor antigen like-ly enhances the antitumor immune response. Furthermore, CG0070 also carries the gene for human granulo-cyte macrophage-colony stimulating fac-tor, which is a cytokine that has been shown to induce long-lasting specific antitumor immunity in animal models. CG0070 has demonstrated compelling efficacy results in phase I and phase II trials, and is currently being evaluated in a registration trial on BCG unre-



Figure 2. HS410/vesigenurtacel-L mechanism of action (modified from Heat Bio-logics).


sponsive high risk NMIBC (BOND2, NCT02365818). This trial is specifically studying treatment related changes in PDL-1 expression to establish the ratio-nale for possible combination therapy with a checkpoint inhibitor. Systemic administration of check-point blockers is an exciting strategy for immunotherapy of NMIBC. Three agents are being tested in single arm, phase II trials on BCG unresponsive high risk NMIBC, each following a potential path towards FDA registration (NCT02844816, NCT02901548 and NCT02625961). A potential alternative to systemic administration is intratumor-al injection of these agents, which would alleviate concerns for systemic toxicity. van Hooren et al have shown in mouse models of bladder cancer that intratu-moral injection of a CTLA-4 inhibitor was as effective as systemic admin-istration in reducing tumor burden but induced lower levels of circulating cytokines (fig. 3).13 Local anti-CTLA-4 therapy in combination with systemic anti-PD-1 therapy resulted in some com-

plete responses and was superior to each therapy alone. A trial strategy is being developed to test this approach in patients with bladder cancer. While checkpoint blockade fills the headlines, many other highly significant advances are being made with respect to intravesical immunotherapy, which promise to advance the field at least incrementally. BCG therapy is likely to continue to play an important role in the treatment of NMIBC for many years to come.

1. Morales A, Eidinger D and Bruce AW: Intracavi-tary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976; 116: 180.

2. Rosenberg JE, Hoffman-Censits J, Powles T et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have pro-gressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909.

3. Rentsch CA, Birkhäuser FD, Biot C et al: Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immuno-therapy. Eur Urol 2014; 66: 677.

4. Witjes JA, Dalbagni G, Karnes RJ et al: The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer. Urol Oncol 2016; 34: 484.e19.

5. Steinberg RL, Brooks N, Thomas LJ et al: Bacillus

Calmette-Guerin strain has no significant effect on recurrence-free survival when used intravesically with interferon-alpha2b for non-muscle invasive bladder cancer. Presented at annual meeting of the Society of Urologic Oncology, San Antonio, Texas, December 1-2, 2016.

6. Biot C, Rentsch CA, Gsponer JR et al: Preexisting BCG-specific T cells improve intravesical immuno-therapy for bladder cancer. Sci Transl Med 2012; 4: 137ra172.

7. Rentsch C, Wetterauer C, Gsponer J et al: A listeriolysin expressing BCG with favourable immunogenicity and preclinical toxicity as a novel treatment for non-muscle invasive bladder cancer. J Urol, suppl., 2014; 191: e428, abstract MP39-08.

8. Rentsch CA, Mayor G, Rieken M et al: Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure to conventional BCG therapy. Presented at annual meeting of the International Bladder Cancer Network, Bochum, Germany, October 28, 2016.

9. Morales A, Herr H, Steinberg G et al: Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guérin. J Urol 2015; 193: 1135.

10. Steinberg GD, Shore ND, Karsh L et al: Top-line results from vesigenurtacel-l (HS-410) in combina-tion with BCG from a randomized, blinded phase 2 trial in patients with non-muscle invasive blad-der cancer (NMIBC). Presented at annual meeting of the Society of Urologic Oncology, San Antonio, Texas, December 1-2, 2016.

11. Dinney CP, Fisher MB, Navai N et al: Phase I trial of intravesical recombinant adenovirus medi-ated interferon-alpha2b formulated in Syn3 for bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer. J Urol 2013; 190: 850.

12. Canter D, Park E, Boorjian S et al: Randomized phase II trial of intravesical adenoviral mediated interferon α gene therapy with the excipient Syn3 (rAd IFNα/Syn3) in patients with BCG refractory or relapsing high grade (HG) non muscle invasive bladder cancer (NMIBC). Presented at annual meeting of the International Bladder Cancer Net-work, Bochum, Germany, October 28, 2016.

13. van Hooren L, Sandin LC, Moskalev I et al: Intra-lesional administration of CTLA-4 blocking mono-clonal antibodies as a means to optimize bladder cancer therapy. Presented at annual meeting of the International Bladder Cancer Network, Bochum, Germany, October 28, 2016.

Figure 3. Intratumoral injection of anti-CTLA-4 in mouse model of bladder cancer. A, tumor before injection. B, needle is visualized in tumor. C, fluid bolus is visual-ized in tumor after injection.



Systemic Immunotherapy for Bladder CancerMark Schoenberg, MD,* Professor and Chair, Montefiore Medical Center and The Albert Einstein College of Medicine, Bronx, New York

Thucydides, (460-400 BCE), author of The History of the Peloponnesian War, noted that survivors of the Plague of Ath-ens (430 BCE) could care for the sick

without fear of experiencing disease recurrence, and in so doing introduced the concept of immunity. Centuries of investigation have produced a refined understanding of this complex aspect of human physiology, including the differences between the innate (ancient, highly conserved and immediate) and adaptive (acquired, slow, specific, T and B cell mediated) immune systems as well as their relevance to the devel-opment of cancer. Dr. William Coley’s observations in the 19th century connected acute infec-tion (and inflammation) with subse-quent tumor regression, and Dr. Lloyd Old provided evidence that immune stimulation by bacillus Calmette-Guérin (BCG) could be used to treat patients with melanoma. Morales intro-duced urologists to BCG for the treat-ment of carcinoma in situ of the blad-der, and Rosenberg et al demonstrated that the systemic administration of a

potent immune modulator, cytokine IL-2, could produce disease regression in a small proportion of patients with renal cell carcinoma and melanoma. Immunotherapy for cancer became familiar to urologists for the treat-ment of specific patient populations but the broader potential of this approach would await more specific elucidation of the mechanisms whereby tumors inter-act with and alter a phenomenon cur-rently known as immune surveillance. Although a variety of immunothera-peutic strategies have been pursued to treat cancer (vaccine therapy, chime-ric antigen receptor), recent advances in our understanding of T-cell biol-ogy related to specific molecules called checkpoints have resulted in the cre-ation of novel agents that have recently made their way into clinical practice. The modern era of applied immuno-mechanics was ushered in by inves-tigators who appreciated that specific T-cell populations provide a continu-ous surveillance system whereby the body is monitored for and protected against antigens that constitute “danger signals” (“nonself” antigens associated with viruses, bacteria or cancer cells).1 Danger signals are presented to specific T-cell populations by antigen present-

ing cells (APCs), which include macro-phages and dendritic cells that express MHC I and II proteins. Antigen pre-sentation stimulates CD4+ (T helper cells) and CD8+ (killer T cells) to coor-dinate the destruction of targets with exquisite specificity. This paradigm gives rise to a conceptual dilemma. If surveillance is efficient and the adaptive immune system is equipped to elimi-nate cancer cells as they arise through-out the life of the host, how does a malignant tumor develop? The answer appears to involve understanding how the immune system has evolved to strike a balance between its protective and destructive powers. That balance is now thought to be achieved, at least in part, through mul-tistep T-cell activation or inhibition elucidated by the pioneering work of many.2 They showed that 1) APC-MHC complexes are responsible for antigen presentation to T cells and since tumor cells lack MHC or co-stimulato-ry molecules, they do not stimulate a T-cell dependent, antitumor immune response; 2) tumor cell death results in tumor specific antigen release that can subsequently result in APC presenta-tion in the context of MHC, permit-ting T-cell receptor antigen interaction,


*Financial and/or other relationship with Urogen Pharma LTD.

