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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 30  |  Issue : 1  |  Page : 2-7

Programmed death-1 and programmed death ligand-1 blockade for advanced urothelial carcinoma


1 Department of Oncology, National Taiwan University Hospital; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine; National Taiwan University Cancer Center, Taipei, Taiwan
2 Department of Oncology, National Taiwan University Hospital; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
3 Department of Urology, National Taiwan University Hospital; Department of Urology, National Taiwan University College of Medicine, Taipei, Taiwan

Date of Web Publication2-Jan-2019

Correspondence Address:
Yeong-Shiau Pu
Department of Urology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_105_18

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  Abstract 

Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the paradigm of anticancer therapy in many cancer types, including advanced urothelial carcinoma (UC). Two anti-programmed death-1 (PD-1) monoclonal antibodies (pembrolizumab and nivolumab) and three anti-PD ligand-1 (PD-L1) monoclonal antibodies (atezolizumab, durvalumab, and avelumab) have demonstrated their efficacy in the treatment of advanced UC. The response rate of the above ICIs in unselected patients with advanced UC is about 20%. Several on-going large-scale phase III studies explore whether different combinations with ICIs improve the efficacy. To date, there have been several phase I, II, and III studies that examined the efficacy of single-agent PD-1 or anti-PD-L1 blockade in platinum-failed advanced UC patients, and two phase II studies demonstrated the efficacy of PD-1/PD-L1 blockade as the first-line therapy in cisplatin-ineligible advanced UC patients. Here, we review and compare the efficacy and adverse events of the five ICIs in advanced UC.

Keywords: Immune checkpoint, programmed death ligand-1, programmed death-1, urothelial carcinoma


How to cite this article:
Guo JC, Tsai YC, Pu YS. Programmed death-1 and programmed death ligand-1 blockade for advanced urothelial carcinoma. Urol Sci 2019;30:2-7

How to cite this URL:
Guo JC, Tsai YC, Pu YS. Programmed death-1 and programmed death ligand-1 blockade for advanced urothelial carcinoma. Urol Sci [serial online] 2019 [cited 2019 Jan 19];30:2-7. Available from: http://www.e-urol-sci.com/text.asp?2019/30/1/2/249260


  Introduction Top


Urothelial carcinoma (UC) is a common malignancy arising from the urothelium. In 2012, there were >400,000 new cases of bladder cancer and >165,000 cancer deaths globally.[1] In Taiwan, the incidence of renal pelvis, ureter, and bladder UC increases in recent decades.[2]

Chemotherapy is the only systemic therapy for advanced UC. Cisplatin-based chemotherapy regimens, such as methotrexate/vinblastine/doxorubicin/cisplatin and gemcitabine/cisplatin, had become the first-line standard therapy for advanced UC for more than decades.[3] Although the objective response rate (ORR) was >40%, the median progression-free survival (PFS) and median overall survival (OS) were about 8 and 15 months, respectively.[3] For patients with advanced UC, but ineligible to cisplatin (impaired renal function and Eastern Cooperative Oncology Group performance status of 2), carboplatin-based chemotherapy regimens such as GC and methotrexate/carboplatin/vinblastine (M-CAVI) were the options as first-line therapy.[4] Comparing with best supportive care, vinflunine demonstrated superior ORR and PFS but not OS in the intention-to-treat (ITT) population.[5] No effective second-line systemic therapy confers the poor prognosis for patients with advanced UC-failed platinum-based chemotherapy.

Immunotherapies such as intravesical bacillus Calmette–Guérin, comparing with intravesical doxorubicin, reduced the local recurrence in early bladder UC patients.[6] Immune checkpoint, an inhibitory pathway, is important for self-tolerance and for modulating the immune response avoiding collateral tissue damage. Blocking the immune checkpoints could enhance anticancer immunity and becomes the new paradigm for anticancer therapy.[7] Ipilimumab, an anticytotoxic T-lymphocyte-associated protein 4 monoclonal antibody, is the first approved drug for advanced melanoma patients.[8] Programmed cell death protein-1 (PD-1) and PD ligand-1 (PD-L1) are another kind of immune checkpoint. PD-1 and PD-L1 blockade alone have demonstrated significant clinical benefits for several cancer types, such as melanoma, renal cell carcinoma, and nonsmall cell lung cancer.[9],[10],[11]

UC is also on the wave for renaissance of immunotherapy. Two anti-PD-1 monoclonal antibodies (pembrolizumab and nivolumab) and three anti-PD-L1 monoclonal antibodies (atezolizumab, durvalumab, and avelumab) have demonstrated their efficacies in advanced UC. In this mini-review, we describe the results of published clinical trials about these five agents.


