Atezolizumab: a PD-L1–Blocking Antibody for Bladder Cancer Brant A

Published OnlineFirst November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-1417

CCR Drug Updates Clinical Cancer Research Atezolizumab: A PD-L1–Blocking Antibody for Bladder Cancer Brant A. Inman1, Thomas A. Longo1, Sundhar Ramalingam2, and Michael R. Harrison2

Abstract

Atezolizumab (Tecentriq, MPDL3280A; Genentech/Roche) 15%, the complete response rate was 5%, and 1-year overall is an FcgRbinding–deficient, fully humanized IgG1 mAb survival was 36%. In subjects that were chemotherapy na€ve designed to interfere with the binding of PD-L1 ligand to its and cisplatin ineligible, the objective response rate was 24%, two receptors, PD-1 and B7.1. By blocking the PD-L1/PD-1 the complete response rate was 7%, and 1-year overall survival immune checkpoint, atezolizumab reduces immunosuppres- was 57%. Better responses were associated with higher PD-L1 sive signals found within the tumor microenvironment and, expression on the tumor-infiltrating leukocytes. These data consequently, increases T-cell–mediated immunity against the suggest that patients with advanced bladder cancer treated tumor. Atezolizumab has been FDA approved as second-line with atezolizumab have significantly better response rates and therapy for advanced bladder cancer. This accelerated approval survival than historical controls treated with other second-line was based on phase II trial data in patients with metastatic regimens. The toxicity profile of atezolizumab is also favor- bladder cancer that showed unexpected and durable tumor able. Trials are currently assessing whether atezolizumab is responses. In subjects whose tumors progressed on first-line effective in earlier bladder cancer stages and in the first-line platinum-based chemotherapy, the objective response rate was metastatic setting. Clin Cancer Res; 23(8); 1–5. 2016 AACR.

Introduction might regulate local immunity in a paracrine fashion (2). Factors affecting tumor PD-L1 expression are numerous and The programmed cell death 1 (PD-1, CD279) receptor and its include microenvironment cytokines, PI3K–Akt pathway acti- ligand, programmed cell death 1 ligand 1 (PD-L1, CD274, B7- vation, MAPK pathway activation, STAT1 signaling, and epige- H1), comprise one of the main immune checkpoint pathways netic control through a variety of miRNAs (3). Importantly, that downregulates immune activity (1). PD-1 is a transmem- tumors expressing PD-1/PD-L1 have been shown in several brane protein and is found mainly on activated T cells, B cells, studies to have worse survival outcomes, which is a major and macrophages. When PD-1 binds one of its two known reason that PD-L1–targeted therapies have been developed ligands, PD-L1 and programmed cell death 1 ligand 2 (PD-L2, clinically. In bladder cancer, PD-L1 expression is associated CD273), T-cell function is downregulated as manifested by with higher tumor grade, stage progression, poor responsive- decreasedIL2andIFNg production. The PD-L1 ligand binds ness to bacillus Calmette–Guerin (BCG) immunotherapy, and not only to PD-1 but also to B7.1 (CD80), another T-cell worsening survival (4–6). costimulatory molecule, but this interaction is less well under- stood. Although PD-L1 is widely expressed by antigen-presenting cells (e.g., macrophages, B cells, dendritic cells) as a way of Pharmacologic and Immunologic fine-tuning peripheral immune activation and avoiding auto- Characteristics of Atezolizumab immunity, its expression can also be induced on T cells and Atezolizumab (Tecentriq, MPDL3280A; Genentech/Roche) is a other cell types (such as epithelial and endothelial cells) with fully humanized IgG1 mAb that blocks the interaction of PD-L1 exposure to proinflammatory cytokines such as IFNg (1). with both PD-1 and B7.1, but not the interaction of PD-L2 with Many tumor types, including bladder cancer, express PD-L1 PD-1 (Fig. 1; ref. 7). The pharmacokinetics of atezolizumab were either on the tumor cells themselves or on immune cells (IC) initially studied in cynomolgus monkeys and mice, where its that are infiltrating the tumor. Furthermore, PD-L1 mRNA can volume of distribution was calculated to be approximately that of be alternatively spliced to produce a soluble non-membrane– the plasma volume. The in vivo biodistribution of atezolizumab bound version of the protein, which is biologically active and 24 hours after infusion is, in order of magnitude, the spleen, lungs, kidneys, liver, heart, and muscle. In tumor-bearing animals, the drug also accumulates intratumorally, initially at the pushing 1 2 Division of Urology, Duke Cancer Institute, Durham, North Carolina. Medical border of the tumor and progressing later to the tumor core, Oncology, Duke Cancer Institute, Durham, North Carolina. particularly if the tumor is necrotic (7). The pharmacokinetic Corresponding Author: Brant A. Inman, Duke University Medical Center, DUMC curve of atezolizumab is dose dependent (nonlinear) because of 103868, Durham, NC 27710. Phone: 919-684-1322; Fax: 919-668-7093; E-mail: target-mediated drug disposition (binding of drug to the PD-L1 [email protected] ligand in the body). Saturation of PD-L1 receptors by atezolizu- doi: 10.1158/1078-0432.CCR-16-1417 mab on circulating CD4 and CD8 T cells occurs between 24 and 48 2016 American Association for Cancer Research. hours after dosing with serum concentrations >0.5 mg/mL.

