1. Simoneaux, Richard

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Approximately 90 percent of all bladder cancer patients have urothelial carcinoma (UC). Cases of UC are frequently non-muscle invasive and can thus be effectively managed surgically or with intravesical therapies. However, approximately 10-15 percent of patients with UC may develop disease that is invasive, locally advanced, and metastatic. For these patients having metastatic disease, their outlook is somewhat poor, as their 5-year rate of survival is only approximately 5 percent. In addition, at diagnosis, roughly 10 percent of patients have locally advanced or metastatic disease.

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For patients newly diagnosed with metastatic UC, assuming they can tolerate the considerable side effects, cisplatin-based combination therapies are frequently employed as a first-line therapy. However, a significant portion (~30-50%) of these patients are deemed cisplatin-ineligible as a result of comorbidities. Recently, the use of different immunotherapies, including checkpoint inhibitors, has been implemented in this patient population.


One checkpoint inhibitor being evaluated in these patients is the fully humanized anti-PD-L1 monoclonal antibody avelumab. In a recent planned interim analysis of the phase III JAVELIN Bladder 100 trial (NCT02603432), avelumab was found to have met its primary study endpoint of improved overall survival (OS). One participating clinician in this study is Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research, and Director at Barts Cancer Centre.


"Improvement in overall survival has been hard to achieve in the frontline setting; the novel trial design in this study may have contributed to its success," Powles noted.


Treating Metastatic Urothelial Carcinoma

According to the National Comprehensive Cancer Network (NCCN) Guidelines for Bladder Cancer (Version 3.2020), for cisplatin-eligible patients with locally advanced or metastatic bladder cancer, the preferred systemic first-line therapies are gemcitabine plus cisplatin or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (DDMVAC) with growth factor support.


For the patients in that population who are cisplatin-ineligible, the following regimens are preferred as first-line therapies: gemcitabine and carboplatin; atezolizumab (for those patients with tumors expressing PD-L1 or for those ineligible for any other platinum-containing chemotherapy, regardless of PD-L1 expression); or pembrolizumab (for those patients with tumors expressing PD-L1 or for those ineligible for any other platinum-containing chemotherapy, regardless of PD-L1 expression).


For cisplatin-ineligible patients, gemcitabine or gemcitabine plus paclitaxel are two recommended regimens, while the combination of ifosfamide, doxorubicin, and gemcitabine is considered "useful under certain circumstances."


Patients requiring second-line systemic therapy (i.e., post-platinum) have a number of therapeutic options available. For these patients, the guidelines recommend participation in clinical trials utilizing novel therapies. The preferred regimen is pembrolizumab, while alternative preferred regimens include the checkpoint inhibitors avelumab, atezolizumab, durvalumab, and nivolumab, as well as the fibroblast growth factor receptor inhibitor erdafitinib. Other recommended regimens for this patient subset include gemcitabine and the taxanes docetaxel and paclitaxel. Regimens that are deemed "useful in certain circumstances based on prior medical therapy" for these patients include ifosfamide, doxorubicin, and gemcitabine; gemcitabine and cisplatin; gemcitabine and paclitaxel; and DDVMAC with growth factor support.


Urothelial Carcinoma & Immunotherapy

In recent years, there has been a spate of development for new checkpoint inhibitor based immunotherapies for patients diagnosed with locally advanced or metastatic UC.


In May 2016, the FDA approved the use of the first checkpoint inhibitor, the anti-PD-L1 monoclonal antibody atezolizumab, for use in patients with locally advanced or metastatic UC who had disease that worsened during or subsequent to platinum-based chemotherapy, or within 12 months of receiving platinum-based chemotherapy, either prior to (i.e., neoadjuvant) or after (i.e., adjuvant) surgical treatment.


Subsequently, in April 2017, the FDA granted atezolizumab accelerated approval for the patients having locally advanced or metastatic UC that were cisplatin-ineligible. This decision was made based on the results obtained in a preplanned cohort from the IMvigor210 Study (NCT02951767). However, in June 2018, that approval was further modified. As a result of that modification, atezolizumab is now indicated for patients who are cisplatin-ineligible with tumors having PD-L1 expression values 5 percent or greater, or those who were not eligible for any platinum-based therapy, regardless of PD-L1 expression level. This action was taken as a result of decreased survival being associated with the use of atezolizumab monotherapy relative to platinum-containing chemotherapy regimens in clinical trials with locally advanced or metastatic UC patients having low PD-L1 expression levels.


