The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma
Abstract
Results from JAVELIN Bladder 100 established avelumab (anti–PD-L1) first-line maintenance as the standard-of-care treatment for patients with advanced urothelial carcinoma (UC) that has not progressed with first-line platinum-based chemotherapy. We describe the design of JAVELIN Bladder Medley (NCT05327530), an ongoing phase II, multicenter, randomized, open-label, parallel-arm, umbrella trial. Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti–Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.
Plain language summary
Urothelial cancer develops in the urinary tract, which contains the parts of the body that move urine from the kidneys to outside of the body. Urothelial cancer is called advanced when it has spread outside of the urinary tract. Chemotherapy is often the first main treatment given to people with advanced urothelial cancer. Avelumab is an immunotherapy drug that can help the body's immune system find and destroy cancer cells. Results from a trial called JAVELIN Bladder 100 looked at avelumab maintenance treatment, which is given after chemotherapy. The trial showed that avelumab maintenance treatment helped people with advanced urothelial cancer live longer than people who were not treated with avelumab. Avelumab also helped people have a longer time without their cancer getting worse. Avelumab is the only approved maintenance treatment available for people with advanced urothelial cancer that has not worsened after chemotherapy. The JAVELIN Bladder Medley trial will assess whether avelumab maintenance treatment given in combination with other anticancer drugs can help people with advanced urothelial cancer live longer and have a longer time without their cancer getting worse compared with avelumab alone. Researchers will also look at the side effects people have when they receive avelumab alone or combined with the other anticancer drugs in this trial. Results will show whether the benefit of avelumab maintenance treatment can be improved by combining avelumab with other anticancer drugs. People started joining this trial in August 2022. Results will be reported in the future.
Clinical Trial Registration: NCT05327530 (ClinicalTrials.gov)
Tweetable abstract
Recruiting! JAVELIN Bladder Medley: a phase II umbrella trial exploring novel combinations with avelumab as #1LMaintenanceTherapy for advanced #UrothelialCarcinoma after 1L chemotherapy (NCT05327530).
Graphical abstract
Bladder cancer, which accounts for >90% of urothelial carcinoma (UC) cases, is the tenth most common cancer worldwide, with approximately 573,000 new cases reported and 213,000 deaths attributed to bladder cancer globally in 2020 [1,2]. In the USA, approximately 12% of patients have locally advanced or metastatic UC (advanced UC) at diagnosis [3]. The 5-year overall survival (OS) rate for metastatic bladder cancer is <10% [3]. Across several real-world studies, only about 30–40% of patients who received first-line (1L) therapy for advanced UC subsequently received second-line treatment [4–6]. Therefore, optimal 1L treatment with sustained long-term benefits is crucial to reduce ‘attrition’ of patients between treatment lines and improve outcomes. The pivotal, phase III, randomized JAVELIN Bladder 100 trial (NCT02603432) established the ‘JAVELIN Bladder regimen’ (1L platinum-based chemotherapy as induction treatment followed by avelumab in patients without disease progression as switch-maintenance treatment) as the standard of care for eligible patients with advanced UC. The JAVELIN Bladder 100 trial provided level 1 evidence, showing a significant OS and progression-free survival (PFS) benefit with avelumab 1L maintenance + best supportive care (BSC) versus BSC alone [2,7–9].
Avelumab, a fully human IgG1 anti–PD-L1 monoclonal antibody, selectively binds to PD-L1 and competitively blocks its interaction with the inhibitory T-cell receptor, PD-1 [10]. PD-1/PD-L1 blockade removes the suppression of T-cell activity, allowing for T cell–mediated, adaptive antitumor immune responses [10]. Furthermore, avelumab has a wild-type Fc region that can induce antitumor activity in vitro via both adaptive effector cells (T cells) and innate immune effector cells (antibody-dependent cell-mediated cytotoxicity [ADCC] via natural killer [NK] cells) [10,11]. In vitro studies demonstrated that avelumab can lyse a range of human tumor cells, including bladder carcinomas [11]. Avelumab is approved in various countries as monotherapy for maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with 1L platinum-based chemotherapy and for patients with locally advanced or metastatic UC that has progressed after platinum-based chemotherapy, as monotherapy for patients with metastatic Merkel cell carcinoma, and in combination with axitinib as 1L treatment for patients with advanced renal cell carcinoma [12,13].
