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The landscape of immunotherapy in metastatic urothelial carcinoma

Teo, Min Yuen; Iyer, Gopa

doi: 10.1097/MOU.0000000000000676

Purpose of review This review provides an overview of clinical trials recently completed or currently ongoing evaluating the role of checkpoint blockade in metastatic urothelial carcinoma.

Recent findings In 2016, five immunotherapy agents were approved for metastatic urothelial carcinoma patients who had progressed on platinum-based chemotherapy All five agents evinced an approximately 20% overall response rate coupled with durability of response in a subset of these patients. Several putative predictive biomarkers of sensitivity to checkpoint blockade have been examined although which of these should be incorporated into standard practice is unclear. Moreover, as most patients do not respond to checkpoint blockade, research has focused on combination therapies in both the first-line and second-line settings.

Summary The durability of response and general tolerability of checkpoint blockade has transformed the treatment of metastatic urothelial carcinoma. However, only a minority of patients responds to single-agent therapy. Potential approaches to overcome this challenge include the incorporation of combination checkpoint blockade as well as chemotherapy and targeted agents.

Genitourinary Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Correspondence to Gopa Iyer, MD, Genitourinary Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 1006, USA. Tel: +1 646 888 4737; e-mail:

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Checkpoint blockade has transformed the treatment landscape for metastatic urothelial carcinoma. Five immunotherapy agents have been Food and Drug Administration (FDA) approved in patients who have progressed following platinum-based chemotherapy [1–5]. Additionally, two agents, atezolizumab and pembrolizumab, have been approved under specific conditions in treatment-naïve cisplatin-ineligible patients [6,7] Despite the durability of responses with immunotherapy and the favorable toxicity profile of agents within this class, most patients do not respond to treatment. This review summarizes the phase III data supporting checkpoint blockade in the second-line metastatic urothelial carcinoma setting as well as recent efficacy and tolerability data and ongoing clinical trials for combination therapies in both the first-line and second-line settings (Fig. 1).

Box 1

Box 1



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KEYNOTE-045 is the first phase III randomized controlled trial of pembrolizumab versus cytotoxic chemotherapy (investigator's choice of taxane or vinflunine) in patients with metastatic urothelial carcinoma to show a survival benefit for checkpoint blockade in the second-line metastatic setting and improved tolerability with pembrolizumab [2]. Of 542 patients randomized 1 : 1 to pembrolizumab or chemotherapy, the objective response rate (ORR) was 21% with pembrolizumab and 11% with chemotherapy. The median 1-year and 2-year overall survival (OS) rates were 44.2 and 26.9%, respectively, with pembrolizumab versus 29.8 and 14.3% with chemotherapy, at a median follow-up of 27.7 months. The median overall survival (OS) was 10.1 versus 7.3 months with pembrolizumab versus chemotherapy, respectively (hazard ratio 0.70; 95% CI 0.57–0.85; P < 0.001). In patients receiving pembrolizumab, the median duration of response had not been reached (range 1.6+ to 30+ months) and was 4.4 months with chemotherapy (range, 1.4+ to 29.9+ months). Although ORR was higher in patients with PD-L1-positive tumors (20.3 versus 6.7%), responses were observed with any level of expression.

In contrast, the IMvigor211 study was a phase III randomized controlled trial of atezolizumab versus chemotherapy (investigator's choice of taxane or vinflunine) in patients with platinum-treated metastatic urothelial carcinoma that did not show a survival benefit with checkpoint blockade [8▪▪]. A predefined hierarchical analysis of the primary endpoint of OS was performed based on PD-L1 positivity on tumor-infiltrating immune cells. In patients with at least 5% PD-L1 positivity, no difference in OS was noted between atezolizumab versus chemotherapy (11.1 versus 10.6 months, respectively, stratified hazard ratio 0.87; 95% CI 0.63–1.21; P = 0.41). Although ORR was similar between the two modalities (23 versus 22%), atezolizumab therapy was associated with improved duration of response (median 15.9 versus 8.3 months; hazard ratio 0.57; 95% CI 0.26–1.26), with 62% of responders exhibiting ongoing responses compared with 20% of chemotherapy responders. Potential factors contributing to the absence of an OS benefit in the biomarker-positive patients in this study include: PD-L1 positivity was enriched in both atezolizumab and chemotherapy responders and OS in the vinflunine-treated patients was higher than expected based on historical data.