Figure. A, T-cell APC interaction. B, T-cell tumor interaction. Reprinted with permission.3


which is the first step in T-cell activation (a process referred to as cross-prim-ing); 3) a second, co-stimulatory step is achieved by interaction of the T-cell surface receptor CD28 with B7 ligands on an APC; and 4) T-cell surface pro-teins such as CTLA-4 can interact with B7 proteins on the surface of APC to inhibit T-cell activation (part A of fig-ure).3 Another inhibitory checkpoint elaborated by tumor cells known as PD-L1 can interact with PD-1 on the T cell resulting in inhibition of T-cell acti-vation. The recently reported discovery of a new family of checkpoints, and a growing list of stimulatory and inhibito-ry cell surface molecules underscore the complexity of T-cell regulation and the opportunity presented by these novel targets for therapeutic intervention (part B of figure).4, 5

The immunogenicity of cancers appears to correlate with the intrinsic quantity of somatic mutations in a given cell.6 Melanoma, nonsmall cell lung cancer and urothelial bladder can-cer are characterized by some of the highest levels of mutational burden of all human malignancies. Somatic muta-tions are associated with cell surface neo-antigen generation by tumor cells. These antigens are recognized as for-eign by APC and T cells. The cytolytic function of T cells (particularly CD8+ T cells) is progressively suppressed as tumor cells induce PDL-1 which inter-acts negatively with the PD-1 receptor on the T-cell surface. Although the scientific foundation for exploiting this relative “antigenicity” coupled with our new understanding of T-cell activation was laid at the end of the 20th cen-tury, it was not until 2010 that check-point blocking monoclonal antibodies were shown to improve the survival of patients with cancer. Multicenter studies of patients with metastatic mela-noma resulted in FDA (U.S. Food and Drug Administration) approval of the CTLA-4 blocking antibody, ipi-limumab, in 2011. Approval of PD-1/PDL-1 blocking antibodies was granted in 2014 for patients with melanoma and lung cancer, and in early 2016 for

patients with metastatic urothelial can-cer after first line systemic therapy fails. Powles et al,7 Rosenberg et al,8 and Tsiatas and Grivas9 were among the first to report that the systemic admin-istration of PDL-1 blocking antibod-ies improved survival in patients with metastatic urothelial cancer. In addi-tion, these investigators noted that the response to systemic PDL-1 blocking antibody was greatest in patients with tumors or tumor infiltrating lympho-cytes that expressed PDL-1 by immuno-histochemistry (IHC). Rosenberg et al reported that tumor mutational burden predicted response to PDL-1 blockade in their cohort.8 Reports from several phase 2 trials, CheckMate-275 (Bristol-Myers Squibb) and KEYNOTE-052 (Merck), underscore the activity of immunotherapy in advanced urothelial cancer. The KEYNOTE study is note-worthy because it examined the effi-cacy of checkpoint blockade in cisplatin ineligible patients. Investigators for this trial have reported a 24% response rate overall and a 37% response rate in patients in whom 10% of tumor cells or tumor infiltrating lymphocytes expressed PDL-1. Predicting which patients with advanced urothelial cancer are most likely to respond to checkpoint block-ade is a matter of ongoing investiga-tion and debate. IHC for the pres-ence of checkpoint molecules in tumor specimens is currently used to identify individuals with a greater likelihood of response but clinical trial data sug-gest that even patients with low levels or absent checkpoint protein in the tumors may benefit from blockade for reasons that remain obscure. It is pos-sible that the transient expression of checkpoint molecules leads to relative underestimation of their expression in individual tumor specimens. Con-founding the matter is lack of agree-ment among investigators about the clinical significance of different degrees of checkpoint IHC staining. Develop-ment of companion biomarkers for the various checkpoint inhibitors will be required to optimize application of

these powerful new agents. Manipulation of the immune system by checkpoint blockade has produced remarkable results in patients with sev-eral dire forms of malignancy, includ-ing advanced urothelial cancer. Tumors evade destruction when checkpoint molecules are used to circumvent the normal homeostatic influences of the adaptive immune system. As clinicians attempt to restore normal surveillance mechanisms through the administration of blocking antibodies, off-target inflam-matory effects have emerged as a new type of treatment associated morbid-ity known as immune related adverse events (IRAEs). The toxicity associated with checkpoint blockade appears to vary depending on which agent is used but these drugs are generally associ-ated with inflammatory changes that can impact multiple organ systems (fig. 2).10 Most IRAEs can be managed with steroids and most resolve with treat-ment. Of importance, since the long-term effects of checkpoint blockade are currently unknown, it will be important to monitor patients for late IRAEs, par-ticularly those who require an extended course of treatment. Although immune checkpoint inhibi-tors are being rapidly integrated into management schemes for patients with advanced urothelial cancer, attention has also focused on the relevance of these agents to the treatment of local-ized disease. Treatment of stage T1-T2 disease with checkpoints in the neo-adjuvant setting is under way. These agents may also have a role in trimodal-ity (bladder sparing) protocols in com-bination with transurethral resection and radiation therapy. Finally, check-points are currently under investigation as potential therapy for BCG refracto-ry nonmuscle invasive bladder cancer when administered either systemically or intravesically.11 The results of these trials are eagerly anticipated by urolo-gists seeking more effective tools for treating patients with this potentially life threatening disease. Acknowledgement. The author is indebt-ed to Drs. Gary Steinberg, Xingxing




Zang and Dean Bajorin for helpful sug-gestions related to this article.1. Matzinger P: The evolution of the danger theory.

Interview by Lauren Constable, Commissioning Editor. Expert Rev Clin Immunol 2012; 8: 311.

2. Allison JP: Immune checkpoint blockade in cancer therapy: the 2015 Lasker-DeBakey Clini-cal Medical Research Award. JAMA 2015; 314: 1113.

3. Donin NM, Lenis AT, Holden S et al: Immuno-therapy for the treatment of urothelial carcinoma. J Urol 2017; 197: 14.

4. Janakiram M, Shah UA, Liu W et al: The third group of the B7-CD28 immune checkpoint fam-

ily: HHLA2, TMIGD2, B7x and B7-H3. Unpub-lished results.

5. Zhou TC, Sankin AI, Porcelli SA et al: A review of the PD-1/PD-L1 checkpoint in bladder can-cer: from mediator of immune escape to target for treatment. Urol Oncol 2016; doi: 10.1016/j.urolonc.2016.10.004.

6. Liontos M, Anastasiou I, Bamias A et al: DNA damage, tumor mutational load and their impact on immune responses against cancer. Ann Transl Med 2016; 4: 264.

7. Powles T, Eder JP, Fine GD et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515: 558.

8. Rosenberg JE, Hoffman-Censits J, Powles T et al:

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909.

9. Tsiatas M and Grivas P: Immunobiology and immunotherapy in genitourinary malignancies. Ann Transl Med 2016; 4: 270.

10. Michot JM, Bigenwald C, Champiat S et al: Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54: 139.

11. Singh P and Black P: Emerging role of checkpoint inhibition in localized bladder cancer. Urol Oncol 2016; 34: 548.

Immunotherapy for Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the eighth most common cause of cancer in the United States with more than 60,000 new cases diagnosed each year. Approximately a third of the patients present with metastatic RCC (mRCC) requiring systemic therapy. Addition-ally, of the 70% of patients with local-ized disease that is amenable to surgical resection 20% to 30% will ultimately have advanced disease requiring sys-temic therapy.1 Overall, more than half of the patients with RCC will, at some point during the disease course, require systemic therapy. Despite significant advancements in the last decade in the development of targeted therapies in the form of vascu-lar endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and mammalian target of rapamycin inhibi-tors, median OS remains relatively poor at 22 to 29 months, and newer agents are sorely needed. The emergence of

immunotherapy in the form of immune checkpoint inhibitors that target PD-1, PDL-1 and CTLA-4 has revolutionized the treatment of a variety of cancers in the last few years. The expression and interaction between PD-1 on T cells and PDL-1 on tumor and tumor infiltrating cells can induce inhibition of the immune system, resulting in less effective immuno-surveillance and thus tumor progression. Antibodies against checkpoint inhibitors, eg PD-1, PDL-1 and CTLA-4, serve to overturn this immune inhibition and reestablish a robust antitumor immune response.2, 3