In the phase III JAVELIN Bladder 100 trial, patients with histologically confirmed, unresectable locally advanced or metastatic UC without progression following 1L platinum-based chemotherapy (gemcitabine + either cisplatin or carboplatin) were randomized (in a 1:1 ratio) 4–10 weeks after the last dose of 1L chemotherapy [9,14]. Randomization was stratified by metastatic site at start of 1L chemotherapy (visceral vs nonvisceral) and best response to 1L chemotherapy (complete response [CR] or partial response [PR] vs stable disease [SD]). After ≥2 years of follow-up in all patients, OS and PFS continued to be prolonged with avelumab + BSC versus BSC alone [15]. Median OS measured from randomization (i.e., start of maintenance) was 23.8 versus 15.0 months, respectively (hazard ratio [HR], 0.76 [95% CI: 0.63–0.91]; two-sided p = 0.0036; Figure 1). OS rates at 2 years were 49.8% in the avelumab + BSC arm versus 38.4% in the BSC alone arm. OS analyses favored avelumab + BSC versus BSC alone across various clinical subgroups, including those defined by PD-L1 status, 1L chemotherapy regimen and best response to 1L chemotherapy (CR, PR or SD). Median PFS by investigator was 5.5 versus 2.1 months, respectively (HR, 0.54 [95% CI: 0.46–0.64]; two-sided p < 0.0001); 2-year PFS rates were 23.4 versus 7.1%. Long-term safety of avelumab 1L maintenance was also demonstrated with no new safety signals identified with longer follow-up or treatment duration. The most common treatment-related adverse events with avelumab + BSC were pruritus (14.8%), hypothyroidism (11.0%), fatigue (10.8%), diarrhea (10.5%) and asthenia (10.5%) [15]. A plain language summary of the initial results from the JAVELIN Bladder 100 trial has been published and is available in multiple languages [14].
Kaplan–Meier estimate of (A) OS and (B) investigator-assessed PFS.
Reproduced with permission from Powles T, et al. [15] © 2023 American Society of Clinical Oncology.
BSC: Best supportive care; HR: Hazard ratio; mo: Months; OS: Overall survival; PFS: Progression-free survival.
Maintenance treatment with avelumab in combination with other antitumor agents that enhance or target different pathways has the potential to provide increased efficacy compared with avelumab alone. Although avelumab 1L maintenance significantly prolongs OS and PFS versus BSC alone, most patients will eventually have disease progression [9]; thus, improved maintenance treatment could benefit more patients.
Analyses from the JAVELIN Bladder 100 trial investigated potential biomarkers associated with OS benefit in patients with advanced UC receiving avelumab 1L maintenance + BSC versus BSC alone [16]. In these exploratory analyses, TIGIT, a key component of an emerging immune checkpoint network, was found to be strongly associated with longer OS in the avelumab + BSC arm than in the BSC alone arm [16]. Shorter OS was observed in the avelumab + BSC arm in the presence of TIGIT ligands, suggesting that concurrent TIGIT inhibition may increase the efficacy benefit of avelumab 1L maintenance. Additionally, several innate immunity (NK cells, macrophages, dendritic cells) as well as adaptive immunity (B cells, CD4+ T cells, CD8+ T cells) gene sets were found to be associated with longer OS with avelumab + BSC versus BSC alone [16].
The JAVELIN Bladder Medley trial (NCT05327530 [first posted, 14 April 2022], EudraCT number: 2021-003669-36) is investigating the combination of avelumab with three other agents as 1L maintenance treatment. The rationale for the three other agents that will be combined with avelumab are shown in Figure 2 [10,11,16–21]. The first agent, sacituzumab govitecan, is a first-in-class anti–Trop-2/topoisomerase inhibitor conjugate that binds to Trop-2 (a transmembrane Ca2+ signal transducer), which is overexpressed on the surface of a variety of cancer cells, resulting in internalization and release of the topoisomerase inhibitor within the cell, which induces DNA damage and apoptosis [17–19,22]. Sacituzumab govitecan is approved in the USA and EU for the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received ≥2 prior systemic therapies with ≥1 for metastatic disease and in the USA for patients with unresectable locally advanced or metastatic hormone receptor-positive, HER2− breast cancer who have received ≥3 prior systemic therapies including endocrine-based therapy [23,24]. Based on data from the phase II TROPHY-U-01 trial (cohort 1) [25], sacituzumab govitecan received accelerated US FDA approval in the USA for patients with advanced UC previously treated with platinum-based chemotherapy and an anti–PD-1/PD-L1 inhibitor [23]; the confirmatory phase III TROPiCS-04 trial is ongoing [26]. Additionally, results from cohort 3 of the TROPHY-U-01 trial have shown that sacituzumab govitecan in combination with pembrolizumab (anti–PD-1) had promising efficacy and manageable safety in patients with metastatic UC that had progressed with platinum-based chemotherapy [27].
APC: Antigen-presenting cell; IL-15R: IL-15 receptor; NK: Natural killer; PEG: Polyethylene glycol.