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Antigen MHC II TCR TCR MHC I Tumor APC T cell PD-1 cell Figure 1. PD-L1 Mechanism of action of atezolizumab. APC, antigen-presenting cell; Atez, CD28 PD-1 atezolizumab; TCR, T-cell receptor. B7.1 Atez Atez

PCD4989G (NCT01375842), a phase I dose-escalation trial Efficacy in subjects with a variety of metastatic solid tumors, adminis- Phase I tered atezolizumab at doses ranging from 0.03 to 20 mg/kg (8). Atezolizumab was first evaluated in bladder cancer in an expan- When given every 3 weeks, a dose of 15 mg/kg was sufficient to sion cohort of the PCD4989G trial (9). Patients with bladder maintain a trough level of >6 mg/mL, which results in >95% cancer were initially selected by PD-L1 status (see "Biomarkers" saturation of intratumoral PD-L1 receptors in murine models section), but after 21 patients were enrolled, the trial was opened to with a good margin of error that allows for interpatient vari- all subjects with bladder cancer. Sixty-seven patients were evalu- ability in drug delivery to the tumor. A dose of 1,200 mg was able for efficacy, and PD-L1 expression was high in 10 (15%), consequently proposed as the optimal dose for future human moderate in 20 (30%), low in 23 (34%), absent in 12 (18%), and studies (assumes an 80 kg person), administered over 60 min- unknown in two (3%). Subjects were heavily pretreated, with 62 utes for the first infusion cycle and, if well tolerated, over 30 (93%) having previous platinum-based chemotherapy and 48 minutes for subsequent cycles. The volume of distribution is (72%) having at least two prior systemic therapy regimens. Poor estimated to be 6.9 L, the half-life 27 days, and steady state prognostic features were also prevalent, including 39 (59%) achieved by the third cycle (week 9). In mice and monkeys, with an Easter Cooperative Oncology Group (ECOG) performance antitherapeutic antibodies that potentially neutralize atezolizu- status of 1, 26 (42%) with a time from previous chemotherapy of mab start to develop around day 7 and are universally present by <3 months, and 50 (75%) with visceral metastases. The objective day 14 posttreatment (7). In a sample of 275 subjects treated in response rates (ORR), observed at a median of 42 days, were 43% phase I, 42% developed antitherapeutic antibodies at some for patients with high/moderate PD-L1 group and 11% for those point after starting atezolizumab, although these did not appear with low/absent PD-L1 group. Complete responses (CR) were to affect the pharmacokinetics, efficacy, or safety of the drug. In noted in 7% of subjects, and all had high/moderate PD-L1 expres- addition, mild hepatic impairment and moderate renal dysfunc- sion. At the time of data lock, 16 of the 17 initial responders had tion [glomerular filtration rate (GFR) 30–89 mL/minute] do not not progressed and the median duration of response had not been appear to affect atezolizumab dosing, although the pharmaco- reached. On the basis of these results, atezolizumab received kinetics in severe renal impairment (GFR <30 mL/minute) or breakthrough therapy designation status by the FDA in June 2014. moderate hepatic dysfunction (>1.5 ULN for liver function At the 2015 American Society of Clinical Oncology (ASCO) tests) are unknown. Similarly, the genotoxicity, carcinogenicity, Annual Meeting, bladder cancer survival data from the and fertility effects of atezolizumab are unknown. PCD4989G trial were presented (10). Of 87 evaluable subjects, A key feature of atezolizumab is that it is FcgR-binding the ORR was 50% for the high/moderate PD-L1 group and 17% in deficient due to an asparagine-to-alanine substitution at position the low/absent PD-L1 group. Median duration of response had 298 of the CH2 domains of each heavy chain, which means that it not been reached, and 67% of responders had ongoing responses. cannot bind to Fc receptors on phagocytes and, therefore, does not Median progression-free survival (PFS) was 6 months in the high/ cause antibody-dependent cell-mediated cytotoxicity (ADCC; moderate PD-L1 group and 1 month in the low/absent PD-L1 ref.8). This is important because PD-L1 is heavily expressed by group, with 1-year PFS rates of 39% and 10%, respectively. T cells and other leukocytes, and binding of a mAb to their cell Median overall survival (OS) was not reached in the high/mod- membrane could result in ADCC-mediated depletion of tumor- erate PD-L1 group and was 7.6 months in the low/absent PD-L1 specific T cells, an event that could worsen antitumor immunity group, with 1-year OS rates of 57% and 38%, respectively. instead of improving it. The immunologic effects of atezolizumab treatment have been only preliminarily reported from subjects on clinical Phase II trials. Cytokine changes that have been observed include tran- IMvigor210 (NCT02108652) is a multicenter, single-arm, sient increases in IL18, IFNg, and CXCL11 and a transient two-cohort phase II trial of atezolizumab treatment in bladder decrease in IL6 (8, 9). Cellular changes include increases in cancer, and cohort 2 of this trial consisted of subjects with þ proliferating CD8 Tcells(8,9). inoperable locally advanced or metastatic bladder cancer