Role of RCC Immunotherapy

Before the early 2000s, the only FDA (U.S. Food and Drug Administration) approved therapy for mRCC was high dose interleukin-2 (HD IL-2), which was also one of the first immunotherapeutics ever used in oncology. The benefits of HD IL-2 are well established and rest in its ability to lead to a durable response in approximately 5% to 10% of patients.4 Unfortunately, the pro-inflammatory cytokine storm induced by HD IL-2 results in significant toxicity that often requires intensive care unit monitoring. Indeed, the rate of death secondary to IL-2 therapy is as high as 4%.4 As such, despite its ability to produce a long-term response in a small subset of patients, given the relatively high morbidity and rare mortality associated with its use, HD IL-2 treatment is limited to highly specialized centers, and reserved for

young patients with good performance status and minimal comorbidities, typi-cally with clear cell histology. A number of models incorporating clinical param-eters, disease burden, histology and bio-markers have been investigated to select those patients most likely to benefit from HD IL-2 but currently no uniformly accepted predictive model exists.5 In addition to the relatively infre-quently used HD IL-2, immunotherapy with the cytokine interferon-alfa (IFNa) has significant historical precedent in mRCC. However, currently there is no role for IFNa as monotherapy based on studies (notably, CALGB 90206 and AVOREN) that demonstrated superi-or outcomes when IFNa is combined with bevacizumab compared to the use of IFNa alone. Given the plethora of agents currently approved for mRCC, the role for IFNa as monotherapy or even combined with bevacizumab is cur-rently limited.

Current Update on RCC Immunotherapy

Unlike the high toxicities seen with the use of HD IL-2, immunotherapy with checkpoint inhibitors is far better toler-ated. Nivolumab is an IgG4 antibody inhibitor of PD-1 and was the first checkpoint inhibitor to receive FDA approval for the treatment of mRCC. CheckMate 025 was a phase III trial that compared nivolumab to the standard of care everolimus in 821 patients with mRCC and disease progression fol-


*Financial and/or other relationship with Roche/Genentech, Bristol-Myers Squibb, Merck, Exelixis, Astra Zeneca, Dendreon and Bayer.

Moshe C. Ornstein, MD, MA

Petros Grivas, MD, PhD*


Department of Hematology and Medical Oncol-ogy, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio


lowing treatment with VEGF targeted therapy.6 The patients were random-ized in 1:1 fashion to receive nivolumab or everolimus. The study met its pri-mary outcome demonstrating superior median OS with nivolumab compared to everolimus (25.0 vs 19.6 months, HR 0.73, 98.5% CI 0.57-0.93, p=0.002). Similarly the overall response rates were superior in the nivolumab arm (25% vs 5%, OR 5.98, 95% CI 3.68-9.72, p <0.001), while toxicity and quality of life also favored nivolumab. Based on these findings, in November 2015 the FDA approved the use of nivolumab in patients with advanced RCC who had been previously treated with an anti-angiogenic agent. A benefit of immunotherapy is the potential for rapid and durable respons-es. Although only approximately 25% of patients treated with nivolumab achieve some response, a relatively high propor-tion of patients demonstrate a sustained response. In phase I and phase II trials of nivolumab for mRCC the survival rates were 41% and 34% at 3 and 5 years, respectively, for 34 patients in the phase I trial, and 35% of 167 patients in phase II were alive at 3 years, suggest-ing that a subset of responders have a durable response.7 Currently, nivolumab remains the only approved immune checkpoint inhibitor for mRCC. However, despite a year since its approval, many questions about its use remain unanswered. For instance, a subset of patients who discon-tinue nivolumab for toxicity maintain response to therapy despite not actively receiving the drug. This begs the ques-tion of the necessary duration of ther-apy to sustain a response and whether patients need to be indefinitely treated with continuous nivolumab or whether they can be given extended breaks or come off therapy at some point alto-gether. Similarly, “pseudo-progression” (ie early radiographic appearance of pro-gression due to tumor infiltration and not actual tumor growth) can potentially result in patients transitioning to a subse-quent line of therapy without the oppor-tunity to potentially benefit further from

nivolumab. Therefore, further defining the role of nivolumab continuation at the time of radiological progression is critical and involves multifactorial clinical deci-sion making, which applies in general to immunotherapeutic modalities. Other questions yet to be answered about nivolumab therapy is the detection of a clear biomarker to predict which patients should be offered a different treatment instead. A number of studies are assessing the immuno-modulatory effects of nivolumab to help prospectively identify biomarkers to predict response but nothing of clinical usefulness has been developed. Importantly, however, PDL-1 expression seems to be prognostic of poorer outcome but was not shown to predict response to nivolumab.6 More studies are needed to discover and vali-date putative biomarkers.

Future Directions for RCC Immunotherapy

In addition to other areas of interest, the future of immunotherapy for RCC can be divided into 1) assessment of novel immune checkpoint inhibitors; 2) use of checkpoint inhibitors for treatment naïve mRCC as well as in neoadju-vant and adjuvant settings; 3) combi-nations and/or sequences with other therapies (immunotherapies, targeted or other therapies); 4) potential treatment with anti-PDL-1 after progression on nivolumab; and 5) delineation of inher-ent and acquired resistance mechanisms to inform future clinical trial designs. Another novel checkpoint inhibitor currently in development for mRCC is ipilimumab, an anti-CTLA-4 mono-clonal antibody. Early studies of ipilim-umab in combination with nivolumab demonstrated high response rates and PFS,8 while a phase III trial (CheckMate 214) with ipilimumab/nivolumab com-bination vs sunitinib completed enroll-ment and results are pending. Other immune checkpoint inhibitors in ongo-ing or completed phase II and III trials for mRCC are the PDL-1 inhibitors atezolizumab (NCT02420821), avelum-ab (NCT02684006) and durvalumab, and the PD-1 inhibitor pembrolizumab,

all of which are being tested either alone or combined with other agents.9 The role of immune checkpoint blockade in the neoadjuvant and/or adjuvant setting is also being investigated in a num-ber of clinical trials that are industry sponsored, investigator initiated or from cooperative groups (NCT02575222 and NCT0221011). The plethora of immu-notherapy trials in mRCC suggests that it is foreseeable that immunotherapy could potentially change the treatment landscape of mRCC, while the devel-opment of predictive biomarkers and refined clinical assessment tools may fur-ther improve patient selection, clinical use and benefit-to-risk ratio of several agents. In addition to checkpoint inhibitors and HD IL-2, a potential role remains for immunotherapy with vaccines for RCC. Recently, results of the large phase III trial IMPRINT investigat-ing the multi-peptide cancer vaccine IMA901 in combination with sunitinib for mRCC demonstrated no OS ben-efit.10 However, other vaccines con-tinue to show promise in this setting. The autologous dendritic cell vaccine, AGS-003 demonstrated promising PFS and OS outcomes in a phase II trial.11 The phase III ADAPT trial comparing sunitinib with or without AGS-003 has completed accrual and results are pend-ing (NCT01582672).

Conclusions

It’s an exciting time for immunotherapy in oncology in general and for RCC in particular. With HD IL-2 as an option for select patients and nivolumab as an accepted standard of care after anti-angiogenic therapy, many patients with mRCC are benefiting. Although many questions remain about the currently approved therapies, and the develop-ment of additional immunotherapeu-tics and novel combinations/sequences, the future of immunotherapy for RCC remains bright. Further understanding of RCC molecular biology and immu-nology is essential, and can support the rationale development of breakthrough treatments.




1. Dabestani S, Thorstenson A, Lindblad P et al: Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 2016; 34: 1081.

2. Brahmer JR, Tykodi SS, Chow LQ et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455.

3. Topalian SL, Hodi FS, Brahmer JR et al: Safety, activity, and immune correlates of anti-PD-1 anti-body in cancer. N Engl J Med 2012; 366: 2443.

4. Fyfe G, Fisher RI, Rosenberg SA et al: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995; 13: 688.

5. McDermott DF, Cheng SC, Signoretti S et al: The high-dose aldesleukin "select" trial: a trial to pro-spectively validate predictive models of response

to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015; 21: 561.


7. McDermott DF, Motzer RJ, Atkins MB et al: Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II stud-ies. J Clin Oncol, suppl., 2016; 34: abstract 4507.