The second agent, M6223, is an investigational, fully human antibody that binds to TIGIT on the surface of T cells, blocking its interaction with its ligands, CD155 and CD112 and inhibiting TIGIT-mediated immunosuppression [20]. Additionally, M6223 has been shown to interrupt TIGIT's interaction with CD226 [20], an adhesion molecule that is highly expressed on the surface of NK cells and CD8+ T cells [28]. This interruption leads to increased CD226 signaling that in turn promotes the migration, activation, proliferation, differentiation and function of CD8+ T cells. CD226 and other proteins, including TIGIT, are also involved in regulating NK cell function [28]. Dual inhibition of TIGIT and PD-L1 is expected to have an additive or synergistic effect to restore the antitumor immune response, as TIGIT modulates a key immunomodulatory pathway distinct from the PD-1/PD-L1 axis and is coexpressed with PD-1 on immune cell subsets [29,30]. In preclinical studies, combining an anti–PD-1 and anti-TIGIT resulted in increased efficacy compared with each agent alone in a glioblastoma multiforme mouse model [31]; furthermore, combining PD-L1 and TIGIT blockade in a colorectal cancer mouse model significantly enhanced antitumor activity compared with monotherapy [29]. In vitro studies have also shown that combining M6223 with avelumab elicits additive responses in NK cells, indicating that CD16-mediated ADCC likely augments TIGIT blockade [32]. Despite recent failures of two phase III trials of anti-TIGIT + anti–PD-L1 antibodies in lung cancer [33–35], several phase I/II trials have shown antitumor activity with combinations of novel anti-TIGIT agents + PD-1/PD-L1 inhibitors in various tumor types. For example, etigilimab (anti-TIGIT) + nivolumab (anti–PD-1) showed preliminary clinical benefit in a phase Ia/b open-label trial in locally advanced or metastatic solid tumors (NCT03119428) [36]. In a first-in-human, open-label phase I trial (NCT02964013), vibostolimab (anti-TIGIT) combined with pembrolizumab was well tolerated and had promising antitumor activity in advanced solid tumors [37]. Finally, CITYSCAPE (NCT03563716), a randomized, double-blind, phase II trial, showed an increase in objective response rate and PFS with tiragolumab (anti-TIGIT) + atezolizumab (anti–PD-L1) versus placebo + atezolizumab as 1L treatment for PD-L1+ NSCLC [38]. Numerous ongoing phase III trials continue to assess combinations of anti-TIGIT agents + PD-1/PD-L1 inhibitors in a variety of tumor types.
The third agent being combined with avelumab, NKTR-255, is an investigational IL-15 receptor agonist, which consists of recombinant human IL-15 covalently bound to a 40-kDa polyethylene glycol moiety. NKTR-255 binds IL-15 receptors on immune cells resulting in a sustained IL-15 pathway signal, leading to proliferation and activation of CD8+ T cells (preferentially memory subpopulations) and NK cells, and enhanced antitumor activity [21,39]. In vitro, IL-15 stimulation of NK cells was shown to enhance cytokine production (e.g., IFN-γ and TNF-α) and NK cell degranulation triggered by avelumab; cytotoxicity of tumor cells was also increased [40]. Additionally, in preclinical models, NKTR-255 has been shown to enhance efficacy in combination with an antibody that functions through ADCC [41].
Objectives
JAVELIN Bladder Medley is a phase II trial assessing the safety and efficacy of avelumab in combination with other antitumor agents as 1L maintenance treatment in patients with advanced UC that has not progressed with 1L platinum-based chemotherapy.
Trial design
JAVELIN Bladder Medley is a multicenter, randomized, open-label, parallel-arm, umbrella trial (Figure 3). A total of 252 patients without progression following platinum-based chemotherapy will be enrolled by investigators and randomized 1:2:2:2 (via interactive response technology per a computer-generated randomization list) to receive either avelumab 800 mg every 2 weeks as monotherapy (control group) or in combination with sacituzumab govitecan 10 mg/kg on days 1 and 8 of 21-day treatment cycles, M6223 1600 mg every 2 weeks or NKTR-255 3 μg/kg every 4 weeks. Randomization will occur 4–10 weeks after the last dose of 1L chemotherapy and will be stratified by the presence of visceral metastases at the start of 1L chemotherapy (yes vs no). Treatment will continue until progression, unacceptable toxicity, withdrawal of consent or initiation of a new anticancer treatment. Patients with toxicities related to a combination agent will be permitted to continue treatment with the other drug alone if the investigator judges there may be clinical benefit. Approximately 21 patients will be randomized in a safety run-in phase (≥3 patients in the avelumab monotherapy group and ≥6 patients in each combination group). Available accumulated safety, clinical and pharmacokinetic data will be regularly assessed by an internal data monitoring committee (DMC). The first DMC meeting will take place 5 weeks after the last of the 21 patients has been randomized into the safety run-in phase. Additionally, a medical/safety surveillance team will regularly complete safety reviews throughout the trial. The trial opened for enrollment in June 2022 and the first patient was randomized in August 2022; the estimated primary completion date is August 2026. Data from the avelumab monotherapy group are planned to be extended using external data (i.e., data from the avelumab + BSC arm of the JAVELIN Bladder 100 trial) [9].