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progressing after prior platinum-based chemotherapy (11). nausea (14%), decreased appetite (12%), pruritus (10%), pyrex- Of 310 evaluable subjects, 100 (32%) had high/moderate ia (9%), diarrhea (8%), rash (7%), arthralgia (7%), and vomit- PD-L1 expression, 107 (37%) low PD-L1, and 103 (33%) ing (6%). There were no treatment-related deaths, but atezoli- absent PD-L1. Using RECIST v1.1, an ORR was noted in zumab therapy was interrupted in 20% of subjects and discon- 15%, including a CR rate of 5%. The ORR was 26% in the tinued in 4% due to AEs. high/moderate PD-L1 group, 11% in the low PD-L1 group, and Atezolizumab's immunotherapeutic mechanism of action 8% in the absent PD-L1 group. With a median follow-up of has led to special attention regarding immune-related AEs 11.7 months, median duration of response was not reached, (irAE). In IMvigor210, irAEs occurred in 7% of subjects, with although median PFS was 2.1 months and median OS was 7.9 pneumonitis, increased liver enzymes, rash, and dyspnea being months. On the basis of these results, the FDA approved the most commonly observed (1% each; ref.11). Systemic atezolizumab for the treatment of bladder cancer in patients corticosteroid treatment (for any AE, not just irAEs) was with locally advanced or metastatic urothelial carcinoma who required in 22% of patients. have progressed (i) during/after platinum-based chemotherapy Detailed reviews of the management of immune checkpoint or (ii) within 12 months of neoadjuvant or adjuvant treatment inhibitor–induced toxicity are available elsewhere (17, 18). How- with platinum-based chemotherapy (12). ever, depending on the severity of the irAE, withholding atezo- Updated data from IMvigor210 were reported at the 2016 lizumab and providing temporary immunosuppression with ASCO Annual Meeting and included new data on cohort 1, topical/systemic corticosteroids, TNFa antagonists, mycopheno- subjects who had bladder cancer metastases, were chemotherapy late mofetil, or other agents is highly effective. For many moderate na€ve, and were cisplatin ineligible (13). The most common irAEs, atezolizumab treatment may be withheld for a few weeks reason for cisplatin ineligibility was renal dysfunction (71%), and then the therapy restarted once the irAE has resolved. More and 66% had visceral metastasis. A total of 119 patients were serious and potentially life-threatening irAEs, such as pneumo- evaluable for response, and the ORR was 24%, including 7% CRs. nitis, hepatitis, colitis, endocrinopathies, neurologic and ocular Median duration of response was not reached, with 75% (21/28) toxicities, and pancreatitis, usually preclude further treatment of responses ongoing. Interestingly, the ORR for the high/mod- with atezolizumab. erate PD-L1 group was 28%, and for subjects with upper tract (renal pelvis or ureter) primary tumors, the ORR was 42%. With a median follow-up of 14.4 months, median OS was 14.8 months Biomarkers and 1-year OS rate was 57%. Attempts have been made to develop biomarkers that predict In summary, evidence from phase I and II trials suggests durable which patients will respond to atezolizumab and which will not, activity of atezolizumab in advanced bladder cancer that has and principle among these is its target PD-L1. PD-L1 protein can progressed during or after platinum-based chemotherapy. A com- be measured as a biomarker on the cell membrane or in soluble bined analysis of 10 phase II trials of second-line therapies form in biofluids (2). Currently, it is unclear which form of PD-L1 for metastatic bladder cancer showed an average 1-year OS of (membrane bound or soluble) or which cell type with cell 20% (14). Given that the 1-year OS of cohort 2 of IMvigor210 membrane expression (tumor cells, tumor-infiltrating leuko- of 36% is nearly double that, a randomized phase III trial cytes, endothelial cells in the tumor vasculature) is important comparing atezolizumab with standard chemotherapy in subjects for predicting disease outcome and response to therapy. Numer- with platinum-refractory metastatic bladder cancer is underway ous factors affect measurement of the PD-L1 biomarker, including (IMvigor211, NCT02302807). For cisplatin-ineligible subjects, the specific mAb clones used in the assays, the cutoff points although the ORR of cohort 1 of the IMvigor210 (24%) was not used to define positivity, and the method used for detecting better than the historic control of gemcitabine/carboplatin che- the presence of PD-L1 (IHC, quantitative PCR, ELISA, etc.). motherapy (36%), the median OS (14.8 months) does appear Furthermore, the immune system is dynamic, and measuring any better than chemotherapy (9.3 months), suggesting that a ran- immunologic biomarker at a single time point in time or space domized comparison is warranted (15). may be insufficient to fully characterize the immune response in the tumor microenvironment. A blueprint proposal for standard- izing PD-L1 measurement was made at the FDA-AACR-ASCO Safety workshop titled "Complexities in Personalized Medicine" (March In general, atezolizumab has been well tolerated across all 24, 2015; Washington, DC). This proposal, put forth by pharma- studies in bladder cancer, with most adverse events (AE) being ceutical and diagnostic companies, hopes to lay the groundwork mild to moderate in grade. This is important as patients with for developing companion diagnostic biomarkers for PD-1/PD- bladder cancer are often elderly and have multiple comorbid- L1–targeted immunotherapies. ities and, consequently, many may not be chemotherapy can- Early results have suggested that PD-L1–positive bladder didates (16). In IMvigor210, 310 patients were evaluable for tumors respond better to atezolizumab than negative ones safety, and AEs of any grade were reported in 97% of patients, (9, 11). However, in bladder cancer and other tumors, clinical with 55% having grade 3 or 4 AEs (11). The most common AEs activity is still observed with PD-1/PD-L1 immune checkpoint were fatigue (49%), nausea (26%), decreased appetite (27%), inhibitors in tumors that are classified as PD-L1 negative (19). In pyrexia (22%), and diarrhea (20%). The most frequent high- both the PCD4989G and IMvigor210 trials, tumor PD-L1 expres- grade (grade 3) AEs were anemia (9%), fatigue (6%), dyspnea sion was analyzed by Ventana SP142 IHC assay that measures (4%), nausea (2%), and hypertension (2%). Importantly, many tumor-infiltrating IC PD-L1 expression (8, 9, 11), which is cate- AEs were not treatment related, and treatment-related AEs (trAE) gorized as high (IC3, 10%), moderate (IC2, 5%–10%), low occurred in 69% of patients and only 16% of subjects had high- (IC1, 1%–5%), or absent (IC0, <1%). The Ventana SP142 assay is grade trAEs. The most common trAEs were fatigue (30%), FDA approved as a companion diagnostic for atezolizumab.