8. Hammers HJ, Plimack ER, Infante JR et al: Expanded cohort results from CheckMate 016: a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol, suppl., 2015; 33: abstract 4516.

9. McDermott DF, Sosman JA, Sznol M et al: Atezolizumab, an anti-programmed death-ligand

1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune cor-relates from a phase Ia study. J Clin Oncol 2016; 34: 833.

10. Rini BI, Stenzl A, Zdrojowy R et al: IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2016; 17: 1599.

11. Amin A, Dudek AZ, Logan TF et al: Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J Immu-nother Cancer 2015; 3: 14.

Immunotherapy for Prostate CancerSusan F. Slovin, MD, PhD, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, New York

Immuno the r apy has taken on a new guise. While initially thought of as large-ly investigational, it relied heavily on the identification of

novel tumor antigens around which the therapy was designed. DNA, viral and carbohydrate vaccines with and without carriers, immune adjuvants or unusual administration platforms such as a gene gun have all met with lim-ited success as have many clinical trials. Ironically, these suboptimal approaches have paved the way toward a better understanding of how the immune sys-tem can be altered to facilitate antitumor responses. Enthusiasm for reexploring immune therapy was debuted with FDA (U.S. Food and Drug Administration) approv-al of sipuleucel-T (APC 8015) as the first immunotherapy to provide a survival benefit for a solid tumor, prostate can-cer. It is an autologous cellular product therapy that capitalizes on the expansion and effector function of dendritic cells (CD54+) (fig. 1). In the pivotal phase III trial of asymp-tomatic or minimally symptomatic pros-tate cancer 352 men were randomized 2:1 in favor of the therapy arm.1 The cells were incubated with a prostatic acid

phosphatase fusion protein coupled with granulocyte macrophage-colony stimu-lating factor (GM-CSF) and then admin-istered as 3 separate infusions each 2 weeks apart. While generally well tolerated, the most common side effects

occurred during infusions and included chills, fatigue, fever, back pain, nausea, joint ache and headache with rare car-diovascular events such as stroke, pul-monary embolus and transient ischemic attacks. Despite the median survival



Figure 1. Overview of dendritic cell (DC) function indicating multiplicity of effec-tor DCs that can influence behavior of T cells including immunity, tolerance and immune deviation. CTL, cytotoxic T lymphocyte. TCR, T-cell receptor. Reprinted with permission from Sousa CR: Nature Rev Imm 2006; 6: 476.


benefit of 4.1 months, minimal or no antitumor responses were seen.

The original trials did not follow patients beyond 6 months but, while there might have been some immune enhancement, the development of an antitumor response might have taken longer than anticipated with a cytotoxic agent or a checkpoint inhibitor. This extrapolation was based on observations with checkpoint inhibitors for melanoma which first showed a disease flare on imaging followed by delayed disease regression (see Appendix). This has not been the case for prostate cancer. However, sipuleucel-T appears to have a subtle impact within the immu-nologic milieu. There is evidence to suggest that antigen specific T and B cell responses can be generated early, ie after the first infusion, which could be res-stimulated subsequently in vitro. Cytokines associated with T-cell activa-tion were detected and could later be

detected in the cell culture fluids follow-ing the second and third stimulations. The cytokines, interleukins (IL) 2, 4, 5, 6, 10, 13 and 17, and interferon gamma were detected. Tumor necrosis factor-alpha was also induced. T-cell activation markers CD134 and CD136 on CD4+ and CD8+ T cells were increased after culture with the fusion protein. Recall responses suggestive of sensitivity to the treatment were detected.2, 3 An alternate mechanism of action, antigen spreading (fig. 2), was evaluated by analyzing sera from patients in the phase III IMPACT trial.4 Of the evalu-able sera the presence of IgG responses against secondary antigens was consis-tently observed 3 to 4 months after treat-ment in the sipuleucel-T arm but not in the control arm. IgG responses against an array of secondary antigens, includ-ing an oncogene (K-RAS) and a pros-tate specific antigen (PSA) (KLK2/hK2), were confirmed in sipuleucel-T treat-

ed patients, while responses were not observed in control patients.4 Antigen spread was observed after sipuleucel-T treatment in ProACT, an independent study in patients with metastatic castra-tion-resistant prostate cancer (mCRPC). In IMPACT overall survival was longer for patients treated with sipuleucel-T with IgG response greater than or equal to 2 secondary antigens than in those without such response.4

Sipuleucel-T

Earlier rather than later? Many urolo-gists have considered exploiting the sub-tle effects of sipuleucel-T in biochemical-ly relapsed prostate cancer after primary therapy as this therapy may change the immune milieu earlier in the disease pro-cess making subsequent therapies more effective. To date, there have been no convincing data to support its earlier use. Attempts to enhance this approach have been made by others including combi-



Figure 2. Antigen spreading. Cytokine activation of APCs can induce increased protease production and different processing of captured self-antigens, resulting in presenta-tion of cryptic epitopes. Presentation of these cryptic epi-topes can activate self-reactive TH1 cells. Reprinted with permission from Vanderlugt CL and Miller SD: Nature Rev Imm 2002; 2: 85.

Figure 3. Summary of overall survival metastatic castration resistant prostate cancer trials by baseline ng/ml PSA (*). Reprinted with permission from Schellhammer PF, Chodak G, Whitmore JB et al: Urology 2013; 81: 1297.


nation of sipuleucel-T with biological agents such as GM-CSF, chemotherapy or radiopharmaceuticals (fig. 3).

Immune Platforms

Despite the enthusiasm for using immu-notherapy for prostate cancer, the over-all response rates using different plat-forms have been suboptimal. PROST-VAC, a DNA vaccine comprised of a recombinant vaccinia vector as the pri-mary immunotherapy backbone,5 has a unique design platform that engen-ders a more diverse immunological co-stimulation. It is followed by booster immunization using a recombinant fowlpox vector. The vectors contain transgenes for PSA and “TRICOM,” the latter being 3 co-stimulatory mol-ecules intracellular adhesion molecule-1 (CD54), B7.1 (CD80) and leukocyte function-associated antigen-1 (CD58). Unlike sipuleucel-T, this construct was based on the inherent immunogenicity of the pox virus. An anti-PSA directed T-cell response was generated and other antigens were potentially exposed that could activate other T cells. This was in part thought to be how sipuleucel-T works via antigen spreading. Results of phase I and phase II trials have been encouraging with the phase II trial sug-gesting a survival benefit comparable to that of sipuleucel-T.5 The results of the completed pivotal phase III trial are eagerly awaited.

Checkpoint Inhibitors for Prostate Cancer

Significant and durable responses have been seen with checkpoint inhibitors used for renal6 and bladder7 cancers. Unlike prostate cancer, bladder and kid-ney cancers have always been thought to have an immune basis for their response to therapies, including the observa-tions of sudden regression of metastatic disease when the primary lesion was removed. In superficial bladder cancer the addition of bacillus Calmette-Guérin (BCG), a weakened bacterial patho-gen well known as an immunological

adjuvant, has served as an immune modulator. Its mechanism of action is predicated on the generation of a local inflammatory response but new data suggest that there may be more defined mechanisms at play. Bladder cancer is one of several solid tumors, including melanoma, renal cell and nonsmall cell lung cancers, that are hypermutated. Huang et al reported that mutations such as a PTEN deficiency could render multiple types of cells hyper-susceptible to infection by Mycoplasma and BCG.8 This conclusion was based on the obser-vation that the lipid phosphatase activity of PTEN is required for attenuating infection. Prostate cancer was the first genito-urinary malignancy to be treated with the monoclonal antibody ipilimumab directed against the checkpoint molecule CTLA-4.9 Ipilimumab was approved for melanoma in the setting of improved survival and antitumor effects. CTLA-4 is a protein receptor that resides with-in the T cells and down-regulates the

immune system. Upon T-cell engage-ment with dendritic or antigen present-ing cells (APCs), the T cell must have certain co-stimulatory molecules that tell it to either proliferate or abort its interac-tion with the APC. CD28 and CTLA-4 are receptors on T cells that play key roles in the initial activation and control of cellular immunity. CD28 provides a co-stimulatory signal upon binding to target ligands on APCs. Converse-ly, CTLA-4 is transiently expressed following T-cell activation. The signal delivered via CTLA-4 down-regulates T-cell function and inhibits excessive expansion of activated T cells acting as a brake. A phase I/II dose-escalating trial of ipilimumab alone or following radia-tion to bone lesions, the latter done to induce antigen release, in patients with mCRPC demonstrated safety and toler-ability in both arms.9 A small number of anticipated autoimmune events such as colitis and hypophysitis occurred, regardless of dose, and required treat-