Approximately 21 patients will be randomized in a safety run-in phase (≥3 patients in the avelumab monotherapy group and ≥6 patients in each combination group).
* stratified based on the presence or absence of visceral metastases at the start of 1l chemotherapy.
† The control group of 36 randomized patients is planned to be extended using data from an external source (i.e., the phase III JAVELIN Bladder 100 trial) [9].
1L: First line; ICI: Immune checkpoint inhibitor; Q2W: Every 2 weeks; Q4W: Every 4 weeks; PD: Progressive disease; R: Randomization; UC: Urothelial carcinoma.
Key eligibility criteria
For all groups, eligible patients will be aged ≥18 years and have histologically confirmed, unresectable locally advanced or metastatic UC that has not progressed (per Response Evaluation Criteria In Solid Tumors version 1.1 [RECIST 1.1]) with 4–6 cycles of 1L platinum-based chemotherapy (gemcitabine + cisplatin and/or carboplatin). Patients must also have available archival formalin-fixed paraffin-embedded tumor samples (from their most recent primary or metastatic tumor biopsy or resection obtained prior to 1L chemotherapy but within 24 months prior to randomization) or newly obtained baseline tumor samples. Other eligibility criteria include adequate renal, hepatic and bone marrow function. Patients must not have received prior immunotherapy, ILs, anti–Trop-2 antibodies, or any of the investigational drugs used in combination with avelumab. Key inclusion and exclusion criteria are summarized in Table 1.
| Inclusion criteria | Exclusion criteria |
|---|---|
| • Age ≥18 years • Histologically confirmed, unresectable locally advanced or metastatic UC (stage IIIA/IIIB with N1-N3, or stage IV disease at the start of 1L chemotherapy) • Both transitional cell and mixed transitional/nontransitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology • No disease progression (per RECIST 1.1) following 4–6 cycles of 1L platinum-based chemotherapy (gemcitabine + cisplatin and/or gemcitabine + carboplatin) • Last dose of 1L chemotherapy received 4–10 weeks prior to randomization • Archival formalin-fixed paraffin-embedded tumor samples (from most recent primary or metastatic tumor biopsy or resection obtained prior to 1L chemotherapy but ≤24 months prior to randomization) or fresh baseline tumor samples • Estimated life expectancy of ≥3 months • ECOG PS 0–1 • Adequate bone marrow function, including ANC ≥1500/mm3 or ≥1.5 × 109/L, platelets ≥100,000/mm3 or ≥100 × 109/L and hemoglobin ≥9 g/dL • Adequate renal function, defined as estimated creatine clearance ≥30 ml/min • Adequate liver function, including total serum bilirubin ≤1.5 × ULN, AST and ALT ≤2.5 × ULN (≤5 × ULN AST/ALT for patients with liver metastasis) | • Prior treatment with immunotherapy (IL-2, IL-15, IFN-α, or an anti–PD-1, anti–PD-L1, anti–PD-L2, anti-CD137, or CTLA-4 antibody [including ipilimumab]), anti–Trop-2 antibodies, any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, or any of the investigational drugs to be used in combination with avelumab • Prior adjuvant or neoadjuvant systemic therapy ≤12 months before randomization • Major surgery ≤4 weeks or major radiation therapy ≤2 weeks prior to randomization • Current or prior use of immunosuppressive medication ≤7 days prior to randomization, except intranasal, inhaled, topical steroids or local steroid injections, systemic corticosteroids ≤10 mg/day of prednisone or equivalent, or steroids as premedication for hypersensitivity reactions • Symptomatic central nervous system metastases requiring steroids • Persisting toxicity related to prior therapy (NCI CTCAE v5.0 grade >1) • Diagnosis of any other malignancy unless a complete remission without further recurrence was achieved and the patient was deemed to have been cured with no additional therapy required or anticipated to be required • Clinically significant cardiovascular disease <6 months prior to enrolment • Known severe hypersensitivity reactions to monoclonal antibodies (grade ≥3), any history of anaphylaxis, or uncontrolled asthma • Known prior or suspected hypersensitivity to trial drugs or any component in their formulations • Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy • Female patients who are pregnant or breastfeeding |
Objectives & end points
The primary objectives of the trial are to evaluate PFS by investigator assessment of 1L maintenance treatment with avelumab-based combinations compared with avelumab monotherapy and to access the safety and tolerability of avelumab combination regimens. Secondary objectives include OS, objective response and duration of response by investigator and patient-reported outcomes (e.g., disease-related physical symptoms and health-related quality of life) of 1L maintenance treatment with avelumab-based combinations compared with avelumab monotherapy. Exploratory objectives include biomarker analyses. End points are further detailed in Table 2.
