key: cord-0929835-pydarqry
authors: Ten Eyck, Jennifer E; Kahlon, Navkirat; Masih, Sonia; Hamouda, Danae M; Petros, Firas G
title: Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes
date: 2022-02-22
journal: Cancer Manag Res
DOI: 10.2147/cmar.s227323
sha: 0eef2193c403d8f10e2ee169c29c72d7f136a14d
doc_id: 929835
cord_uid: pydarqry

BACKGROUND: First-line therapy for treatment of advanced urothelial carcinoma includes combination platinum-based chemotherapies, though resistance and long-term toxicity concerns to these regimens cause limitations in progression-free survival and overall survival. Maintenance treatment with an alternative agent such as the PD-L1 inhibitor, avelumab (Bavencio(®)), after initial chemotherapy has been shown to prolong overall survival. The aim of this review is to provide a landscape clinical use of avelumab in the treatment of advanced urothelial carcinoma with a focus on patient selection and outcomes. METHODS: This review includes the most up to date phases and results from clinical trials published in peer-reviewed journals. RESULTS: Three studies were included, one phase 1B trial, one phase 1B trial with 2 year follow-up, and one phase 3 trial. Patients receiving avelumab maintenance therapy at 10 mg/kg IV every two weeks had an overall better performance status, though those with an increased ECOG-PS, increased Bellmunt risk score, or failure of ≥3 chemotherapies had poorer responses. Patients over the age of 65 had a higher ORR (18–25%) compared to younger patients (13–14%). Patients with PD-L1 positive tumors had a significantly increased CR median ORR (13.8%), median PFS (5.7 months), and median 12-month OS rate (79.1%) compared to control subjects receiving best supportive care (1.2%, 2.1 months, 60.4%, respectively). TRAEs were seen in 86.7% of patients, with 32.4% of patients experiencing a ≥grade 3 AE. The most common AE was IRR (32.4%, ≥grade 3 1.01%) and irAE 25.6% of any grade, including various rashes and pruritus AEs, immune-related thyroid disorders, and immune related hepatitis. There were 3 reported treatment-related deaths (0.05%). Ongoing phases of one of the trials is investigating the use of docetaxel and avelumab together after failure of one chemotherapy. CONCLUSION: Avelumab as a maintenance therapy after platinum-based chemotherapy failure or in platinum-ineligible patients with advanced or metastatic urothelial carcinoma is an effective option with increased ORR, PFS, and OS with a similar safety profile to other chemotherapies. Ongoing studies currently in recruitment and active clinical trials will yield valuable insights into optimizing avelumab therapy in conjunction with chemotherapies and/or immunotherapies, better characterization of response for PD-L1 positive tumors, and a clearer insight into clinically validated prognostic factors to improve patient outcomes.

First-line therapy for treatment of advanced urothelial carcinoma includes combination platinum-based chemotherapy such as gemcitabine plus cisplatin or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) for cisplatin eligible patients. 1 For cisplatin ineligible patients, therapy includes gemcitabine with carboplatin or checkpoint inhibitor (CPI) with atezolizumab and pembrolizumab. 2 Resistance to these chemotherapy regimens, however, causes limitations in progression-free survival and overall survival. Furthermore, long-term platinum-based chemotherapy is not feasible due to the increasing risk of toxicity over time. Median survival for cisplatin-based regimens has been reported as 14-15 months, while carboplatin-based regimens have been reported as 9-10 months. Disease progression for most patients usually occurs within 9 months of treatment initiation. 3 The use of some alternative agents for maintenance treatment following chemotherapy has been shown to prolong overall survival for a subset of tumor types, but in general the prolongation of overall survival with these modalities has not been shown.

A continuous challenge with conventional chemotherapy is the development of tumor immunity. Gottesman et al proposed a mechanism of resistance for cisplatin, which functions by inducing apoptosis in cancer cells through DNA repair interference. 4 These resistance mechanisms include changes in cellular uptake and efflux of the drug, increased biotransformation and detoxification in the liver, and an increase in DNA repair and anti-apoptotic mechanisms. Even so, tumor immunity continues to develop and contribute to limitation of survival prolongation. Maintenance treatment with an alternative agent after initial chemotherapy has been shown to prolong overall survival. Therefore, the aim of this review is to provide a landscape clinical use of avelumab in the treatment of advanced urothelial carcinoma with a focus on patient selection and outcomes.

For this review, literature was identified through PubMed and Embase databases with no limit on publication year or language. Search terms included "avelumab," "Bavencio ® ," "bladder cancer," "malignant bladder cancer," "advanced bladder cancer," "urothelial," "urothelial bladder cancer," "advanced urothelial carcinoma," "metastatic urothelial carcinoma," "urothelial cancer cells," "urothelial abnormalities," "advanced urethra cancer," "malignant urethra cancer," "urethra carcinoma", "urethra disease," "urethra," and "urethra neoplasms." A total of 131 records were identified and screened for appropriate human trials as shown in Figure 1 . 5 Clinicaltrials.gov was cross-referenced using the terms "urothelial carcinoma" for disease and "avelumab" for other to ensure that no completed clinical trials were missed in the literature search. 6

Eight studies evaluating avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, in advanced metastatic urothelial carcinoma were retrieved. Five of the eight studies were previously published phases of clinical trials whose latest phases were available for review. Two of the trials assessed avelumab alone at a dose of 10 mg/kg IV every two weeks in patients who either did or did not have disease progression after first line platinum-based chemotherapy. The third study is investigating the use of docetaxel with avelumab after failure of one platinum-based chemotherapy. The tables in this review cover study design (Table 1 ) and significant outcomes ( Table 2) .