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Checkpoint 275 was a single-arm phase II study of nivolumab in patients with previously treated metastatic urothelial carcinoma [3]. The ORR was 20.4% and at a median follow-up of 24.5 months, the median OS was 8.6 months with a 1-year OS rate of 40%. The combination of the CTLA-4 inhibitor ipilimumab with nivolumab has been FDA-approved in several cancers. This combination was tested in metastatic urothelial carcinoma patients in the second-line setting in CheckMate 032 [9▪▪]. Approximately two-thirds of patients had received at least two prior lines of therapy, and in the combination therapy cohorts, approximately one-third had liver metastases at enrollment. Patients received one of three regimens: nivolumab 3 mg/kg (N3) every 2 weeks, N3 with ipilimumab 1 mg/kg (I1) every 3 weeks for four doses followed by single-agent nivolumab maintenance, or nivolumab 1 mg/kg (N1) with ipilimumab 3 mg/kg (I3) every 3 weeks for four doses followed by single-agent nivolumab maintenance. ORRs for these three cohorts were: 25.6% in 78 patients receiving N3, 26.9% in 104 patients receiving N3 + I1, and 38% in 92 patients receiving N1 with I3. Whenever stratified by PD-L1 expression, ORR was 23.8% in patients with less than 1% PD-L1 tumor expression receiving N1 with I3 versus 58.1% in patients with tumor PD-L1 expression of at least 1%. The median time to response ranged from 1.4 to 2 months across the three groups whereas the median duration of response was 30.5 months [N3, 95% CI 8.3 months to not estimable (NE)], 22.3 months (N3 with I1, 95% CI 12.8 months to NE), and 22.9 months (N1 with I3, 95% CI 9.8 months to NE). The 12-month PFS rates were 17.9% (N3), 22.6% (N3 with I1), and 25.9% (N1 with I3) whereas median OS was 9.9 months for N3, 7.4 months for N3 with I1, and 15.3 months for N1 with I3. Both monotherapy and combination therapy were well tolerated, with grades 3–4 treatment-related adverse events observed in 26.9% (N1), 30.8% (N3 with I1), and 39.1% (N1 with I3) of patients. Grades 3–4 treatment-related serious adverse events were noted in 7.7% (N3), 20.2% (N3 with I1), and 21.7% (N1 with I3) of patients. Fatal pneumonitis was observed in one patient receiving N3 and one patient receiving N3 with I1. The most common treatment-related select adverse events of any grade included endocrine, skin, and gastrointestinal toxicities in the N3 cohort and the same profile with the addition of hepatic toxicity for patients in the combination cohorts. Most treated patients did not have to discontinue therapy secondary to treatment-related adverse events. Although this trial was not designed to directly compare outcomes across cohorts, the addition of I3 results in numerically higher ORR, PFS, and median OS in this heavily pretreated patient population and despite the presence of liver metastases, which have been correlated with resistance to single agent checkpoint blockade in prior trials. Moreover, patients exhibited responses regardless of PD-L1 positivity. The ORR of 58.1% in PD-L1 expressing tumors with N1 with I3 is higher than that observed in other trials of single-agent checkpoint blockade in PD-L1 unselected patient populations.

CHECKMATE 901 is a phase III multiarm randomized study in patients with treatment-naïve metastatic urothelial carcinoma consisting of the following treatment arms: combination I3 with N1 followed by nivolumab maintenance; gemcitabine with cisplatin or carboplatin for up to six cycles; nivolumab with gemcitabine and cisplatin followed by nivolumab maintenance; gemcitabine and cisplatin for six cycles (NCT03036098). Arms three and four will only enroll cisplatin-eligible patients whereas the first two arms will include patients regardless of cisplatin eligibility. The co-primary endpoints include OS and PFS in cisplatin-ineligible patients receiving either combination checkpoint blockade versus chemotherapy, and PFS in cisplatin-eligible patients receiving combination nivolumab with chemotherapy or chemotherapy alone.