| Primary end points |
| • PFS: time from randomization to progressive disease according to RECIST 1.1 per investigator assessment or death • Safety and tolerability of the combinations: occurrence of TEAEs, TRAEs and AEs of special interest throughout the trial |
| Secondary end points |
| • Overall survival: time from randomization to death • Objective response: according to RECIST 1.1 per investigator assessment • Duration of response: time from first documentation of objective response to progressive disease or death, according to RECIST 1.1 per investigator assessment • PK: trial drug concentrations, population PK analyses and exposure-response analyses • Immunogenicity: of all drugs, measured by antidrug antibody assay • Patient-reported outcomes: change from baseline in NCCN/FACT FBlSI-18 DRS-P score |
| Exploratory end points |
| • Disease and health-related QOL (NCCN/FACT FBlSI-18 in total and for each subscale and EQ-VAS) • Pharmacodynamic biomarkers in peripheral blood and/or tumor tissue • Biomarker analyses including, but not limited to, PD-L1 expression, gene expression profiling, tumor mutational burden and circulating tumor DNA longitudinal analysis |
Assessments & data collection
Tumor response will be evaluated by investigators according to RECIST 1.1 via computed tomography or magnetic resonance imaging scans (including those collected pre- and post-1L chemotherapy), until progressive disease, regardless of initiation of subsequent anticancer therapy. Tumor assessments will occur every 8 weeks for the first year following randomization and then every 12 weeks thereafter. Any CR, PR or progression should be confirmed, if clinically feasible, with repeat imaging performed at least 4 weeks after initial scan. Safety will be assessed throughout the trial and will be monitored by the DMC. Adverse events will be coded according to Medical Dictionary for Regulatory Activities terms and graded using National Cancer Institute-Common Terminology Criteria for Adverse Events v5.0.
Blood samples will be taken pre- and post-dose for antidrug antibody analysis and pharmacokinetic analyses to determine the end of infusion concentration and trough concentration for all drugs. Patient-reported outcomes (PRO) will include the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Cancer Symptom Index-18 (FBlSI-18) subscales and EuroQoL visual analogue scale to assess overall wellbeing. Electronic PRO assessments will be conducted every 2 weeks, in line with avelumab infusions, until the occurrence of progressive disease; if the patient continues treatment, electronic PRO assessments will continue to be conducted every 4 weeks. Patients will be monitored for 30- and 90-day safety follow-up periods after the end of treatment and every 12 weeks thereafter for long-term follow-up.
Statistical analyses
A planned interim analysis will be conducted when 56 PFS events have been observed in each treatment-control comparison; the primary analysis is planned at 65 PFS events. This trial will be considered positive if the HR for PFS for at least one treatment-control comparison is ≤0.60 and ≤0.70 at the interim and primary analyses, respectively. Survival analyses will be evaluated using HRs with CIs estimated by the Cox proportional hazards model. Kaplan–Meier estimates will be presented by treatment group. Median PFS, OS and corresponding two-sided 95% CIs will be calculated according to Brookmeyer and Crowley. Objective response rate will be reported with 95% CI. Odds ratio with 95% CI will be estimated based on the Cochran-Mantel-Haenszel method. Duration of response will be summarized by Kaplan–Meier estimates, median and corresponding 95% CI. Safety end points will be analyzed in all patients who have received ≥1 dose of trial treatment. All safety measures will be assessed using descriptive statistics by treatment group. Data in the avelumab monotherapy group (n = 36 randomized patients) are planned to be extended by combining with data from an external source (i.e., data from the avelumab + BSC arm of the JAVELIN Bladder 100 trial) [9]. All patients who fulfil the eligibility criteria will be included. Baseline information will be used to check comparability between randomized patients in this trial and eligible patients from the JAVELIN Bladder 100 trial.
Conclusion
Avelumab 1L maintenance is established as a standard of care in patients with advanced UC that has not progressed with 1L platinum-based chemotherapy [2,7,8]. To further improve outcomes with 1L therapy, extend the long-term benefit with avelumab maintenance and maximize the number of patients who benefit, investigations into novel combinations are warranted.
