Immunohistochemistry (IHC) to enhance the prognostic allocation of locally advanced and metastatic urothelial cancer (UC) undergoing first-line chemotherapy (CT).

4526 Background: Approval of anti–PD-L1/anti–PD-1 CPI agents has changed the mUC tx landscape, but real-world (RW) tx patterns are not well described. Here, we describe pt characteristics, time on tx (TOT), tx-cycle distribution, relative dose intensity (RDI) and subsequent tx for pts receiving atezolizumab (atezo), nivolumab (nivo) or pembrolizumab (pembro) monotherapy. Methods: Pts diagnosed with mUC who completed atezo, nivo or pembro in the first-line (1L) or prior-platinum second-line and beyond (2L+) settings by April 30, 2018, were identified from the US-based Flatiron Health electronic health record–derived database. TOT was defined as time from first to last CPI administration + 1 cycle, tx cycles as number of CPI doses received during TOT and RDI as ratio of actual to planned dose per week to reflect any dose interruption. Results: RW data from pts receiving atezo, nivo and pembro were analyzed (Table). Up to 38% of pts had ECOG PS > 1. Median TOT ranged from 2.1-2.8 mo, with overlapping 95% CIs; mean TOT ranged from 2.7-4.1 mo. Over 50% of pts had ≤ 4 tx cycles. 21%-38% of pts did not have RDI within 95%-105% of the labeled dose. Most common subsequent txs were platinum-based chemotherapy combinations with gemcitabine or taxanes (post–1L CPI) and taxane monotherapy or other CPI monotherapy/combinations (post–2L+ CPI). Conclusions: Here, we present the largest analysis of RW CPI use in mUC to date. Overall, this unadjusted descriptive analysis showed relative comparability of pt and tx characteristics and TOT across CPI-treated groups. Insights into RW tx allow for an understanding of how clinical trial data translate to broader pt populations, including those with ECOG PS > 1, and may be useful for practitioners. [Table: see text]

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PIVOT-10: Phase II study of bempegaldesleukin plus nivolumab in cisplatin-ineligible advanced urothelial cancer

Future Oncology ◽

10.2217/fon-2020-0795 ◽

2020 ◽

Author(s):

Robert A Huddart ◽

Arlene O Siefker-Radtke ◽

Arjun V Balar ◽

Mehmet A Bilen ◽

Thomas Powles ◽

...

Keyword(s):

Phase Ii ◽

Urothelial Cancer ◽

Objective Response ◽

Locally Advanced ◽

Response Rates ◽

Complete Response ◽

First Line ◽

First Line Therapy ◽

Programmed Death ◽

Metastatic Urothelial Cancer

The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).

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A Phase 3, Randomized, Open-Label, Multicenter, Global Study of First-Line Durvalumab + SoC Chemotherapy and Durvalumab + Tremelimumab and SoC Chemotherapy vs SoC Chemotherapy Alone in Unresectable Locally Advanced or Metastatic Urothelial Cancer

10.26226/morressier.5d778ff6ba50d8c980533462 ◽

2019 ◽

Author(s):

Matthew Galsky ◽

Lana Packham

Keyword(s):

Urothelial Cancer ◽

Locally Advanced ◽

First Line ◽

Open Label ◽

Phase 3 ◽

Metastatic Urothelial Cancer ◽

Global Study

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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

The Lancet Oncology ◽

10.1016/s1470-2045(17)30616-2 ◽

2017 ◽

Vol 18 (11) ◽

pp. 1483-1492 ◽

Cited By ~ 421

Author(s):

Arjun V Balar ◽

Daniel Castellano ◽

Peter H O'Donnell ◽

Petros Grivas ◽

Jacqueline Vuky ◽

...

Keyword(s):

Urothelial Cancer ◽

Locally Advanced ◽

Phase 2 ◽

First Line ◽

Metastatic Urothelial Cancer ◽

Phase 2 Study

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Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy

British Journal of Cancer ◽

10.1038/s41416-018-0229-0 ◽

2018 ◽

Vol 119 (7) ◽

pp. 801-807 ◽

Cited By ~ 9

Author(s):

Tracy L. Rose ◽

David D. Chism ◽

Ajjai S. Alva ◽

Allison M. Deal ◽

Susan J. Maygarden ◽

...

Keyword(s):

Phase Ii ◽

Urothelial Cancer ◽

Phase Ii Trial ◽

First Line ◽

Metastatic Urothelial Cancer ◽

Line Chemotherapy

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Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): Long-term efficacy from phase 2 study IMvigor210.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.4523 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 4523-4523 ◽

Cited By ~ 18

Author(s):

Arjun Vasant Balar ◽

Robert Dreicer ◽

Yohann Loriot ◽

Jose Luis Perez-Gracia ◽

Jean H. Hoffman-Censits ◽

...

Keyword(s):

Urothelial Cancer ◽

Locally Advanced ◽

Phase 2 ◽

First Line ◽

Term Efficacy ◽

Metastatic Urothelial Cancer ◽

Phase 2 Study

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A phase Ib single-arm study of bintrafusp alfa for the treatment of pretreated, locally advanced/unresectable or metastatic urothelial cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.tps501 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. TPS501-TPS501

Author(s):

Petros Grivas ◽

Rafael Morales-Barrera ◽

Srikala S. Sridhar ◽

Yohann Loriot ◽

Michiel Simon Van Der Heijden ◽

...