The combination of anti-PD-1 therapy with CTLA-4 inhibition has been assessed in a phase I trial of durvalumab with tremelimumab in patients with platinum-refractory metastatic urothelial carcinoma [10]. The ORR was 20.8% and the median duration of response was not reached (range 1.9–24.9 months). The median PFS and OS were 1.9 and 9.5 months, respectively, and responses were observed independent of PD-L1 expression status although numerically higher in PD-L1- positive patients. Grades 3–4 treatment-related adverse events were observed in 28.6% of patients. This ORR was not significantly different from durvalumab monotherapy (17.8%) whereas the rate of grades 3–4 toxicities was higher with combination therapy.

The NILE study is a randomized global trial examining durvalumab with tremelimumab and standard-of-care chemotherapy, durvalumab with standard-of-care chemotherapy, or standard of chemotherapy alone in treatment-naïve patients with metastatic urothelial carcinoma (NCT03682068). Patients are randomized in a 1 : 1 : 1 fashion and the primary endpoints include PFS and OS.

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KEYNOTE-361 is a randomized phase III trial testing the efficacy and safety of combination pembrolizumab plus chemotherapy versus chemotherapy alone in treatment naïve metastatic urothelial carcinoma patients (NCT02853305). Gemcitabine and cisplatin or carboplatin will be administered based upon cisplatin eligibility. Patients will be randomized 1 : 1 : 1 to pembrolizumab with chemotherapy, pembrolizumab alone, or chemotherapy alone. The primary endpoints are PFS and OS with secondary endpoints of ORR and tolerability.

A similar study, IMvigor 130, is a randomized phase III trial evaluating the efficacy of atezolizumab and chemotherapy versus chemotherapy alone in platinum-eligible metastatic urothelial carcinoma patients in the first-line setting (NCT02807636). Patients are randomized 1 : 1 : 1 to platinum, gemcitabine, and atezolizumab or placebo, or atezolizumab alone. The co-primary endpoints in the intent-to-treat population include PFS and OS in the atezolizumab with chemotherapy versus chemotherapy and placebo cohorts and OS in the atezolizumab alone versus chemotherapy with placebo cohorts.

An interim safety analysis of both studies indicated that cisplatin-ineligible patients whose tumors exhibited low PD-L1 status had inferior outcomes when treated with immunotherapy compared with carboplatin-based chemotherapy. In 2018, the FDA and the European Medical Agency both amended atezolizumab and pembrolizumab approvals to mandate PD-L1 testing (using drug-specific companion diagnostic tests) in the cisplatin-ineligible patient population. Those patients with low or no PD-L1 expression should receive carboplatin-based chemotherapy as first-line management. Patients who are platinum-ineligible may receive checkpoint blockade independent of PD-L1 expression status.

The HCRN GU14-182 study assessed the efficacy of maintenance pembrolizumab versus placebo in patients with metastatic urothelial carcinoma who achieved at least stable disease after first-line platinum-based chemotherapy [11▪]. The rationale for this study was based on the observation that most patients progress after first-line chemotherapy within 1 year.

Patients were randomized 1 : 1 to pembrolizumab versus placebo and stratified based on location of metastatic sites and response to first-line chemotherapy. Patients received 24 months of treatment in the absence of progression. The primary endpoint was PFS, and crossover was allowed for those patients who progressed on placebo and were candidates for pembrolizumab. Secondary endpoints included ORR, safety, and OS. The primary endpoint was met, with pembrolizumab therapy showing significant improvement in PFS compared with placebo (P = 0.036). The use of switch maintenance will need to be weighed in the context of the pending efficacy data from the first-line combination chemotherapy and immunotherapy studies discussed previously.