  Five Anti-Programmed Cell Death Protein-1 (PD-1) and Anti-Programmed Death Ligand-1 Antibodies Approved for Urothelial Carcinoma Top


There have been five human or humanized anti-PD-1/PD-L1 monoclonal antibodies approved by the US Food and Drug Administration (FDA) in different stages [Table 1]. Two IgG4 antibodies, pembrolizumab and nivolumab, are anti-PD-1 antibodies.[12],[13] Three IgG1 antibodies, atezolizumab, durvalumab, and avelumab, are anti-PD-L1 antibodies.[14],[15],[16] Modifying fragment crystallizable domain of antibodies to avoid antibody-dependent cellular cytotoxicity (ADCC) was performed on atezolizumab and durvalumab. Only avelumab retains the ability of ADCC.[14],[15],[16] Taiwan FDA also approved two anti-PD-1 antibodies (pembrolizumab and nivolumab) and one anti-PD-L1 antibodies (atezolizumab) in advanced UC currently.
Table 1: Summary of five anti-programmed cell death protein-1 (PD-1) and anti-programmed death ligand-1 antibodies approved for the treatment of urothelial carcinoma

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  Anti-Programmed Cell Death Protein-1 (PD-1) and Anti-Programmed Death Ligand-1 Antibodies as the first-Line Therapy for Patients with Cisplatin-Ineligible Advanced Urothelial Carcinoma Top


Patient with advanced UC, especially upper urinary tract UC, are easily become cisplatin-ineligible due to nephrectomy for localized disease and (neo) adjuvant platinum-based chemotherapy. The prognosis of cisplatin-ineligible patients with advanced UC is generally inferior to cisplatin-eligible patients. The median PFS and OS for cisplatin-ineligible patients with advanced UC were about 4–6 and 8–9 months, respectively.[4] The ORR to GC or M-CAVI is about 30%–40%.[4] KEYNOTE-052, a single-arm phase II study, demonstrated the efficacy of pembrolizumab (200 mg, intravenous every 3 weeks) in cisplatin-ineligible patients with advanced UC. The primary endpoint was ORR in patients with PD-L1-expressing tumors. A total of 374 patients were enrolled and the ORR was 24%. Median PFS and OS were 2.0 (95% confidence interval [CI] 2.0–3.0) and 11.5 months (95% CI 10.0–13.3), respectively.[17] Atezolizumab also showed anticancer activity for cisplatin-ineligible patients with advanced UC from IMvigor210, a single-arm phase II study. The primary endpoint was independently confirmed ORR per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1). A total of 123 patients were enrolled and the ORR was 23%. Median PFS and OS were 2.7 (95% CI 2.1–4.2) and 15.9 months (95% CI 10.4 to not reached), respectively.[18] In summary, both pembrolizumab and atezolizumab have demonstrated their efficacy in cisplatin-ineligible patients with advanced UC. [Table 2] summarizes these two clinical trials.
Table 2: Anti-programmed cell death protein-1 (PD-1) or programmed death ligand-1 for the first-line cisplatin-ineligible patients with advanced urothelial carcinoma

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  Anti-Programmed Cell Death Protein-1 (PD-1) and Anti-Programmed Death Ligand-1 Antibodies as the Second-Line Therapy for Patients With Platinum-Failed Advanced Urothelial Carcinoma Top


The prognosis of advanced UC patients failed to platinum-based chemotherapy is poor. The median PFS and OS for patients receiving vinflunine as the second-line after platinum-based chemotherapy were 3.0 and 6.9 months, respectively; the median PFS and OS for patients receiving best supportive care were 1.5 and 4.6 months, respectively. The ORR of vinflunine was only 8.6%.[5] Generally, the prognosis for advanced UC patients failed to platinum-based chemotherapy is poor.