Figure 4. Identifying appropriate patient who can benefit from immune therapies remains unclear, although tumor mutational load, intensity of infiltration of intra-tumoral CD8+ T cells, and expression of PD-1 and PDL-1 may be of benefit as biomarkers of response to checkpoint therapies such a pembrolizumab. As seen in diagram, there is significant functional interrelationship among these factors which may be unique to the individual tumor. Reprinted with permission from Topalilan SL, Taube JM, Anders RA et al: Nat Rev Cancer 2016; 16: 275.



ment with high doses of steroids. Most of these events resolved with time but some patients had residual autoim-mune disease that mandated perma-nent dependence on steroids. Several patients sustained durable remissions but a phase III trial of ipilimumab with or without prior radiation in patients after docetaxel failed did not confirm an overall survival benefit (fig. 2).10 There was also the suggestion that patients with visceral metastases had a worse prognosis and poorer survival.10 Benefits of combining ipilimumab with vaccines have been suggested. A recent analysis of the CA184-095 final study results indicated that this ran-domized, double-blind, phase III trial in asymptomatic or minimally symp-tomatic patients with mCRPC did not meet its primary end point for OS but demonstrated modest improvements in PFS and PSA response after treatment with ipilimumab versus placebo.11 Two large randomized trials have now con-clusively shown that ipilimumab does not extend OS in unselected populations of patients with mCRPC but results in measurable antitumor activity. Given the selectivity of responses, it may be that unique biomarkers may portend benefit to these drugs (fig. 4).12 Recent phase I data indicated activity of the PD-1 checkpoint inhibitor pem-brolizumab in patients with mCRPC.13 Pembrolizumab is a human monoclonal antibody against PD-1 CD279, which is a cell surface receptor expressed on T cells and pro-B cells. PD-1 binds to ligands PDL-1 and PDL-2. PDL-1 is highly expressed on cancer cells and may facilitate cancer immune evasions.

Patients with disease progression while on enzalutamide were treated with pem-brolizumab every 3 weeks for 4 doses. An early unexpected signal of complete responses was seen in a small number of patients with advanced visceral disease. Activity of this drug in prostate cancer awaits confirmation in larger studies. Another approach is “armored” or chimeric antigen receptor directed T cells, whereby the patient’s own T cells can be redirected to recognize and kill tumor cells that express a particular antigen on its surface. Significant anti-tumor responses have been seen in hematologic malignancies but are limit-ed in prostate cancer.14-16 In conclusion, immunotherapy is a viable avenue of endeavor that merits continued efforts.

Appendix. What we need from immu-notherapy

• Product needs to be off-the-shelf• Minimal and tolerable side effects• Reasonable costs• Anticipated time to treatment effect• Assessment of biological effect either

through standard imaging or rel-evant biomarkers

• Accountability for possible pseudo-progression

1. Kantoff PW, Higano CS, Shore ND et al: Sipu-leucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411.

2. Sheikh NA, Petrylak D, Kantoff PW et al: Sipuleu-cel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical tri-als in men with castration-resistant prostate cancer. Cancer Immunol Immunother 2013; 62: 137.

3. Mulders PF, De Santis M, Powles T et al: Tar-geted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy. Cancer Immunol Immunother 2015; 64: 655.

4. Drake CG, Fan L-Q, Thakurta DG et al: Antigen

spread and survival with sipuleucel-T in patients with advanced prostate cancer. J Clin Oncol, suppl., 2014; 32: abstract 88.

5. Kantoff PW, Schuetz TJ, Blumenstein BA et al: Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28: 1099.

6. Rosenberg JE, Hoffman-Censits J, Powles T et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have pro-gressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909.


8. Huang G, Redelman-Sidi G, Rosen N et al: Inhibi-tion of mycobacterial infection by the tumor sup-pressor PTEN. J Biol Chem 2012; 287: 23196.

9. Slovin SF, Higano CS, Hamid O et al: Ipilim-umab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol 2013; 24: 1813.

10. Kwon ED, Drake CG, Scher HI et al: Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700.

11. Beer TM, Kwon ED, Drake CG et al: Random-ized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemothera-py-naive castration-resistant prostate cancer. J Clin Oncol 2016; doi: 10.1200/JCO.2016.69.1584.

12. Topalian SL, Taube JM, Anders RA et al: Mech-anism-driven biomarkers to guide immune check-point blockade in cancer therapy. Nat Rev Cancer 2016; 16: 275.

13. Graff JN, Alumkal JJ, Drake CJ et al: Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 2016; doi: 10.18632/oncotarget.10547.

14. Gade TP, Hassen W, Santos E et al: Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res 2005; 65: 9080.

15. Junghans RP, Ma Q, Rathore R et al: Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate 2016; 76: 1257.

16. Slovin SF, Wang X, Hullings M et al: Chimeric antigen receptor (CAR+) modified T cells target-ing prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). J Clin Oncol, suppl., 2013; 31: abstract 72.

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Genete

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

THE NEXT ERA OF TREATMENT

TECENTRIQ®: THE FIRST AND ONLY FDA-APPROVED ANTI-PDL1 CANCER IMMUNOTHERAPY

For previously treated locally advanced or metastatic urothelial carcinoma

PD-L1=programmed death-ligand 1.

IndicationTECENTRIQ (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:• Have disease progression during or following platinum-containing chemotherapy• Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapyThis indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety InformationSerious Adverse Reactions

Please refer to the full Prescribing Information for important dose management information specific to adverse reactions.

Immune-Related Pneumonitis• Immune-mediated pneumonitis or interstitial lung disease, including 2 fatal cases, occurred with TECENTRIQ treatment• Across clinical trials, 2.6% of patients developed pneumonitis• Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer steroids for ≥Grade 2 pneumonitis.

Withhold TECENTRIQ until resolution of Grade 2 pneumonitis. Permanently discontinue for Grade 3 or 4 pneumonitis

Immune-Related Hepatitis• Immune-mediated hepatitis, including a fatal case, and liver test abnormalities have occurred with TECENTRIQ treatment• Across clinical trials, Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%). In patients with

urothelial carcinoma(UC), immune-mediated hepatitis occurred in 1.3% of patients• Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment• Administer corticosteroids for ≥Grade 2 transaminase elevations, with or without concomitant elevation in total bilirubin.

Withhold TECENTRIQ for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis

TECENTRIQ® DELIVERED DURABLE RESPONSES

ONE FIXED DOSE, ONCE EVERY 3 WEEKS

UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY

EVERY3 WEEKS

FIXED DOSE1200 MG IV

60-MINUTEINITIAL INFUSION

30-MINUTESUBSEQUENT INFUSIONS

IF TOLERATED

Recommended dosing and administration1

Infection• Severe infections, including sepsis, herpes encephalitis, and mycobacterial

infection leading to retroperitoneal hemorrhage occurred in patients receiving TECENTRIQ

• Across clinical trials, infections occurred in 38.4% of patients• In urothelial carcinoma, infection occurred in 37.7% of patients. Grade 3

or 4 infection occurred in 11.5% of patients, while 3 patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 7.1% of patients

• Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold TECENTRIQ for ≥Grade 3 infection

Infusion-R elated reactions• Severe infusion reactions have occurred in patients in clinical trials of

TECENTRIQ. Infusion-related reactions occurred in 1.7% in UC• Interrupt or slow the rate of infusion in patients with mild or moderate

infusion reactions. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions

Embryo-Fetal Toxicity• Based on its mechanism of action, TECENTRIQ can cause fetal harm when

administered to a pregnant woman. Advise pregnant women or women planning to become pregnant of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose of TECENTRIQ

Nursing Mothers• Because of the potential for serious adverse reactions in breastfed infants

from TECENTRIQ, advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose

Most Common Adverse ReactionsThe most common adverse reactions (rate ≥20%) in UC included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%).You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see Brief Summary of Prescribing Information on adjacent pages.