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The PIVOT-02 study is investigating the efficacy and safety of nivolumab with NKTR-214 (bempegaldesleukin), a human recombinant IL2 compound linked to polyethylene glycol (PEG) moieties[12], across several tumor types, including cisplatin-ineligible, treatment-naïve metastatic urothelial carcinoma patients. Intravenous administration of the PEGylated compound leads to slow release of the PEG molecules. NKTR-214 subsequently binds preferentially to the IL2Rβγ receptor (CD122) expressed on the surface of CD8+ cytotoxic T cells and natural killer cells within the tumor microenvironment, enhancing immune-mediated antitumor effect. Additionally, in-vivo mouse models of cancer demonstrated that NKTR-214 does not concomitantly stimulate T-regulatory (T-reg) cells, with an intratumor CD8+ to T-reg ratio of more than 400 : 1. Of 34 metastatic urothelial carcinoma patients receiving NKTR-214 0.006 mg/kg with nivolumab 360 mg every 3 weeks, 23 were evaluable for efficacy, having undergone at least one imaging study [13▪▪]. Combination therapy displayed an impressive 48% ORR (11/23 patients, 95% CI 27–69%), including four (23%) complete responses. In those patients whose tumor PD-L1 status was available, the ORR was 56 versus 50% in PD-L1-positive and PD-L1-negative patients, respectively. The rate of grade three TRAEs was 18 and 8.8% of patients stopped therapy because of TRAEs. The toxicity profile (in order of decreasing frequency) included fatigue, pyrexia, chills, and flu-like symptoms. These data suggest a role for combination therapy in cisplatin-ineligible patients, especially in patients without PD-L1-expressing tumors given the equivalent efficacy between these two cohorts. In a subset of 22 patients, pretreatment tumor biopsies were available for an ongoing biomarker analysis. Data presented at the 2019 ASCO meeting indicate that patients with an unfavorable tumor immune microenvironment, defined in part as having low levels of CD8+ T cells and percent CD3+ by IHC, still exhibit responses to combination therapy. Additionally, 11 patients with matched baseline and on-treatment biopsies revealed conversion from PD-L1-negative to PD-L1-positive expression status in 60% (6 of 10) [13▪▪].

PIVOT-10 is a randomized clinical trial of NKTR-214 with nivolumab versus gemcitabine and carboplatin in cisplatin-ineligible, treatment-naïve patients with metastatic urothelial carcinoma whose tumors display low PD-L1 expression (NCT03785925). The primary endpoint is ORR in patients with low PD-L1 expression with the chemotherapy arm serving as a reference for ORR with carboplatin-based chemotherapy in PD-L1 low tumors. The trial allows for patients on gemcitabine and carboplatin to receive nivolumab with NKTR-214 at the time of progression.

Several trials are now evaluating combinations of anti-PD-1/L1 agents and checkpoint inhibitors, such as TIM3 and LAG-3, as well as enzyme-directed treatments, including IDO-1 inhibitors.

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor of the fibroblast growth factor and vascular endothelial growth factor (VEGF) receptors, RET and KIT. It has been FDA-approved in several cancer types, including in combination with everolimus in advanced renal cell carcinoma [14]. The combination of lenvatinib with pembrolizumab was evaluated in a phase Ib/II trial in renal cell and endometrial cancer patients as well as 20 patients with metastatic urothelial carcinoma [15,16]. Most patients had received prior treatment, but 20% were treatment-naïve and no enrolled patient had received checkpoint blockade. The ORR was 25%, including one complete response, and the median PFS was 5.4 months with a 1-year PFS rate of 26%, indicating durability of response. Although 50% of patients were PD-L1 positive, responses were observed in PD-L1-negative patients. The rate of treatment-related adverse events was significant, with grades 3–4 toxicities observed in half of patients. The most common treatment-related adverse events of any grade included proteinuria, hypertension, diarrhea, fatigue, and hypothyroidism (thought to represent a synergistic toxicity between pembrolizumab and lenvatinib). Dose reduction was required in approximately one-third of patients with cessation of therapy in 20% of patients because of treatment-related adverse events. One patient died of a gastrointestinal hemorrhage likely secondary to perforation. A phase III trial of the combination is planned in metastatic urothelial carcinoma, LEAP-011, in which treatment-naïve cisplatin-ineligible patients with positive PD-L1 expression, or patients who are platinum-ineligible regardless of PD-L1 expression status, will receive pembrolizumab with lenvatinib or pembrolizumab with placebo (NCT03898180). Primary endpoints include PFS and OS. Similar trials are evaluating other anti-VEGF agents, including bevacizumab, sitravatinib, and cabozantinib, in combination with immunotherapy.

