JAVELIN Bladder 100 Trial TE Articles

Articles

ANZUP Mini ASM 2021: Evolving Treatment Landscape for Metastatic Urothelial Cancer

(UroToday.com) The ANZUP 2021 annual scientific meeting included a presentation by Dr. Matthew Galsky discussing the evolving treatment landscape for metastatic urothelial cancer. Dr. Galsky started by highlighting that urothelial carcinoma is not an uncommon malignancy, accounting for 82,000 new diagnoses/year in the United States and ~429,000 new diagnoses/year worldwide. However, until recently, the FDA approvals for new therapeutics in urothelial cancer over the last 30 years has been dismal:

Published October 19, 2021
ASCO 2020: Checkpoint Inhibition in Metastatic Urothelial Carcinoma: Timing is Everything

(UroToday.com) In this presentation, Elizabeth Plimack, MD, discussed the findings from LBA1, a phase 3 randomized study of maintenance avelumab in advanced urothelial cancer patients who have not progressed with first-line platinum-based chemotherapy.

Published May 31, 2020
ASCO 2020: JAVELIN Bladder 100 Phase III Results: Maintenance Avelumab + Best Supportive Care vs BSC Alone After Platinum-Based First-Line Chemotherapy in Advanced Urothelial Carcinoma

(UroToday.com) Advanced urothelial carcinoma resulted in over 200,000 deaths across the world in 2018. Though the majority of patients eligible for such therapy respond to platinum-based chemotherapy, disease progression occurs relatively quickly and a half or less of patients receive second-line treatment. Though PD-L1/PD-1 immune checkpoint blockade (ICB) agents are standard 2^nd-line therapy for disease progression after platinum, not all patients receive this therapy and only a minority of patients have a durable clinical benefit. Avelumab, an antibody against PD-L1, is approved in the second-line post-platinum treatment setting.

Published May 31, 2020
ASCO 2021: Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma in the JAVELIN Bladder 100 Trial: Subgroup Analysis by Duration of Treatment-Free Interval from End of Chemotherapy to Start of Maintenance
(UroToday.com) The phase 3 JAVELIN Bladder 100 trial, which enrolled patients with advanced urothelial carcinoma that had not progressed with first-line platinum-containing chemotherapy, showed that maintenance therapy with avelumab + best supportive care significantly prolonged overall survival (OS) compared with best supportive care alone (HR 0.69, 95% CI 0.56 to 0.86; 1-sided p = 0.0005).¹ However, the optimal timing for starting avelumab after completing first-line chemotherapy is unknown. In the trial, patients received avelumab + best supportive care or best supportive care alone after a treatment-free interval of 4 to 10 weeks from completion of first-line treatment in order to allow resolution of any chemotherapy-related toxicities and tumor assessment to confirm eligibility. At the 2021 American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, Dr. Srikala Sridhar and colleagues presented results of a post hoc analysis assessing efficacy by duration of the treatment-free interval from completion of first-line chemotherapy.

Published June 4, 2021
ASCO 2021: Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Analysis of Clinical and Genomic Subgroups from the JAVELIN Bladder 100 Trial
(UroToday.com) In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line maintenance + best supportive care significantly prolonged overall survival versus best supportive care alone in patients with advanced urothelial carcinoma that had not progressed on first-line platinum-based chemotherapy (HR 0.69, 95% CI 0.56 to 0.86; 1-sided p = 0.0005).¹ Based on these results, avelumab first-line maintenance was approved in the USA, Canada, Europe, Japan, etc for patients who are progression-free following platinum-based chemotherapy. At the 2021 American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, Dr. Thomas Powles and colleagues presented results of post hoc analyses in previously unreported clinical and genomic subgroups.

Published June 4, 2021
ASCO 2021: Avelumab First-Line Maintenance plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma: Analysis of Time to End of Next-Line Therapy in JAVELIN Bladder 100
(UroToday.com) Avelumab first-line maintenance is approved in various countries for patients with advanced urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy based on significantly prolonged overall survival (OS) seen with avelumab + best supportive care versus best supportive care alone in the phase 3 JAVELIN Bladder 100 trial (HR 0.69, 95% CI 0.56 to 0.86; 1-sided p = 0.0005).¹ In the trial, OS was prolonged despite the more frequent use of subsequent anticancer therapy in the best supportive care alone arm (42.3% in the avelumab + best supportive care arm vs 61.7% in the best supportive care alone arm), most commonly with immune checkpoint inhibitors (6.3% vs 43.7%, respectively). To further characterize the efficacy benefits of avelumab first-line maintenance, at the 2021 ASCO annual meeting Dr. Petros Grivas and colleagues reported results of a post hoc analysis of time to end of next-line therapy (for any reason) in the randomized trial population.