This phase II JAVELIN Bladder Medley trial will evaluate the combination of avelumab with other antitumor drugs as 1L maintenance for patients with advanced UC that has not progressed with 1L platinum-based chemotherapy. The trial aims to show whether avelumab-based combinations as 1L switch maintenance therapy can improve PFS compared with avelumab 1L maintenance alone. The safety and tolerability of avelumab combination regimens will also be evaluated. The trial is open, and enrollment is planned at ≈100 sites in Australia, Belgium, Canada, Denmark, France, Germany, Greece, Italy, Korea, Spain, Taiwan, the UK and USA. The estimated primary completion date is August 2026.
Several other phase II/III trials are ongoing that are also assessing avelumab 1L maintenance in combination with various agents in patients with advanced UC, including the following examples: MAIN-CAV (NCT05092958), a randomized phase III trial assessing avelumab + cabozantinib (multi-tyrosine kinase inhibitor) maintenance versus avelumab alone; TALASUR (NCT04678362), a phase II trial investigating avelumab + talazoparib (PARP inhibitor); AVENU (NCT05107427), a phase II trial assessing avelumab + MRx0518 (live biotherapeutic) and PRESERVE3 (NCT04887831), a phase II trial investigating 1L chemotherapy + trilaciclib (CDK 4/6 inhibitor) followed by avelumab + trilaciclib maintenance versus 1L chemotherapy followed by avelumab alone.
In summary, the phase II JAVELIN Bladder Medley umbrella trial exploring novel avelumab-based combinations as 1L maintenance therapy is expected to inform future clinical trials, aiming to further improve clinical benefit in the 1L setting for patients with advanced UC. JAVELIN Bladder Medley opened for enrollment in June 2022 and, as of the time of this publication, is currently recruiting patients. For additional information on the JAVELIN Bladder Medley trial, please visit https://clinicaltrials.gov/ct2/show/NCT05327530.
Background
The pivotal, phase III JAVELIN Bladder 100 trial (NCT02603432) showed that avelumab (anti–PD-L1) first-line (1L) maintenance + best supportive care significantly prolonged overall survival and progression-free survival (PFS) compared with best supportive care alone in patients with advanced urothelial carcinoma (UC) that had not progressed with 1L platinum-based chemotherapy.
Trial results established the JAVELIN Bladder regimen (1L platinum-based chemotherapy followed by avelumab 1L maintenance in patients without disease progression) as the standard of care for eligible patients with advanced UC in numerous countries.
Switch maintenance treatment with avelumab in combination with other antitumor agents that enhance or target different pathways has the potential to provide increased efficacy benefit compared with avelumab alone.
The JAVELIN Bladder Medley trial design
JAVELIN Bladder Medley (NCT05327530) is a phase II, multicenter, randomized, open-label, parallel-arm, umbrella trial assessing the safety and efficacy of avelumab in combination with other antitumor agents as 1L maintenance treatment for patients with advanced UC that has not progressed with 1L platinum-based chemotherapy.
Patients will be randomized 1:2:2:2 to receive switch maintenance treatment with either avelumab as monotherapy, or in combination with sacituzumab govitecan (anti–Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15).
Randomization will occur 4–10 weeks after the last dose of 1L chemotherapy and will be stratified by the presence of visceral metastases at the start of 1L chemotherapy.
The trial opened for enrollment in June 2022, and the estimated primary completion date is August 2026.
Eligible patients have histologically confirmed, unresectable locally advanced or metastatic UC with no progression (per Response Evaluation Criteria In Solid Tumors version 1.1 [RECIST 1.1]), following 4–6 cycles of 1L platinum-based chemotherapy (gemcitabine + cisplatin and/or carboplatin).
The primary end points are PFS according to RECIST 1.1 per investigator assessment and safety and tolerability of the combination regimens.
Key secondary end points include overall survival, objective response and duration of response according to RECIST 1.1 per investigator and patient-reported outcomes.
Conclusion
The JAVELIN Bladder Medley trial will explore novel avelumab-based combinations as 1L maintenance therapy with the aim to further improve clinical benefit in the 1L setting for patients with advanced UC.
Supplementary data
An infographic accompanies this paper. To view or download this infographic in your browser please click here: https://www.futuremedicine.com/doi/suppl/10.2217/fon-2023-0492
Author contributions
All authors drafted, critically reviewed or revised the manuscript for important intellectual content. All authors reviewed the final version and agreed with the content and approved of the decision to submit.
Acknowledgments
The authors thank the patients and their families, investigators, co-investigators and the study teams at each of the participating centers. For further information about the study, please contact either US Medical Information (+1 888-275-7376; eMediUSA@emdserono.com) or Communication Center (+49 6151 72 5200; service@merckgroup.com).
