Atezolizumab: a PD-L1–Blocking Antibody for Bladder Cancer Brant A
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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. Ó2016 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-present- ing 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 Ó2016 American Association for Cancer Research. hours after dosing with serum concentrations >0.5 mg/mL. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-1417 Inman et al. 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 © 2016 American Association for Cancer Research 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.