KEYNOTE-012 was a phase Ib study about pembrolizumab (10 mg/kg, intravenous every 2 weeks) for advanced UC patients with tumor or tumor stroma at least 1% PD-L1 expression. The primary endpoints were safety, tolerability, and ORR according to the RECIST 1.1. More than 75% patients received at least one line systemic therapy for advanced disease. A total of 27 patients were enrolled and the ORR was 26%. Median PFS and OS were 2.0 (95% CI 2.0–3.0) and 13.0 months (95% CI 5.0–20.0), respectively.[12] KEYNOTE-045, a phase III trial focusing on advanced UC patients, recurred or progressed after platinum-based chemotherapy compared pembrolizumab (200 mg, intravenous every 3 weeks) with investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary endpoints were OS and PFS assessed in the total population and in patients with a tumor PD-L1 combined positive score (CPS) of 10% or more. The median OS in the total population was 10.3 months (95% CI 8.0–11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI 6.1–8.3) in the chemotherapy group (hazard ratio [HR] for death, 0.73; 95% CI 0.59–0.91; P = 0.002). The median OS among patients with a tumor PD-L1 CPS of 10% or more was 8.0 months (95% CI 5.0–12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI 4.0–7.4) in the chemotherapy group (HR, 0.57; 95% CI 0.37–0.88; P = 0.005). There was no significant difference in the duration of PFS in the total population (HR for death or disease progression, 0.98; 95% CI 0.81–1.19; P = 0.42) or among patients with a tumor PD-L1 CPS of 10% or more (HR, 0.89; 95% CI 0.61–1.28; P = 0.24). The ORR was significantly higher in pembrolizumab group (21.1%; 95% CI 16.4–26.5) than in the chemotherapy group (11.4%; 95% CI 7.9–15.8; P = 0.001). Pembrolizumab has demonstrated superior efficacy than chemotherapy as the second-line therapy for advanced UC patients who have failed platinum-based chemotherapy in this large-scale phase III clinical trial.[19]

Phase I expansion study of atezolizumab, with an adaptive design allowed for biomarker-positive enriched cohorts and focusing on metastatic UC, demonstrated high ORR especially tumor-expressing PD-L1-positive tumor-infiltrating immune cells (ICs, IC2/3 ORR, 40% [95% CI 26–55]; IC0/1 ORR, 11% [95% CI 4–25]).[14],[20] Atezolizumab also demonstrated similar efficacy in a total of 310 advanced UC patients progressed following platinum-based chemotherapy from IMvigor210. ORR was 15% (95% CI 11–19) in all 310 patients, 26% (95% CI 18–36) in IC2/3 group, and 18% (95% CI 13–24) in IC1/2/3 group by independent review according to the RECIST 1.1.[21] Increased levels of PD-L1 expression on ICs associated with ORR in both early studies made the important statistical design in further phase III study. IMvigor211, a phase III trial focusing on advanced UC patients recurred or progressed after platinum-based chemotherapy, compared atezolizumab (1200 mg, intravenous every 3 weeks) with investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine.[22] The study design of IMvigor211 was similar to KEYNOTE-045, but the statistical analysis and primary endpoints were different. The primary endpoints of IMvigor211 were OS tested with a hierarchical fixed-sequence procedure in prespecified populations: IC2/3, followed by IC1/2/3, followed by the ITT population. However, the OS was not statistically different between the atezolizumab and chemotherapy group for patients with IC2/3 (the median OS was 11.1 months [95% CI 8.6–15.5] in the atezolizumab group vs. 10.6 months [95% CI 8.4–12.2] in the chemotherapy group [stratified HR for death, 0.87; 95% CI 0.63–1.21; P = 0.41]) and precluded further formal statistical comparisons. Although the ORR was higher in IC2/3 group than ITT population (23.0% [95% CI 15.6–31.9] and 13.4% [95% CI 10.5–16.9]) and the median OS was numerically longer for atezolizumab group than chemotherapy group in ITT population (8.6 [95% CI 7.8–9.6] vs. 8.0 months [95% CI 7.2–8.6], stratified HR for death, 0.85; 95% CI 0.73–0.99), these subsequent analyses were exploratory in nature.

CheckMate-032 was a phase I/II trial about nivolumab (3 mg/kg, intravenous every 2 weeks) for advanced UC patients not selected by PD-L1 expression.[13] The primary endpoint was ORR by investigator assessment. A total of 78 patients with advanced UC progressed after platinum-based chemotherapy were enrolled. The ORR was 24.4% (95% CI 15.3–35.4). Median PFS and OS were 2.8 (95% CI 1.5–5.9) and 9.7 months (95% CI 7.3–16.2), respectively. Another larger phase II trial, CheckMate-275, enrolled 270 patients with similar clinical scenario also demonstrated clinical efficacy. The ORR was 19.6% (95% CI 15.0–24.9).[23] Median PFS and OS were 2.0 (95% CI 1.9–2.6) and 8.7 months (95% CI 6.1 to not reached), respectively.