Published June 4, 2021
ASCO GU 2020: New Standards in First-Line Therapy for Advanced Disease
San Francisco, CA (UroToday.com) Dr. Cora Sternberg gave an overview of the new standards of first-line therapy in advanced urothelial bladder carcinoma.

There has been almost no progress at all during the last 30 years in the management of advanced urothelial carcinoma (figure 1). However, in the last 5 years, five new immunotherapeutic agents have been introduced for the treatment of advanced urothelial carcinoma (figure 2), bringing significant improvement for advanced urothelial bladder cancer patients.

Published February 16, 2020
ASCO GU 2021: Avelumab First-Line Maintenance plus Best Supportive Care (BSC) Versus BSC Alone for Advanced Urothelial Carcinoma: JAVELIN Bladder 100 Japanese Subgroup Analysis
(UroToday.com) Advanced urothelial carcinoma has among the worst prognosis for tumors treated by genitourinary oncologists. Standard of care dictates that patients receive platinum-based induction chemotherapy. However, even with this treatment, rates of recurrence and disease progression are high and overall survival is quite short due to the development of chemotherapy resistance. In the JAVELIN Bladder 100 study which was reported at ASCO 2020 Annual Meeting, the addition of avelumab, a PD-L1 directed therapy, as first-line maintenance to best supportive care demonstrated improvements in overall survival for patients who did not have disease progression during their initial cytotoxic chemotherapy induction.

Published February 11, 2021
ASCO GU 2021: Avelumab First-Line Maintenance Plus Best Supportive Care vs Best Supportive Care Alone For Advanced Urothelial Carcinoma: JAVELIN Bladder 100 Subgroup Analysis Based On Duration And Cycles Of First-Line Chemotherapy

(UroToday.com) Avelumab first-line maintenance therapy is approved in the United States for patients with advanced urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy based on significantly prolonged overall survival versus best supportive care alone (median 21.4 months versus 14.3 months; HR 0.69, 95% CI 0.56-0.86) as reported in the phase III JAVELIN Bladder 100 trial (NCT02603432).¹ However, the optimal duration of first-line chemotherapy is unknown and some patients are unable to receive six cycles. At the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Yohann Loriot and colleagues presented results of their post hoc analysis of the JAVELIN Bladder 100 trial, specifically efficacy by duration or number of cycles of first-line chemotherapy.

Published February 14, 2021
ASCO GU 2022: Avelumab First-Line Maintenance + Best Supportive Care Versus BSC Alone in Asian Patients With Advanced Urothelial Carcinoma: JAVELIN Bladder 100 Subgroup Analysis

(UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma, in Poster Session B, Dr. Eto presented results of a subgroup analysis of Asian patients enrolled on JAVELIN Bladder 100, investigation avelumab maintenance in patients with advanced urothelial carcinoma (UC). In the primary report of this trial (NCT02603432), avelumab first-line maintenance therapy with best supportive care (BSC) showed significantly longer overall survival compared to BSC alone in patients with advanced UC that had not progressed with first-line platinum-based chemotherapy.

Published February 18, 2022
ASCO GU 2022: First Line Avelumab in PD-L1+ve Metastatic or Locally Advanced Urothelial Cancer Patients Unfit for Cisplatin: The ARIES Trial

(UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022, the Rapid Abstract Session highlighted key abstract in urothelial carcinoma, including work by Dr. Iacovelli and colleagues who examined first-line avelumab in patients with PD-L1+ve metastatic or locally advanced urothelial cancer (aUC) who are unfit for cisplatin. Avelumab IS approved as maintenance therapy after platinum-based first-line (1L) therapy for patients with aUC based on data from the phase III JAVELIN Bladder 100 trial.

Published February 18, 2022
AUA 2021: Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Analysis of Clinical and Genomic Subgroups From the JAVELIN Bladder 100 Trial

(UroToday.com) As a follow-up to the JAVELIN BLADDER 100 trial,¹ which demonstrated the efficacy of avelumab as first-line maintenance therapy for patients with advanced urothelial carcinoma who have NOT progressed on first-line platinum-based chemotherapy, Dr. Bellmunt and colleagues herein report post hoc analyses in previously unreported clinical and genomic subgroups.

Published September 12, 2021
AUA 2021: Avelumab First-Line Maintenance Plus Best Supportive Care vs Best Supportive Care Alone for Advanced Urothelial Carcinoma: Analysis of Time to End of Next-Line Therapy in JAVELIN Bladder 100

(UroToday.com) As a follow-up to the JAVELIN BLADDER 100 trial,¹ which demonstrated the efficacy of avelumab as a first line maintenance therapy for patients with advanced urothelial carcinoma who have NOT progressed on first line platinum based chemotherapy, Dr. Bellmunt and colleagues herein report a secondary analysis of time to end of next-line therapy in patients treated with avelumab vs. best supportive care (BSC).