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Table 1. Selected clinical trials of atezolizumab in bladder cancer Study Disease state Trial arms Primary outcomes Trial status NCT02302807, IMvigor211, –Locally advanced or metastatic BC –Atezolizumab OS Accrual complete phase III –Second line (failed platinum) –Investigator's choice chemotherapy (vinﬂunine, paclitaxel, or docetaxel) NCT02807636, IMvigor130, –Locally advanced or metastatic BC –Atezolizumab þ PFS, OS Currently recruiting phase III –First line (platinum ineligible) gemcitabine/ patients carboplatin –Placebo þ gemcitabine/ carboplatin NCT02450331, IMvigor010, –Muscle-invasive BC, postcystectomy –Atezolizumab 1 year DFS Currently recruiting phase III (T3 if no neoadjuvant chemo, –Observation patients T2 if neoadjuvant chemo) NCT02662309, ABACUS, –Muscle-invasive BC, precystectomy, Atezolizumab 2 cycles Response rate, immune Currently recruiting phase II cisplatin ineligible monitoring patients NCT02451423, phase II –BCG-refractory non-muscle–invasive BC, Sequential dosing, 3-week Response rate, immune Currently recruiting precystectomy cycles of atezolizumab monitoring patients –Muscle-invasive BC, precystectomy, cisplatin ineligible NCT02792192, GU123, phase –BCG-refractory non-muscle–invasive BC BCG þ atezolizumab DFS Currently recruiting Ib/II patients Abbreviations: BC, bladder cancer; chemo, chemotherapy; DFS, disease-free survival.