Financial & competing interests disclosure
This trial is sponsored by Merck (CrossRef Funder ID: 10.13039/100009945). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Financial & competing interests disclosure
Sacituzumab govitecan is provided by Gilead Sciences and NKTR-255 is provided by Nektar Therapeutics. J Hoffman-Censits has served in consulting or advisory roles for Seattle Genetics (Seagen); and reports other disclosures for Ikena Oncology, QED Therapeutics and Seagen. P Grivas has served in consulting or advisory role for 4D Pharma PLC, Aadi Bioscience, Asieris Pharmaceuticals, AstraZeneca, Astellas Pharma, Boston Gene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, Genentech/Roche, Gilead Sciences, Guardant Health, G1 Therapeutics, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence Health, Merck, Mirati Therapeutics, MSD, Pfizer, PureTech, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, Silverback Therapeutics, Strata Oncology, UroGen; and his institution has received research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Merck, Mirati Therapeutics, MSD, Pfizer and QED Therapeutics. T Powles has served in consulting or advisory roles for Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, MSD, Novartis, Pfizer, Roche and Seattle Genetics; has received travel and accommodation expenses from AstraZeneca, Ipsen, MSD, Pfizer and Roche; and has received institutional research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, MSD, Novartis, Pfizer, Roche and Seattle Genetics. J Hawley has served in consulting or advisory roles for Seagen, and has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Dendreon and Regeneron. K Tyroller reports employment by EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, and stock and other ownership interests in Merck. S Seeberger, S Guenther and N Jacob report employment by Merck Healthcare KGaA, Darmstadt, Germany. K Tadjalli Mehr reports employment by Merck Healthcare KGaA, Darmstadt, Germany, and stock and other ownership interests in Merck. N M Hahn has received institutional research funding from Astex, AstraZeneca, Bristol Myers Squibb, Genentech, HTG Molecular Diagnostics, Incyte, Inovio, MSD, Pieris and Seattle Genetics; has served in consulting or advisory roles for BioGears, Boehringer Ingelheim, Champions Oncology, CicloMed, Ferring, Genentech, GlaxoSmithKline, Guidepoint Global, Health Advances, Incyte, Janssen, KeyQuest Health, Merck, Mirati, MSD, Pfizer, Protara Therapeutics, RemeGen, Seattle Genetics, TransMed and Verity Pharma; and has received honoraria from Bladder Cancer Academy, Creative Educational Concepts, and the Large Urology Group Practice Association. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Writing disclosure
Medical writing support was provided by Amy Davidson of Clinical Thinking, and was funded by Merck.
Ethical conduct of research
The protocol, any protocol amendments and all other relevant documents are approved by an institutional review board or independent ethics committee at each participating institution before patient enrolment is initiated. The authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for all human experimental investigations. In addition, informed consent has been/will be obtained by investigators from the participants involved.
Data sharing statement
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Open access
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Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
- 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. v3.2023.
- 3. National Cancer Institute, SEER Cancer Stat Facts: Bladder Cancer. Bethesda, MD, USA. https://seer.cancer.gov/statfacts/html/urinb.html (Accessed 5 July 2023).
- 4. . Utilization of systemic therapy for treatment of advanced urothelial carcinoma: lessons from real world experience. Cancer Treat. Res. Commun. 27, 100325 (2021).
- 5. . Treatment pattern and overall survival among patients with locally advanced or metastatic urothelial carcinoma: results from a complete nationwide unselected real-world registry study in Denmark from 2010 to 2017. Ann. Oncol. 32(Suppl. 5), Abstract 707P (2021).
- 6. A real-world data study to evaluate treatment patterns, clinical characteristics and survival outcomes for first- and second-line treatment in locally advanced and metastatic urothelial cancer patients in Germany. J. Cancer 9(8), 1337–1348 (2018).
- 7. Bladder cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33(3), 244–258 (2022).
- 8. The 2021 updated European Association of Urology guidelines on metastatic urothelial carcinoma. Eur. Urol. 81(1), 95–103 (2021).
- 9. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 383(13), 1218–1230 (2020). •• Primary analysis of the phase III JAVELIN Bladder 100 trial showing significantly prolonged overall survival (OS) with avelumab 1L maintenance + best supportive care (BSC) vs BSC alone in patients with disease control after platinum-based chemotherapy.
- 10. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a Phase Ia, multicohort, dose-escalation trial. Lancet Oncol. 18(5), 587–598 (2017).
- 11. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol. Res. 3(10), 1148–1157 (2015).
- 12. Bavencio (avelumab). Prescribing information. EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA (2022).
- 13. Bavencio (avelumab). Summary of product characteristics. Merck Europe B.V., Amsterdam, The Netherlands, an affiliate of Merck KGaA (2023).
- 14. Plain language summary of results from the JAVELIN Bladder 100 study: avelumab maintenance treatment for advanced urothelial cancer. Future Oncol. 18(19), 2361–2371 (2022). • Plain language summary publication of the primary analysis of the phase III JAVELIN Bladder 100 trial.