References: 1. TECENTRIQ Prescribing Information. Genentech, Inc. May 2016. 2. US National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02108652. Accessed August 26, 2016.

Learn more at TECENTRIQ.com/info

• Do not administer as an IV push or bolus

• Do not co-administer other drugs through the same IV line

Most common adverse events1

• The most common adverse events (≥20%) included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%)

— Incidence of grade 3 to 4 adverse events included fatigue (6%), decreased appetite (1%), nausea (2%), urinary tract infection (9%), pyrexia (1%), and constipation (0.3%)

Important Safety Information (cont’d)

PD-L1 testing is not required to prescribe TECENTRIQ

IMvigor210 was a Phase II, multicenter, open-label, 2-cohort trial that included a cohort of 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following a platinum-containing regimen, or within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant regimen. Patients were treated with TECENTRIQ 1200 mg IV q3w. Major efficacy endpoints included ORR as assessed by IRF using RECIST v1.1 and DoR.1,2

CI=confidence interval; CR=complete response; DoR=duration of response; IRF=independent review facility; IV=intravenous; ORR=objective response rate; PR=partial response; q3w=every 3 weeks; RECIST=Response Evaluation Criteria In Solid Tumors.+ denotes censored value.

*Number of IRF-assessed confirmed responders.

• 22% ORR in patients with disease progression following prior neoadjuvant or adjuvant therapy (n=13/59; 95% CI, 12.3, 34.7)

ORR DoR (14.4-month median follow-up)

14.8% ORR(n=46/310*; 95% CI, 11.1, 19.3)

5.5%CR

9.4%PR

MEDIAN DoR NOT REACHED(range: 2.1+, 13.8+)

© 2016 Genentech USA, Inc. All rights reserved. PDL/101215/0083


Durable responses demonstrated across all patients (median follow-up: 14.4 months)1

Immune-Related Colitis• Immune-mediated colitis or diarrhea, including a fatal case of diarrhea-

associated renal failure, have occurred with TECENTRIQ treatment• Across clinical trials, colitis or diarrhea occurred in 19.7% of patients. In UC,

immune-mediated colitis or diarrhea occurred in 0.8% of patients• Monitor patients for signs and symptoms of diarrhea or colitis. Withhold

TECENTRIQ for Grade 2 or Grade 3 diarrhea or colitis. Permanently discontinue for Grade 4 diarrhea or colitis

Immune-Related Endocrinopathies• Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and

type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving TECENTRIQ. Monitor patients for clinical signs and symptoms of endocrinopathies

• Across clinical trials hypo- and hyperthyroidism occurred in 3.9% and 1.0% of patients, respectively. For symptomatic hypothyroidism, withhold TECENTRIQ and initiate hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold TECENTRIQ and initiate an anti-thyroid drug as needed

• Across clinical trials, adrenal insufficiency occurred in 0.4% of patients. For symptomatic adrenal insufficiency, withhold TECENTRIQ and administer corticosteroids

• Hypophysitis occurred in 0.2% of patients with UC. Administer corticosteroids and hormone replacement as clinically indicated. Withhold for Grade 2 or Grade 3, and permanently discontinue for Grade 4 hypophysitis

• New onset diabetes with ketoacidosis occurred in patients. Diabetes mellitus without an alternative etiology occurred in 0.2% of patients with urothelial carcinoma. Initiate treatment with insulin for type 1 diabetes mellitus. For ≥Grade 3 hyperglycemia (fasting glucose >250-500 mg/dL), withhold TECENTRIQ

Other Immune-Related Adverse Reactions• Other immune-related adverse reactions, including meningoencephalitis,

myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in ≤1.0% of patients treated with TECENTRIQ

• Symptomatic pancreatitis without an alternative etiology occurred in 0.1% of patients across clinical trials

• Monitor patients for clinical signs and symptoms of meningitis or encephalitis, as well as symptoms of motor and sensory neuropathy. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis or any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome

• Monitor patients for signs and symptoms of acute pancreatitis. Withhold TECENTRIQ for ≥Grade 3 serum amylase or lipase levels (>2.0 ULN), or Grade 2 or 3 pancreatitis. Permanently discontinue for Grade 4 or any grade of recurrent pancreatitis

TECENTRIQ® DELIVERED DURABLE RESPONSES

ONE FIXED DOSE, ONCE EVERY 3 WEEKS

UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY

EVERY3 WEEKS

FIXED DOSE1200 MG IV

60-MINUTEINITIAL INFUSION

30-MINUTESUBSEQUENT INFUSIONS

IF TOLERATED

Recommended dosing and administration1

Infection• Severe infections, including sepsis, herpes encephalitis, and mycobacterial

infection leading to retroperitoneal hemorrhage occurred in patients receiving TECENTRIQ

• Across clinical trials, infections occurred in 38.4% of patients• In urothelial carcinoma, infection occurred in 37.7% of patients. Grade 3

or 4 infection occurred in 11.5% of patients, while 3 patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 7.1% of patients

• Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold TECENTRIQ for ≥Grade 3 infection

Infusion-R elated reactions• Severe infusion reactions have occurred in patients in clinical trials of

TECENTRIQ. Infusion-related reactions occurred in 1.7% in UC• Interrupt or slow the rate of infusion in patients with mild or moderate

infusion reactions. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions

Embryo-Fetal Toxicity• Based on its mechanism of action, TECENTRIQ can cause fetal harm when

administered to a pregnant woman. Advise pregnant women or women planning to become pregnant of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose of TECENTRIQ

Nursing Mothers• Because of the potential for serious adverse reactions in breastfed infants

from TECENTRIQ, advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose

Most Common Adverse ReactionsThe most common adverse reactions (rate ≥20%) in UC included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%).You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see Brief Summary of Prescribing Information on adjacent pages.

References: 1. TECENTRIQ Prescribing Information. Genentech, Inc. May 2016. 2. US National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02108652. Accessed August 26, 2016.

Learn more at TECENTRIQ.com/info

• Do not administer as an IV push or bolus

• Do not co-administer other drugs through the same IV line

Most common adverse events1

• The most common adverse events (≥20%) included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%)

— Incidence of grade 3 to 4 adverse events included fatigue (6%), decreased appetite (1%), nausea (2%), urinary tract infection (9%), pyrexia (1%), and constipation (0.3%)


PD-L1 testing is not required to prescribe TECENTRIQ

IMvigor210 was a Phase II, multicenter, open-label, 2-cohort trial that included a cohort of 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following a platinum-containing regimen, or within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant regimen. Patients were treated with TECENTRIQ 1200 mg IV q3w. Major efficacy endpoints included ORR as assessed by IRF using RECIST v1.1 and DoR.1,2

CI=confidence interval; CR=complete response; DoR=duration of response; IRF=independent review facility; IV=intravenous; ORR=objective response rate; PR=partial response; q3w=every 3 weeks; RECIST=Response Evaluation Criteria In Solid Tumors.+ denotes censored value.

*Number of IRF-assessed confirmed responders.