Keyword(s):

Antitumor Activity ◽

Safety Profile ◽

Urothelial Cancer ◽

Objective Response ◽

Locally Advanced ◽

Unmet Need ◽

Type I ◽

First Line ◽

Phase Ib ◽

Metastatic Urothelial Cancer

TPS501 Background: Urothelial cancer (UC) is the most common histological subtype of bladder cancer. For patients with metastatic UC, platinum-containing chemotherapy (CT) is the first-line standard of care. With 5 PD-(L)1 inhibitors approved for second-line treatment of platinum-refractory advanced UC, objective response rates (ORRs) in this setting (15% to 21%) and in first-line cisplatin-ineligible patients (23% to 31%) suggest that there remains a significant unmet need for improved outcomes. TGF-β signaling has been associated with resistance to PD-(L)1 inhibitors in patients with UC. Bintrafusp alfa (BA) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In murine models, BA resulted in improved antitumor activity vs TGF-β or PD-L1 monotherapies alone or in combination. In 2 phase I trials (NCT02517398 and NCT02699515), BA demonstrated a manageable safety profile and encouraging clinical efficacy in >670 patients with advanced solid tumors. Here we describe a phase Ib study (NCT04349280) that will assess the clinical activity and safety profile of BA in platinum-experienced patients with locally advanced/unresectable or metastatic UC. Colocalized, simultaneous inhibition of the TGF-β and PD-L1 pathways by BA is hypothesized to elicit greater antitumor activity than anti–PD-(L)1 therapies in patients with UC. Methods: This open-label, multicenter, single-arm trial is accruing patients with histologically confirmed locally advanced/unresectable or metastatic UC (ECOG PS ≤1) with disease progression or recurrence after platinum-based CT. Patients must not have received >2 lines of systemic therapy for metastatic disease or prior therapy targeting T-cell costimulation, or checkpoint or TGF-β pathways. Patients with pneumonitis or a history of noninfectious pneumonitis that required systemic immunosuppression are ineligible. Patients will receive BA 1200 mg every 2 weeks until progression, unacceptable toxicity, death, or study withdrawal, or for up to 2 years. The primary endpoint is investigator-assessed confirmed ORR per RECIST 1.1; key secondary endpoints include duration of response and progression-free survival per the investigator and IRC, overall survival, safety, immunogenicity, and pharmacokinetics. Exploratory biomarker analyses will be conducted using patient samples collected during screening and prior to administration of BA. The base ORR used for the null hypothesis is 21%, and the target ORR is 40%. Using a predictive probability design and an estimated enrollment of 40 patients, the type I error rate is 5.70% and the power is 85.39%. As of September 2020, 3 sites in 2 countries have been activated and no patients have been enrolled. Clinical trial information: NCT04349280.

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A phase III, randomized, open-label, multicenter, global study of first-line durvalumab plus standard of care (SoC) chemotherapy and durvalumab plus tremelimumab, and SoC chemotherapy versus SoC chemotherapy alone in unresectable locally advanced or metastatic urothelial cancer (NILE).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.tps504 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. TPS504-TPS504

Author(s):

Matt D. Galsky ◽

Andrea Necchi ◽

Srikala S. Sridhar ◽

Osamu Ogawa ◽

Natasha Angra ◽

...

Keyword(s):

Primary Endpoint ◽

Urothelial Cancer ◽

Statistical Significance ◽

Locally Advanced ◽

Phase Iii ◽

First Line ◽

Open Label ◽

Primary Endpoints ◽

Metastatic Urothelial Cancer ◽

Biomarker Analysis

TPS504 Background: Despite high response rates with first-Line (1L), standard, platinum-based chemotherapy (CT) (gemcitabine + cisplatin or gemcitabine + carboplatin) for patients (pts) with locally advanced or metastatic urothelial cancer (mUC), prognosis remains poor. Studies of immune checkpoint inhibitors + CT in 1L mUC have demonstrated mixed results. In IMvigor130, an improvement in progression-free survival (PFS) with atezolizumab + CT vs placebo + CT reached statistical significance, although overall survival (OS) had not reached statistical significance at the interim analysis. A subgroup analysis suggested a possible larger effect size for PFS and OS for pts with high PD-L1 expression. In KEYNOTE-361, no improvement in either PFS or OS was observed with pembrolizumab + CT vs CT alone. The combination of durvalumab (anti–PD-L1 antibody) and tremelimumab (anti–CTLA-4 antibody) has shown activity in previously treated mUC. In the DANUBE trial of 1L mUC, the co-primary endpoints were OS compared between durvalumab and CT in pts whose tumor cells and/or tumor-infiltrating immune cells express high levels of PD-L1 (≥25%) and between durvalumab + tremelimumab and CT regardless of PD-L1 expression. While neither co-primary endpoint was met, durvalumab + tremelimumab showed evidence of activity, particularly in the PD-L1–high population (hazard ratio: 0.74 [95% CI 0.59–0.93]). Collectively, these results led to an update to the NILE protocol, focusing on pts with PD-L1–high expression. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, phase III global trial that will randomize ~1215 previously untreated pts with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Eligible pts aged ≥18 years will be randomized 1:1:1 to durvalumab + CT (Arm 1), durvalumab + tremelimumab + CT (Arm 2), or CT (Arm 3). A tumor tissue sample for biomarker analysis is mandatory as PD-L1 status is a stratification factor. The original co-primary endpoints were PFS and OS for durvalumab + CT vs CT in the intention-to-treat population. However, based on the DANUBE trial results, the primary endpoint was revised to a co-primary endpoint OS in pts with high PD-L1 expression for Arm 1 vs Arm 3 and Arm 2 vs Arm 3. Secondary endpoints will include OS, OS rate at 24 months, PFS, objective response rate, proportion of pts alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, health-related quality of life, and safety. Pharmacokinetics, immunogenicity, and biomarkers are exploratory endpoints. The study opened for enrollment in September 2018. Clinical trial information: NCT03682068.

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