In May 2017, the FDA granted approval to the anti-PD1 monoclonal antibody pembrolizumab for two separate UC-related indications: accelerated approval for use in the first-line setting for cisplatin-ineligible patients having locally advanced or metastatic UC and approval as a second-line therapy for those with locally advanced or metastatic UC who experienced disease progression during or subsequent to platinum-based chemotherapy or within 12 months of platinum-based neoadjuvant or adjuvant chemotherapy.


The accelerated approval as a first-line therapy in cisplatin-ineligible patients was based on results obtained in the phase II single-arm KEYNOTE-052 trial (NCT02335424). As a result of decreased survival observed for pembrolizumab monotherapy relative to platinum-based therapy in several clinical studies, in June 2018, the FDA amended the indication for the immunotherapy to use in cisplatin-ineligible patients with locally advanced or metastatic UC whose tumors express PD-L1 (i.e., a Combined Positive Score [CPS] of 10 or greater), or in patients ineligible for any platinum-containing chemotherapy, regardless of CPS.


In May 2017, the anti-PD-L1 monoclonal antibody avelumab was granted accelerated approval by the FDA for use in patients with locally advanced or metastatic UC who experienced disease progression during or following platinum-based chemotherapy or within 1 year of neoadjuvant or adjuvant platinum-based chemotherapy. That decision was based on interim safety and efficacy results obtained in the phase Ib JAVELIN Solid Tumor study (NCT01772004). In their statement, the FDA cited confirmed overall response rates (ORRs) of 13.3 percent in patients who had been followed for at least 13 weeks, and 16.1 percent for those followed 6 months or more.


As a follow-up, the phase III JAVELIN Bladder 100 study (NCT02603432), was initiated to assess the survival of avelumab plus best supportive care (BSC) compared to BSC in patients with locally advanced or metastatic urothelial cancer that did not experience progression during or following completion of first-line platinum-based chemotherapy. This trial is the confirmatory study on which the FDA will be basing their decision for full approval of avelumab in this patient population.


JAVELIN Bladder 100

The phase III JAVELIN Bladder 100 (NCT02603432) trial is a multicenter, multinational, randomized, open-label, parallel-arm study assessing avelumab as first-line maintenance therapy plus BSC versus BSC alone in patients with locally advanced or metastatic UC who did not undergo disease progression after completing first-line platinum-containing chemotherapy.


In this study, 700 patients who had locally advanced or metastatic UC that had not undergone progression after induction chemotherapy (per RECIST v1.1) were randomized to either avelumab plus BSC or BSC alone. The primary endpoint is OS in the co-primary populations of all patients (i.e., regardless of PD-L1 tumor positivity) and those patients with PD-L1-positive tumors. Among the secondary endpoints were progression-free survival, objective response (defined as complete response [CR] or partial response [PR]); disease control (defined as CR, PR, non-CR, non-progressive disease, and stable disease [SD]); safety; pharmacokinetics (as assessed by Cmax, Ctrough); immunogenicity, predictive biomarkers and patient-reported outcomes in the co-primary populations.


Among the inclusion criteria were the following: adult (18 years of age); histologically confirmed, unresectable locally advanced or metastatic transitional cell UC; stage IV disease at initiation of first-line chemotherapy; measurable disease (RECIST v1.1) prior to initiating first-line chemotherapy; prior first-line chemotherapy must have consisted of 4-6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin; and no evidence of disease progression following completion of first-line chemotherapy (i.e., ongoing CR, PR, or SD using RECIST v1.1 guidelines).


The exclusion criteria included the following: previous systemic adjuvant or neoadjuvant therapy within 1 year of randomization; previous immunotherapy with interleukin-2 (IL-2), interferon-a (IFN-[alpha]), or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA 4 antibody (e.g., ipilimumab), or any other antibody or drug which specifically targets T-cell co-stimulation or immune checkpoint pathways; persistent treatment-related toxicity from previous therapy; symptomatic central nervous system metastases requiring steroid therapy.


When asked what the needs were for this patient subpopulation, Powles replied, "We need to determine the proper sequencing for front-line chemotherapy, and determine if immunotherapy may become a standard of care."


When queried about the next steps for this study, he noted, "We will be presenting this data and publishing these results."


Richard Simoneaux is a contributing writer.