Although many studies have found tumor cell membrane PD-L1 ences between atezolizumab–gemcitabine–carboplatin and car- expression to be prognostic of bladder cancer outcome (4, 6, 20), boplatin–gemcitabine in untreated cisplatin-ineligible metastatic the IMvigor210 trial did not confirm this finding. Instead, only bladder cancer patients. tumor-infiltrating IC PD-L1 expression predicted treatment The benefit of atezolizumab is also being examined in localized response and outcome (9). It is important to realize that tumor bladder cancer disease stages. Currently, cisplatin-based systemic cell PD-L1 expression is strongly correlated with the presence of chemotherapy is the only proven systemic therapy proven to tumor-infiltrating ICs, which in turn predict the response of extend survival in patients with muscle-invasive bladder cancer checkpoint inhibitors (21). In essence, there is an interplay undergoing curative cystectomy (26). However, due to comor- between tumor and the immune system in the tumor microen- bidities, many cystectomy candidates never receive neoadjuvant vironment that determines PD-L1 expression on various cell types or adjuvant cisplatin-based chemotherapy. IMvigor010 will in a dynamic manner. Indeed, serial biopsies of tumors under- determine whether adjuvant atezolizumab improves survival going atezolizumab treatment demonstrate that PD-L1 expres- in subjects with residual muscle-invasive cancer at cystectomy. sion increases in subjects responding to treatment (8). Finally, the GU123 trial will assess the role of atezolizumab Other potential predictive biomarkers of bladder cancer in BCG-unresponsive non-muscle–invasive bladder cancer in a response to atezolizumab include The Cancer Genome Atlas phase Ib/II clinical trial. The results of all these trials will inform molecular subtype and the tumor mutation load (11). How- greatly on the role of atezolizumab across the bladder cancer ever, in other tumor types, a number of other predictive disease spectrum. biomarkers have been associated with atezolizumab response, including a dominant pretreatment effector T-cell signature Disclosure of Potential Conflicts of Interest (22), IFNg gene expression (8, 23), indoleamine 2,3-dioxygen- B.A. Inman reports receiving commercial research grants from Abbott ase expression (8), JAK3 activation (24), and the expression of Laboratories, Dendreon, Genentech, and GlaxoSmithKline and is a consultant/advisory board member for AstraZeneca, Combat Medical, Ferring, other immune checkpoint molecules, to list a few (8). Many Genentech, and Taris Biomedical. M.R. Harrison reports receiving commer- otherbiomarkersexistforotherdrugstargetingthePD-1/PD-L1 cial research grants from Acerta and Genentech, speakers bureau hono- axis (25). Most biomarkers useful for determining the likeli- raria from Genentech, and is a consultant/advisory board member for hood of response to atezolizumab and other immunotherapies AstraZeneca and Genentech. No potential conflicts of interest were disclosed have not been well validated. by the other authors. Authors' Contributions Future Drug Development Conception and design: B.A. Inman, M.R. Harrison Development of methodology: M.R. Harrison Atezolizumab's FDA approval was granted on the basis of good Acquisition of data (provided animals, acquired and managed patients, ORRs and durable responses in the IMvigor210 trial (11). A provided facilities, etc.): B.A. Inman, M.R. Harrison number of other trials are underway (Table 1). To date, there is Analysis and interpretation of data (e.g., statistical analysis, biostatistics, no survival-prolonging second-line therapy in advanced bladder computational analysis): B.A. Inman, M.R. Harrison cancer following progression during/after platinum-based che- Writing, review, and/or revision of the manuscript: B.A. Inman, T.A. Longo, S. Ramalingam, M.R. Harrison motherapy (16). Although data from IMVigor210 are promising, fi fi Administrative, technical, or material support (i.e., reporting or organizing de nite proof of a survival bene t with atezolizumab treatment in data, constructing databases): B.A. Inman the second-line metastatic bladder cancer setting is pending the results of IMvigor211, which has completed its planned accrual of Received August 30, 2016; revised September 19, 2016; accepted September 932 subjects. Another trial (IMvigor130) is examining OS differ- 22, 2016; published OnlineFirst November 30, 2016.

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Atezolizumab: A PD-L1−Blocking Antibody for Bladder Cancer

Brant A. Inman, Thomas A. Longo, Sundhar Ramalingam, et al.

Clin Cancer Res Published OnlineFirst November 30, 2016.

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