Avelumab in recent studies has been found to improve outcomes in patients with locally advanced and metastatic urothelial carcinoma. Patients treated with an avelumab dosing schedule of 10 mg/kg every two weeks until disease progression or unacceptable toxicity after 4 to 10 weeks of completing four to six cycles of chemotherapy with response or stable disease. For maintenance, median overall survival (OS) has been reported to be 21 months in a phase 3 trial with absolute improvement in OS by 7.1 months as compared to placebo by Powles et al. 9 Patients with previously treated advanced/metastatic urothelial carcinoma platinum-based chemotherapy with no previous immunotherapy were found to have a median OS of 7 months in a phase 1B trial by Apolo et al. 7 

In 2017, avelumab was granted an accelerated approval from the Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In 2020, avelumab has been approved for patients with advanced bladder cancer (regardless of PD-L1 tumor status) who do not progress (ie, achieve an objective response or stable disease) following platinum-based chemotherapy and are 

Maintenance avelumab was administered at 10 mg/kg every two weeks until disease progression or unacceptable toxicity after 4 to 10 weeks of completing four to six cycles of chemotherapy whether a response or stable disease has been confirmed on radiographic imaging. The same dose has also been studied as a second line or subsequent line of treatment.

The FDA more recently approved avelumab dose is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity as benefit:risk profiles for the two dosing regimens have been found to be similar. 10 

The response of the elderly population to avelumab was overall very promising compared to that of younger populations. The study population in the JAVELIN solid tumor trial included two subgroups for age, less than 65 years (n = 50) and ≥65 years (n = 111). Patients in the older subgroup experienced an overall higher overall response rate (ORR) (18%, CI 11-26%) compared to the younger subgroup (14%, CI 6-27%). 9 The Apolo et al study population included subjects <75 (11.8-25 .0%) in PD-L1-patients. Overall, patients with PD-L1+ had higher ORR, better median PFS and better OS as compared to PD-L1 negative patients. It is approved for use regardless of PD-L1 status. 7 In JAVELIN Bladder 100 by Powles et al, PD-L1 expression was assessed in tumor samples by means of the Ventana PD-L1 assay (SP263, Ventana Medical Systems). Patients were classified as having PD-L1-positive status if at least one of the following three criteria were met: at least 25% of tumor cells stained for PD-L1, at least 25% of immune cells stained for PD-L1 if more than 1% of the tumor area contained immune cells, or 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells. 51.1% had PD-L1-positive tumors in this study. The patient characteristics were balanced between the two treatment groups (placebo and avelumab maintenance group) for the PD-L1-positive population. This study allowed a crossover to receive immunotherapy as subsequent anticancer drug therapy. Subsequent treatment was given to 42.3% in the avelumab group and 61.7% in the control group, including an anti-PD-1 or anti-PD-L1 antibody in 6.3% in the avelumab group and 43.7% in the control group. Even with a significant number of patients receiving immunotherapy on progression in the placebo arm, avelumab in a maintenance setting, significantly prolonged overall survival in the PD-L1-positive population with overall survival at 1 year of 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40-0.79; P<0.001). The median progression-free survival in avelumab and placebo treated patients was 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43-0.73). 9

Overall, no new toxicity signals were found in any of the studies included in the review. Table 3 . The most common treatment-related adverse events (TRAE) (>10%) of any grade from both trials include fatigue, various immune related rashes and pruritic AE, diarrhea, renal events (including increased creatinine and renal/urinary disorders), and immune-related thyroid disorders (including hypothyroidism, hyperthyroidism). 7, 9 In the Apolo et al article 71.1% patients were found to have treatment-related adverse effects of any grade, 11.6% had TRAEs of grade 3 or higher with fatigue being most common. Treatment-related death occurred in one patient (0.4%), due to pneumonitis. The most common immune-related adverse events (irAE) (any grade) were immune-related rash (11.2%), including various rash/pruritus AE and immune related thyroid disorders (13, 5 .2%), including hypothyroidism, hyperthyroidism and blood thyroid-stimulating hormone increase). In an exploratory post hoc analysis, frequency and extent of infusion related reactions (IRR) in high-risk patient subgroups (such as patients with renal insufficiency, upper tract disease, liver metastases) were similar to the overall population in study compared with the overall population. 15.7% of patients discontinued treatment due to adverse effects in this study. 9 The Powles et al safety population, defined as any patient who received one or more doses of avelumab, also noted common TRAEs (>10%) of arthralgia, asthenia, constipation, back pain, nausea, pyrexia, anorexia, cough, vomiting, anemia, and hematuria. The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. In the avelumab group, median duration of trial treatment was 24.9 weeks and adverse events led to treatment discontinuation in 11.9% patients. Death was attributed by the investigator to the toxicity of trial treatment in two patients (0.6%) in the avelumab group. 29% of patients had irAE 7.0% with grade 3 events. No grade 4 or fatal irAE occurred. The most frequent irAE was thyroid disorders (12.2%). 9% of patients required high-dose glucocorticoids (≥40 mg total daily dose of prednisone or equivalent) for irAE in avelumab-treated patients. 9