Durvalumab (10 mg/kg, intravenous every 2 weeks for up to 12 months), another anti-PD-L1 monoclonal antibody, has demonstrated the clinical efficacy in patients with advanced UC progressed after platinum-based chemotherapy. The ORR of the phase I/II study was 17.8% (95% CI 12.7–24.0).[15],[24] Median PFS and OS were 1.5 months (95% CI 1.4–1.9) and 18.2 months (95% CI 8.1 to not estimable), respectively. A phase I study about avelumab (10 mg/kg, intravenous every 2 weeks) enrolled majority of advanced UC patients failed to platinum-based chemotherapy. The ORR of the phase I/II study was 17% (95% CI 11–24). Median PFS and OS were 6.3 weeks (95% CI 6.0–10.1) and 6.5 months (95% CI 4.8–9.5), respectively.[16],[25]

In summary, the two anti-PD-1 monoclonal antibodies (pembrolizumab and nivolumab) and three anti-PD-L1 monoclonal antibodies (atezolizumab, durvalumab, and avelumab) have demonstrated their efficacies in advanced UC patients failed to platinum-based chemotherapy. [Table 3] summarizes these clinical trials focusing on advanced UC patients failed to platinum-based chemotherapy.
Table 3: Anti-programmed cell death protein-1 (PD-1) or programmed death ligand-1 therapies as the second-line therapy for patients with advanced urothelial carcinoma who failed platinum-based chemotherapy

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  Programmed Death Ligand-1 Expression Status and Objective Response Rate Top


Because the five monoclonal antibodies block PD-1/PD-L1 axis, the expression of PD-L1 becomes unequivocally biomarker under active investigation. However, the data are still controversial due to different assays or antibodies, cutoff values, and evaluations. For example, in KEYNOTE-052 study, high PD-L1 expression (≥10%) defined by CPS (the percentage of PD-L1-expressing tumor and -infiltrating ICs [macrophages or lymphocytes] relative to the total number of tumor cells [TCs]) was associated with higher ORR (38%) and low PD-L1 expression (<10%) defined by CPS was associated with lower ORR (18%).[17] However, in KEYNOTE-045 study, high and low PD-L1 expressions have similar ORR (22% and 21%, respectively).[19] In summary, higher PD-L1 expression may be associated with higher ORR, but lower PD-L1 expression does not completely offset the chance of response. [Table 4] summarizes the PD-L1 expression and the ORR in published studies.
Table 4: Programmed death ligand-1 expression and objective response rate

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  Immune-Related Adverse Effects of Immune Checkpoint Inhibitors Top


Toxicities from immune checkpoint inhibitors (ICIs) can be divided into infusion reactions and immune-related adverse events (irAEs). Any tissue or organ can be involved although some irAEs are more common than others. The most frequently occurring irAEs affect skin, colon, endocrine organs, liver, and lungs. Others are very infrequent but may be very serious, even lethal, such as neurological disorders and myocarditis.[26],[27]

The two phase III studies comparing pembrolizumab (KEYNOTE-045) or atezolizumab (IMvigor211) with chemotherapy as the second-line therapy for patients with platinum-failed advanced UC demonstrated the safety.[19],[22] Generally, any grade adverse events (AEs) and Grade 3, 4, or 5 AEs were less in ICIs group than chemotherapy group. However, irAEs, such as hypothyroidism, hyperthyroidism, pneumonitis, colitis, nephritis, and adrenal insufficiency, were more common in ICIs group than chemotherapy group.

Close and careful monitoring and managing these new-type AE–irAEs could prevent high-grade irAEs develop. Several guidelines for the management of irAEs are also available now.[26],[27],[28]


  Conclusion Top


PD-1/PD-L1 blockade has changed the paradigm of treatment for patients with advanced UC and our daily practice. The ORR is about 20% [Figure 1], and several ways to enhance the clinical efficacy of PD-1/PD-L1 blockade alone such as combination with either conventional therapeutic modality, targeted therapy, or other kinds of immunotherapy are undergoing. Besides, the median OS is summarized in [Figure 2]. PD-L1 expression alone is not satisfied biomarkers and studies about better predictive biomarkers are under active investigations. ICI-related AEs were generally lower than chemotherapy. However, irAEs should be closely monitored and managed.
Figure 1: The objective response rate of programmed cell death protein-1 (PD-1) or programmed death ligand-1 blockade for patients with advanced urothelial carcinoma

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Figure 2: The median overall survival of programmed cell death protein-1 (PD-1) or programmed death ligand-1 blockade for patients with advanced urothelial carcinoma

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Acknowledgments

We thank Miss Pei-Ling Chen, Department of Urology, National Taiwan University Hospital, for administrative help.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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