Published September 12, 2021
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.

Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1).

Published October 12, 2020
Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease.

Published April 13, 2021
Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma

BACKGROUND Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.

Published September 21, 2020
EMUC 2020: Optimal First Line Therapy in Metastatic Bladder Cancer Disease
(UroToday.com) In an oral presentation in the Refining the Treatment of Bladder Cancer session at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Matthew Glasky presented an overview of optimal first-line approaches to the treatment of metastatic bladder cancer.
Published November 14, 2020
ESMO 2020 Virtual Congress: Avelumab First-Line Maintenance + Best Supportive Care vs. BSC Alone with 1L Chemotherapy for Advanced Urothelial Carcinoma: Subgroup Analyses from JAVELIN Bladder 100
(UroToday.com) The JAVELIN Bladder 100 trial, previously presented at ASCO 2020, was a phase 3 trial of platinum-eligible patients with advanced urothelial carcinoma who had stable disease after standard first line chemotherapy and then were randomized to avelumab maintenance therapy versus best supportive care. This trial demonstrated a significantly longer overall survival in patients who received standard platinum-based chemotherapy for advanced urothelial carcinoma followed by avelumab maintenance therapy.

The schema and key results from the trial are shown below.

In this presentation, Dr. Grivas discussed the overall survival data within pre-specific patient subgroups from this trial.

With regards to physician choice of first-line carboplatin or cisplatin, patient characteristics were relatively balanced between subgroups with regards to PD-L1 status, metastatic sites, and best response, but as expected, the carboplatin patients had lower kidney function and performance status. The PFS and OS benefit of maintenance avelumab was present relative to best supportive care regardless of platinum chemotherapy administered. The median OS for cisplatin/gemcitabine was 25.3 months versus 16.5 months for BSC (HR 0.64, 0.51-0.94) and 19.0 months for carboplatin/gemcitabine versus 12.9 months for BSC (HR 0.66, 0.47 – 0.91).

The trend towards benefit of maintenance avelumab was also observed regardless of best response (complete versus partial versus stable disease).

Additional pre-specified subgroup analyses are shown below. Importantly, no significant interaction was noted between any subgroup variable and overall survival.

In summary, the overall conclusion of the JAVELIN Bladder 100 trial that maintenance avelumab results in significantly longer overall survival in patients with advanced urothelial carcinoma who have stable disease after first-line platinum chemotherapy appears to be consistent across all studied subgroups.

Presented by: Petros Grivas, MD, PhD, Medical Oncologist, Associate Professor, University of Washington School of Medicine, University of Washington, Seattle Washington

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.
Published September 19, 2020
ESMO 2022: Genomic Biomarkers in Peripheral Blood From Patients Enrolled in the JAVELIN Bladder 100 Trial of Avelumab First-line Maintenance in Advanced Urothelial Carcinoma

(UroToday.com) The 2022 European Society of Medical Oncology (ESMO) annual meeting featured a urothelial carcinoma session, including a presentation by Dr. Tom Powles discussing genomic biomarkers in peripheral blood from patients enrolled in the JAVELIN Bladder 100 trial of avelumab first-line maintenance in advanced urothelial carcinoma.

Published September 10, 2022
ESMO Virtual Congress 2020: Avelumab First Line Maintenance + Best Supportive Care vs BSC Alone for Advanced Urothelial Carcinoma: Association between Clinical Outcomes and Exploratory Biomarkers
(UroToday.com) Responses to immune checkpoint blockade in cancer therapy are heterogeneous, with a minority of patients experiencing sustained responses to therapy. The identification of predictive biomarkers for immunotherapy response is an area of intense research interest. In this presentation, Srikala Sridhar, MD, presented an assessment of potential biomarkers for response within the JAVELIN Bladder 100 trial, previously presented at ASCO 2020. This trial showed a significantly longer overall survival in patients who received standard platinum-based chemotherapy for advanced urothelial carcinoma followed by avelumab maintenance therapy. The schema and key results from the trial are shown below.

The assays and thresholds for exploratory analysis comparing biomarkers to overall survival are listed in the table below. Important, p-values were not corrected for multiple hypothesis testing.

PD-L1 expression in greater than 25% of either tumor cells or immune cells were associated with higher overall survival with avelumab maintenance.

Patients with PD-L1 positivity and TMB higher than median were more likely to derive survival benefit from avelumab maintenance therapy, but neither TMB or PD-L1 status alone could completely separate patients by survival benefit.

Certain DNA mutational signatures and gene mutations were associated with survival benefit from avelumab maintenance, specifically mutational signatures enriched in C > T base pair alterations.

The differential expression of immune-related genes such as LAG3, TIGIT and CXCL9 were associated with survival benefit from avelumab.

Interestingly, the presence of cell types expressing Fc gamma receptor variants may also identify patients that derive survival benefit from avelumab.