Continued research is needed in the AVETAX and JAVELIN Bladder 100 clinicals trials as the research progresses through their respective clinical trial phases, including particular attention to the response of PD-L1 positive tumors versus controls. In June 2020, avelumab was granted the FDA approval to change the approved dosage from 10 mg/kg IV every two weeks to a flat-dose of 800 mg IV every two weeks per pharmacological models analyzing exposure-safety and exposure-efficacy models. 10, 12 The flat-rate dosage has yet to be implemented in published clinical trials and will need further verification. The prognostic model for survival in post-platinum patients with metastatic urothelial carcinoma (based on ECOG performance status, liver metastasis, platelet count, neutrophil-to-lymphocyte ratio, and lactate dehydrogenase) also needs further validation with avelumab based trials. It is also important to account for flat-rate versus body-weight dosing and comparing its prognostic outcomes versus the Bellmunt risk score. 13 There are currently 19 active or actively recruiting trials on clinicaltrials.gov for studies involving avelumab and urothelial carcinoma. Many of the active trials are now focusing on the optimal duration of avelumab therapy, combining avelumab with other chemotherapy agents and/or immune therapies, and assessing the efficacy of avelumab therapy after other immune checkpoint inhibitor therapies have failed. Several of these trials have faced delays due to the SARS-CoV-19 pandemic and will hopefully be able to progress at an appropriate pace as the pandemic slows. 6

In 2017, avelumab was granted FDA approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In 2020, avelumab was approved for patients with advanced bladder cancer (regardless of PD-L1 tumor status) who do not progress (ie, achieve an objective response or stable disease) following platinum-based chemotherapy and are eligible to receive checkpoint inhibitor immunotherapy. It has been found to be both an efficacious and tolerable option in those settings. In maintenance settings, it improved ORRs, median PFS, and median OS even with subsequent crossover in the placebo arm to immunotherapy on progression. Benefit was seen in both PD-L1 positive and negative patients. No new toxicity signals were found with avelumab use in urothelial cancer.

Current clinical trials are continuing to assess the efficacy of avelumab on its own as a maintenance therapy with and without disease progression and in combining avelumab with other chemotherapy and immunotherapy options. These trials will be critical in creating future guidelines for advanced or metastatic urothelial carcinoma and how to more effectively treat PD-L1 positive tumors.

In summary, avelumab is an effective and well-tolerated regimen for patients with advanced urothelial cancer who have not progressed on chemotherapy, as well as for patients with progression of disease after receiving platinum-containing chemotherapy. It is now the standard of care in these two settings.

Abbreviations AE, adverse event; CI, confidence interval; CR, complete response; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; FDA, Food and Drug Administration; irAE, immune related adverse event; IRR, Infusion related reaction; IV, intravenous; MI, myocardial infarction; n/a, not applicable; NCT, national clinical trial; ORR, overall response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed cell death ligand 1; PE, pulmonary embolism; PFS, progression free survival; PR, partial response; PS, performance status; Q2wk, every two weeks; SD, stable disease; s/p, status post; TRAE, treatment related adverse event; TSH, thyroid stimulating hormone; UTI, urinary tract infection; VT, venous thrombosis.

clinical practice guidelines in oncology (NCCN guidelines) for bladder cancer

PD-1 and PD-L1 inhibitors after platinum-based chemotherapy or in first-line therapy in cisplatin-ineligible patients: dramatic improvement of prognosis and overall survival after decades of hopelessness in patients with metastatic urothelial cancer. Memo

Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study

Multidrug resistance in cancer: role of ATP-dependent transporters

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN solid tumor study: 2-year updated efficacy and safety analysis

A phase Ib study of combination of avelumab and taxane-based chemotherapy in platinum refractory or ineligible metastatic urothelial cancer (AVETAX study)

Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma

Changing body weight-based dosing to a flat dose for avelumab in metastatic Merkel cell and advanced urothelial carcinoma

The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors

FDA approves avelumab for urothelial carcinoma maintenance treatment

Five-factor prognostic model for survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-L1 inhibitors

Cancer Management and Research is an international, peer-reviewed open access journal focusing on cancer research and the optimal use of preventative and integrated treatment interventions to achieve improved outcomes, enhanced survival and quality of life for the cancer patient. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use

Thank you to Margaret Hoogland, MLS, AHIP at The University of Toledo Library for assistance in the literature search.

The authors report no conflicts of interest in this work.