- 15. Avelumab first-line maintenance for advanced urothelial carcinoma: results from the JAVELIN Bladder 100 trial after ≥2 years of follow-up. J. Clin. Oncol. 41(19), 3486–3492 (2023). •• Updated data from the phase III JAVELIN Bladder 100 trial that continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance + BSC vs BSC alone.
- 16. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat. Med. 27(12), 2200–2211 (2021).
- 17. Sacituzumab govitecan in metastatic triple-negative breast cancer. N. Engl. J. Med. 384(16), 1529–1541 (2021).
- 18. . Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 6(26), 22496–22512 (2015).
- 19. . Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: a case study of anti-TROP-2 sacituzumab govitecan. MAbs 11(6), 987–995 (2019).
- 20. The anti-TIGIT antibody M6223 induces significant anti-tumor efficacy and immune response via multiple mechanisms of action. J. Immunother. Cancer 9(Suppl. 2), Abstract 326 (2021).
- 21. NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy. J. Immunother. Cancer 9(5), e002024 (2021).
- 22. . Targeting Trop-2 in solid tumors: future prospects. Onco. Targets Ther. 12, 1781–1790 (2019).
- 23. Trodelvy (sacituzumab govitecan-hziy). Prescribing information. Gilead Sciences, Inc., Foster City, CA, USA (2023).
- 24. Trodelvy (sacituzumab govitecan-hziy). Summary of product characteristics. Gilead Sciences Ireland UC, Carrigtwohill, Co., Cork, Ireland (2023).
- 25. TROPHY-U-01: a Phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J. Clin. Oncol. 39(22), 2474–2485 (2021).
- 26. TROPiCS-04: study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy. J. Clin. Oncol. 39(Suppl. 6), Abstract TPS498 (2021).
- 27. Primary analysis of TROPHY-U-01 cohort 3, a phase 2 study of sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based therapy. J. Clin. Oncol. 41(Suppl. 6), Abstract 518 (2023). • Primary analysis of a cohort of the phase II TROPHY-U-01 study that showed high objective response and clinical benefit rates with sacituzumab govitecan+pembrolizumab in patients with disease progression after platinum-based chemotherapy.
- 28. . CD226: an emerging role in immunologic diseases. Front. Cell Dev. Biol. 8, 564 (2020).
- 29. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26(6), 923–937 (2014).
- 30. CD155T/TIGIT signaling regulates CD8(+) T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res. 77(22), 6375–6388 (2017).
- 31. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology 7(8), e1466769 (2018).
- 32. . Evaluation of novel anti-TIGIT antibody M6223 as a single agent and in combination with avelumab on human natural killer (NK) cell cytotoxicity. J. Immunother. Cancer 10(Suppl. 2), Abstract 432 (2022). • Preclinical data showing the additive effect of avelumab+M6223 in enhancing natural killer cell activation.
- 33. Genentech press release. Genentech Reports Interim Results for Phase III SKYSCRAPER-01 Study in PD-L1-High Metastatic Non-Small Cell Lung Cancer (2022). https://www.gene.com/media/press-releases/14951/2022-05-10/genentech-reports-interim-results-for-ph (Accessed 5 July 2023).
- 34. Genentech press release. Genentech Provides Update on Phase III SKYSCRAPER-02 Study in Extensive-Stage Small Cell Lung Cancer (2022). https://www.gene.com/media/press-releases/14947/2022-03-29/genentech-provides-update-on-phase-iii-s (Accessed 5 July 2023).
- 35. SKYSCRAPER-02: primary results of a Phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo)+carboplatin+etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC). J. Clin. Oncol. 40(Suppl. 17), Abstract LBA8507 (2022).
- 36. A Phase Ia/b open-label, dose-escalation study of etigilimab alone or in combination with nivolumab in patients with locally advanced or metastatic solid tumors. Clin. Cancer Res. 28(5), 882–892 (2022).
- 37. First-in-human Phase I study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer. Ann. Oncol. 33(2), 169–180 (2022).
- 38. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol. 23(6), 781–792 (2022).
- 39. Pre-clinical efficacy and tolerability of NKTR-255, a polymer-conjugated IL-15 for immuno-oncology. J. Immunother. Cancer 5(Suppl. 2), Abstract P332 (2017).
- 40. . Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against triple negative breast cancer cells. Front. Immunol. 9, 2140 (2018).
- 41. NKTR-255, a polymer-conjugated IL-15 enhances antibody-dependent cellular cytotoxicity mediated by NK cells in a B cell lymphoma model. Blood 134(Suppl. 1), 5302 (2019). • Preclinical data showing NKTR-255 can enhance efficacy when combined with an antibody that functions through antibody-dependent cell-mediated cytotoxicity.