Additional novel combinations with small molecule inhibitors currently being evaluated include checkpoint blockade with PolyADP Ribose Polymerase inhibitors and fibroblast growth factor (FGFR) inhibitors. BAYOU is a phase II trial evaluating durvalumab with olaparib or placebo in platinum-ineligible patients with treatment-naïve metastatic urothelial carcinoma. The FDA recently approved the FGFR inhibitor erdafitinib for patients with metastatic urothelial carcinoma and select FGFR3 or FGFR2 genetic aberrations following at least one line of prior platinum-containing chemotherapy [17▪▪]. Several trials are now exploring the safety and efficacy of FGFR inhibition with checkpoint blockade in the metastatic setting. Enfortumab vedotin, an antibody-drug conjugate targeting nectin 4, displayed an ORR of 44% in pretreated patients with metastatic urothelial carcinoma [18▪▪]. This agent is now being evaluated in combination with chemotherapy and checkpoint blockade in several disease states.

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The FDA approval of checkpoint blockade as monotherapy in metastatic urothelial carcinoma patients following platinum-based chemotherapy has been followed by an incredible number of trials evaluating combinations of checkpoint blockade with chemotherapy and novel agents. With each trial, several correlative analyses have been incorporated to interrogate tumor tissue and the host to define biomarkers of response and resistance. The results of these trials are eagerly awaited.

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Financial support and sponsorship


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Conflicts of interest

M.Y.T. receives research support from Bristol-Myers Squibb (Investigator Initiated Trials), Clovis (site PI), and the Prostate Cancer Foundation.

G.I. has consulted for Mirati Therapeutics, Janssen, and Bayer and receives research support from Novartis, Mirati Therapeutics, Bayer, and DeBio Pharm.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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1. 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; 387:1909–1920.
2. Bellmunt J, de Wit R, Vaughn DJ, et al. KEYNOTE-045 InvestigatorsPembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376:1015–1026.
3. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18:312–322.
4. Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 2016; 34:3119–3125.
5. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol 2017; 35:2117–2124.
6. Balar AV, Galsky MD, Rosenberg JE, et al. IMvigor210 Study Group.Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389:67–76.
7. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:1483–1492.
8▪▪. Powles T, Duran I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018; 391:748–757.

Negative phase three trial of atezolizumab versus chemotherapy in the second-line metastatic setting within a biomarker-selected patient population. This finding underscores the need to identify and validate predictive biomarkers of response to checkpoint blockade.

9▪▪. Sharma P, Siefker-Radtke A, de Braud F, et al. Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: CheckMate 032 nivolumab 1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results. J Clin Oncol 2019; 37:1608–1616.

Positive trial of ipilimumab with nivolumab with response rates exceeding monotherapy and with acceptable tolerability, suggesting a role for the combination within the panoply of monotherapy checkpoint inhibitor options.

10. Balar AV, Mahipal A, Grande E, et al. Durvalumab + tremelimumab in patients with metastatic urothelial cancer. Cancer Res 2018; 78. (13 Suppl):
11▪. Galsky MD, Pal SK, Mortazavi A, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182. J Clin Oncol 2019; 37 (15_suppl):4504.

First positive trial of switch maintenance with pembrolizumab in patients with metastatic urothelial carcinoma following platinum-based chemotherapy.

12. Bentebibel SE, Hurwitz ME, Bernatchez C, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rbetagamma-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019; 9:711–721.
13▪▪. Siefker-Radtke AO, Fishman MN, Balar AV, et al. NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol 2019; 37:388.

Combination NKTR-214 with nivolumab shows impressive activity in the metastatic setting. On the basis of these results, trials are evaluating efficacy earlier in the management of the disease.

14. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; 16:1473–1482.
15. Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019; 20:711–718.
16. Vogelzang NJ, Encarnacion CA, Cohn AL, et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in urothelial cancer. J Clin Oncol 2019; 37 (8_Suppl):11.
17▪▪. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019; 381:338–348.

First FDA approval of targeted therapy in metastatic urothelial carcinoma.

18▪▪. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019; JCO1901140[Epub ahead of print].

Impressive efficacy of antibody–drug conjugate therapy for metastatic urothelial carcinoma in a pretreated patient population.


immune checkpoint blockade; metastatic urothelial carcinoma; predictive biomarkers

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