• 22% ORR in patients with disease progression following prior neoadjuvant or adjuvant therapy (n=13/59; 95% CI, 12.3, 34.7)

ORR DoR (14.4-month median follow-up)

14.8% ORR(n=46/310*; 95% CI, 11.1, 19.3)

5.5%CR

9.4%PR

MEDIAN DoR NOT REACHED(range: 2.1+, 13.8+)

© 2016 Genentech USA, Inc. All rights reserved. PDL/101215/0083


Durable responses demonstrated across all patients (median follow-up: 14.4 months)1

Immune-Related Colitis• Immune-mediated colitis or diarrhea, including a fatal case of diarrhea-

associated renal failure, have occurred with TECENTRIQ treatment• Across clinical trials, colitis or diarrhea occurred in 19.7% of patients. In UC,

immune-mediated colitis or diarrhea occurred in 0.8% of patients• Monitor patients for signs and symptoms of diarrhea or colitis. Withhold

TECENTRIQ for Grade 2 or Grade 3 diarrhea or colitis. Permanently discontinue for Grade 4 diarrhea or colitis

Immune-Related Endocrinopathies• Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and

type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving TECENTRIQ. Monitor patients for clinical signs and symptoms of endocrinopathies

• Across clinical trials hypo- and hyperthyroidism occurred in 3.9% and 1.0% of patients, respectively. For symptomatic hypothyroidism, withhold TECENTRIQ and initiate hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold TECENTRIQ and initiate an anti-thyroid drug as needed

• Across clinical trials, adrenal insufficiency occurred in 0.4% of patients. For symptomatic adrenal insufficiency, withhold TECENTRIQ and administer corticosteroids

• Hypophysitis occurred in 0.2% of patients with UC. Administer corticosteroids and hormone replacement as clinically indicated. Withhold for Grade 2 or Grade 3, and permanently discontinue for Grade 4 hypophysitis

• New onset diabetes with ketoacidosis occurred in patients. Diabetes mellitus without an alternative etiology occurred in 0.2% of patients with urothelial carcinoma. Initiate treatment with insulin for type 1 diabetes mellitus. For ≥Grade 3 hyperglycemia (fasting glucose >250-500 mg/dL), withhold TECENTRIQ

Other Immune-Related Adverse Reactions• Other immune-related adverse reactions, including meningoencephalitis,

myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in ≤1.0% of patients treated with TECENTRIQ

• Symptomatic pancreatitis without an alternative etiology occurred in 0.1% of patients across clinical trials

• Monitor patients for clinical signs and symptoms of meningitis or encephalitis, as well as symptoms of motor and sensory neuropathy. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis or any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome

• Monitor patients for signs and symptoms of acute pancreatitis. Withhold TECENTRIQ for ≥Grade 3 serum amylase or lipase levels (>2.0 ULN), or Grade 2 or 3 pancreatitis. Permanently discontinue for Grade 4 or any grade of recurrent pancreatitis

TECENTRIQ™ (atezolizumab)Initial U.S. Approval: 2016

This is a brief summary of information about TECENTRIQ. Before prescribing, please see full Prescribing Information.

1 INDICATIONS AND USAGETECENTRIQ (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: • Have disease progression during or following platinum-containing chemotherapy • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-

containing chemotherapyThis indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.1)].4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS 5.1 Immune-Related Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Across clinical trials, 2.6% (51/1978) of patients developed pneumonitis. Fatal pneumonitis occurred in two patients. In 523 patients with urothelial carcinoma who received TECENTRIQ, pneumonitis occurred in 6 (1.1%) patients. Of these patients, there was one patient with fatal pneumonitis, one patient with Grade 3, three patients with Grade 2, and one patient with Grade 1 pneumonitis. TECENTRIQ was held in all cases and five patients were treated with corticosteroids. Pneumonitis resolved in three patients. The median time to onset was 2.6 months (range: 15 days to 4.2 months). The median duration was 15 days (range: 6 days to 3.1+ months).Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer steroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Withhold TECENTRIQ until resolution for Grade 2 pneumonitis. Permanently discontinue TECENTRIQ for Grade 3 or 4 pneumonitis [see Dosage and Administration (2.2)].5.2 Immune-Related Hepatitis Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Liver test abnormalities occurred in patients who received TECENTRIQ. Across clinical trials (n=1978), Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%). In patients with urothelial carcinoma (n=523) Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.5%), and total bilirubin (2.1%). Immune-mediated hepatitis occurred in 1.3% of patients. Of these cases, one patient died from hepatitis, five patients had Grade 3, and one patient had Grade 2 hepatitis. The median time to onset was 1.1 months (range: 0.4 to 7.7 months). Of the seven patients with immune-mediated hepatitis, TECENTRIQ was temporarily interrupted in four patients; none of these patients developed recurrence of hepatitis after resuming TECENTRIQ. Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment with TECENTRIQ. Administer corticosteroids at a dose of 1-2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin, followed by corticosteroid taper. Withhold TECENTRIQ for Grade 2 and permanently discontinue TECENTRIQ for Grade 3 or 4 immune-mediated hepatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].5.3 Immune-Related ColitisImmune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Across clinical trials, colitis or diarrhea occurred in 19.7% (389/1978) of all patients and in 18.7% (98/523) of patients with urothelial carcinoma. Ten patients (1.9%) developed Grade 3 or 4 diarrhea. Four patients (0.8%) had immune-mediated colitis or diarrhea with a median time to onset of 1.7 months (range: 1.1 to 3.1 months). Immune-mediated colitis resolved with corticosteroid administration in three of these patients, while the other patient died without resolution of colitis in the setting of diarrhea-associated renal failure.Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with TECENTRIQ for Grade 2 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer 1–2 mg/kg prednisone or equivalent per day. Withhold treatment with TECENTRIQ for Grade 3 diarrhea or colitis. Treat with IV methylprednisolone 1–2 mg/kg per day and convert to oral steroids once the patient has improved. For both Grade 2 and Grade 3 diarrhea or colitis, when symptoms improve to Grade 0 or Grade 1, taper steroids over ≥ 1 month. Resume treatment with TECENTRIQ if the event improves to Grade 0 or 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg oral prednisone per day. Permanently discontinue TECENTRIQ for Grade 4 diarrhea or colitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].5.4 Immune-Related Endocrinopathies Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving TECENTRIQ. Monitor patients for clinical signs and symptoms of endocrinopathies. HypophysitisHypophysitis occurred in 0.2% (1/523) of patients with urothelial cancer receiving TECENTRIQ. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids and hormone replacement as clinically indicated. Withhold TECENTRIQ for Grade 2 or Grade 3 and permanently discontinue for Grade 4 hypophysitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Thyroid DisordersThyroid function was assessed routinely only at baseline and the end of the study. Across clinical trials, hypothyroidism occurred in 3.9% (77/1978) of patients and in 2.5% (13/523) of patients with urothelial carcinoma. One patient had Grade 3 and twelve patients had Grade 1–2 hypothyroidism. The median time to first onset was 5.4 months (range: 21 days to 11.3 months). Thyroid stimulating hormone (TSH) was elevated and above the patient’s baseline in 16% (21/131) of patients with a follow-up measurement.Hyperthyroidism occurred in 1.0% (20/1978) of patients across clinical trials and in 0.6% (3/523) of patients with urothelial carcinoma. Of the three urothelial carcinoma patients, one patient had Grade 2 and two patients had Grade 1 hyperthyroidism. The median time to onset was 3.2 months (range: 1.4 to 5.8 months). TSH was decreased and below the patient’s baseline in 3.8% (5/131) of patients with a follow-up measurement.Monitor thyroid function prior to and periodically during treatment with TECENTRIQ. Asymptomatic patients with abnormal thyroid function tests can receive TECENTRIQ. For symptomatic hypothyroidism, withhold TECENTRIQ and initiate thyroid hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold TECENTRIQ and initiate an anti-thyroid drug as needed. Resume treatment with TECENTRIQ when symptoms of hypothyroidism or hyperthyroidism are controlled and thyroid function is improving [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Adrenal InsufficiencyAdrenal insufficiency occurred in 0.4% (7/1978) of patients across clinical trials, including two patients with Grade 3, four patients with Grade 2, and one patient with Grade 1. Adrenal insufficiency resolved in two patients. For symptomatic adrenal insufficiency, withhold TECENTRIQ and administer methylprednisolone 1–2 mg/kg per day IV followed by oral prednisone 1–2 mg/kg per day or equivalent once symptoms improve. Start steroid taper when symptoms improve to ≤ Grade 1 and taper steroids over ≥ 1 month. Resume treatment with TECENTRIQ if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg oral prednisone per day and the patient is stable on replacement therapy, if required [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Diabetes MellitusNew onset diabetes with ketoacidosis has occurred in patients receiving TECENTRIQ. Diabetes mellitus without an alternative etiology occurred in one (0.2%) patient with urothelial carcinoma. Initiate treatment with insulin for type 1 diabetes mellitus. For ≥ Grade 3 hyperglycemia (fasting glucose >250–500 mg/dL), withhold TECENTRIQ. Resume treatment with TECENTRIQ when metabolic control is achieved on insulin replacement therapy [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].5.5 Other Immune-Related Adverse Reactions Other immune-related adverse reactions including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barré, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in ≤ 1.0% of patients treated with TECENTRIQ. Meningitis / EncephalitisMonitor patients for clinical signs and symptoms of meningitis or encephalitis. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis. Treat with IV steroids (1–2 mg/kg/day methylprednisolone or equivalent) and convert to oral steroids (prednisone 60 mg/day or equivalent) once the patient has improved. When symptoms improve to ≤ Grade 1, taper steroids over ≥ 1 month [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].Motor and Sensory NeuropathyMonitor patients for symptoms of motor and sensory neuropathy. Permanently discontinue TECENTRIQ for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Institute medical intervention as appropriate. Consider initiation of systemic corticosteroids at a dose of 1–2 mg/kg/day prednisone [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].PancreatitisSymptomatic pancreatitis without an alternative etiology occurred in 0.1% (2/1978) of patients across clinical trials. Monitor patients for signs and symptoms of acute pancreatitis. Withhold TECENTRIQ for ≥ Grade 3 serum amylase or lipase levels (> 2.0 ULN), or Grade 2 or 3 pancreatitis. Treat with 1−2 mg/kg IV methylprednisolone or equivalent per day. Once symptoms improve, follow with 1−2 mg/kg of oral prednisone or equivalent per day. Resume treatment with TECENTRIQ if serum amylase and lipase levels improve to ≤ Grade 1 within 12 weeks, symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg oral prednisone or equivalent per day. Permanently discontinue TECENTRIQ for Grade 4 or any grade of recurrent pancreatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.6 InfectionSevere infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving TECENTRIQ. Across clinical trials, infections occurred in 38.4% (759/1978) of patients. In 523 patients with urothelial carcinoma who received TECENTRIQ, infection occurred in 197 (37.7%) patients. Grade 3 or 4 infection occurred in 60 (11.5%) patients, while three patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 37 (7.1%) patients.In a randomized trial in patients with non-small cell lung cancer, infections were more common in patients treated with TECENTRIQ (42%) compared with those treated with docetaxel (33%). Grade 3 or 4 infections occurred in 9.2% of patients treated with TECENTRIQ compared with 2.2% in patients treated with docetaxel. One patient (0.7%) treated with TECENTRIQ died due to infection, compared to two patients (1.5%) treated with docetaxel. Pneumonia was the most common cause of Grade 3 or higher infection, occurring in 6.3% of patients treated with TECENTRIQ.Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold TECENTRIQ for ≥ Grade 3 infection [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].5.7 Infusion-Related ReactionsSevere infusion reactions have occurred in patients in clinical trials of TECENTRIQ. Infusion-related reactions occurred in 1.3% (25/1978) of patients across clinical trials and in 1.7% (9/523) of patients with urothelial carcinoma. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.8 Embryo-Fetal ToxicityBased on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Immune-Related Pneumonitis [see Warnings and Precautions (5.1)] • Immune-Related Hepatitis [see Warnings and Precautions (5.2)] • Immune-Related Colitis [see Warnings and Precautions (5.3)] • Immune-Related Endocrinopathies [see Warnings and Precautions (5.4)] • Other Immune-Related Adverse Reactions [see Warnings and Precautions (5.5)] • Infection [see Warnings and Precautions (5.6)] • Infusion-Related Reactions [see Warnings and Precautions (5.7)]6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in Table 1 reflects exposure to TECENTRIQ in Cohort 2 of Study 1. This cohort enrolled 310 patients in a single arm trial with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received 1200 mg of TECENTRIQ intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (range: 0.1, 46 weeks). The most common adverse reactions (≥ 20%) were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most

common Grade 3–4 adverse reactions (≥ 2%) were urinary tract infection, anemia, fatigue, dehydration, intestinal obstruction, urinary obstruction, hematuria, dyspnea, acute kidney injury, abdominal pain, venous thromboembolism, sepsis, and pneumonia. Three patients (0.9%) who were treated with TECENTRIQ experienced either sepsis, pneumonitis, or intestinal obstruction which led to death. TECENTRIQ was discontinued for adverse reactions in 3.2% (10/310) of the 310 patients. Sepsis led to discontinuation in 0.6% (2/310) of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state. Table 1 summarizes the adverse reactions that occurred in ≥ 10% of patients while Table 2 summarizes Grade 3–4 selected laboratory abnormalities that occurred in ≥ 1% of patients treated with TECENTRIQ in Cohort 2 of Study 1.Table 1: All Grade Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in Study 1

TECENTRIQN = 310

Adverse Reaction All Grades (%) Grades 3 – 4 (%)All Adverse Reactions 96 50Gastrointestinal DisordersNausea 25 2Constipation 21 0.3Diarrhea 18 1Abdominal pain 17 4Vomiting 17 1General Disorders and AdministrationFatigue 52 6Pyrexia 21 1Peripheral edema 18 1Infections and InfestationsUrinary tract infection 22 9Metabolism and Nutrition DisordersDecreased appetite 26 1Musculoskeletal and Connective Tissue DisordersBack/Neck pain 15 2Arthralgia 14 1Renal and urinary disordersHematuria 14 3Respiratory, Thoracic, and Mediastinal DisordersDyspnea 16 4Cough 14 0.3Skin and Subcutaneous Tissue DisordersRash 15 0.3Pruritus 13 0.3

Table 2: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 1 in ≥ 1% of Patients

Laboratory Test Grades 3–4 (%)Lymphopenia 10Hyponatremia 10Anemia 8Hyperglycemia 5Increased Alkaline phosphatase 4Increased Creatinine 3Increased ALT 2Increased AST 2Hypoalbuminemia 1

6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. Among 275 patients in Study 1, 114 patients (41.5%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) anti-therapeutic antibodies (ATA) at one or more post-dose time points. In Study 1, the presence of ATAs did not appear to have a clinically significant impact on pharmacokinetics, safety or efficacy. Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of ATAs to TECENTRIQ with the incidence of antibodies to other products may be misleading.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk SummaryBased on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataAnimal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates

of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. 8.2 LactationRisk SummaryThere is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose. 8.3 Females and Males of Reproductive PotentialContraceptionFemalesBased on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months following the last dose.InfertilityFemalesBased on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].8.4 Pediatric UseThe safety and effectiveness of TECENTRIQ have not been established in pediatric patients.8.5 Geriatric UseOf the 310 patients with urothelial carcinoma treated with TECENTRIQ in Study 1, 59% were 65 years or older. No overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients. 8.6 Renal ImpairmentBased on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].8.7 Hepatic ImpairmentBased on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with mild hepatic impairment. TECENTRIQ has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdose with TECENTRIQ.17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Medication Guide).Inform patients of the risk of immune-related adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or

worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe

nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2)].

• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.3)].

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.4)]

• Meningoencephalitis, myasthenic syndrome/myasthenia gravis, and Guillain-Barré syndrome: Advise patients to contact their healthcare provider immediately for signs or symptoms of meningitis, myasthenic syndrome/myasthenia gravis, or Guillain-Barré syndrome [see Warnings and Precautions (5.5)].

• Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity [see Warnings and Precautions (5.5)].

• Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)].

• Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)].

• Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)].

• Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash [see Dosage and Administration (2.2)].

Embryo-Fetal ToxicityAdvise female patients that TECENTRIQ can cause fetal harm. Instruct females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of TECENTRIQ [see Use in Specific Populations (8.1, 8.3)].LactationAdvise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.2)].

TECENTRIQ™ (atezolizumab)

Manufactured by: PDL/121615/0161Genentech, Inc. Initial U.S. Approval: May 2016A Member of the Roche Group 1 DNA Way TECENTRIQ is a trademark of Genentech, Inc.South San Francisco, CA 94080-4990 © 2016 Genentech, Inc.

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AUANEWSassets.auanet.org/SITES/AUAnet/common/pdfs/auanews/AUANEWS… · TF, a 57-year-old electrician, presented in May 2014 with dark urine, 20 lb weight loss, a hemo-globin 7.2