When previously derived gene expression signatures were applied to expression data from JAVELIN Bladder, higher expression of the JAVELIN-Immuno and T cell-inflamed signatures was associated with higher overall survival with avelumab. Patients with a high JAVELIN-immuno signature score had enrichment in multiple signaling pathways including Notch and TGF-beta.

In conclusion, tumor mutational burden and PD-L1 expression on either tumor or immune cells do not fully identify tumors more likely to derive benefit from avelumab maintenance. This work generated multiple hypotheses that warrant further investigation including (1) the presence of variants in Fc gamma receptors may be implicated in anti-tumor mechanisms and (2) the prospective application of previously published immune response gene expression signatures may ultimately identify patients more likely to derive benefit from avelumab maintenance therapy.

Presented by: Srikala Sridhar, MD, Medical Oncologist and Assistant Professor of Medicine at the Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.

Related Content:

JAVELIN Bladder 100: Avelumab for Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma - Thomas Powles
Published September 19, 2020
ESMO Virtual Congress 2020: Invited Discussant Bladder Cancer (PROs from IMvigor130, Biomarker Exploratory Analyses for Correlates of Overall Survival in JAVELIN Bladder 100, and Updated Cohort 1 Data for Sacituzumab Govitecan in mUC
(UroToday.com) In this discussion, Juergen Gschwend, MD, discussed (patient-reported outcomes from IMvigor130), (biomarker exploratory analyses for correlates of overall survival in JAVELIN Bladder 100), and LB24 (updated cohort 1 data for sacituzumab govitecan in heavily pre-treated metastatic urothelial carcinoma).

He first offered a timeline of the evolution of systemic treatment options in advanced urothelial carcinomas.

In his discussion of Abstract 698O, Dr. Gschwend summarized the data as indicating the addition of immunotherapy with atezolizumab to platinum-based chemotherapy did not negatively impact patient-reported outcomes. He noted that this is an important analysis in the weighing of overall benefit of adding immunotherapy to chemotherapy, especially if the overall survival data eventually show a benefit to combination therapy as well. The findings in 698O are consistent with other data from JAVELIN Bladder 100 showing no compromise in patient-reported outcomes with avelumab maintenance therapy after first-line chemotherapy.

In his discussion of Abstract 699O, Dr. Gschwend noted that the more complex markers beyond tumor mutational burden and PD-L1 status are promising hypotheses for prospective evaluation, but not yet ready for clinical application. He also noted that tissue remains the issue, as differences in profiling of primary and metastatic tissue, as well as spatial heterogeneity within the tumor are likely to impact the applicability of molecular biomarkers.

Finally, in his discussion of Abstract LBA24, Dr. Gschwend made comparisons between the efficacy of sacituzumab with the other antibody-drug conjugate drug in advanced development for heavily pre-treated metastatic urothelial cancer, enfortumab vedotin. These drugs have both been tested in heavily pre-treated patients that have visceral and liver metastases. As shown below, they have comparable single agent activity, but phase 3 randomized clinical data is still required to fully assess their impact.

He concluded by offering a potential schematic for first line treatment options in metastatic urothelial carcinoma, which is shown below. The benefit of adding upfront immune checkpoint blockade to chemotherapy in the first line setting remains unclear in the context of pending survival data in IMvigor130 and negative KEYNOTE-361 and DANUBE trials presented at this conference.

Presented by: Juergen Gschwend, MD, Professor and Chairman of the Department of Urology, rechts der Isar Medical Center, Technical University, Munich, Munich, Germany

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.
Published September 19, 2020
ESMO Virtual Congress 2020: Patient-Reported Outcomes from JAVELIN Bladder 100: Avelumab First-Line Maintenance Plus Best Supportive Care vs Best Supportive Care Alone For Advanced Urothelial Carcinoma

(UroToday.com) Urothelial carcinoma has a substantial impact on patient qualify of life. Patients may experience a multitude of disease-related symptoms, including pain, urinary frequency, physical changes, and mental health issues, with all affect quality of life. Additionally, treatment side effects of chemotherapy have been shown to reduce the quality of life in patients with advanced urothelial carcinoma. In the phase III JAVELIN Bladder 100 trial, avelumab (anti–PD-L1) first-line maintenance plus best supportive care significantly prolonged overall survival (primary endpoint) versus best supportive care alone in patients with advanced urothelial carcinoma without disease progression with first-line induction chemotherapy (HR 0.69, 95% CI 0.56-0.86).¹ At the European Society of Medical Oncology (ESMO) 2020 Virtual Congress, Dr. Thomas Powles and colleagues reported patient-reported outcomes from the JAVELIN Bladder 100 study.

Published September 18, 2020
ESMO Virtual Congress 2020: Subgroup Analyses from JAVELIN Bladder 100: Avelumab first-line (1L) maintenance + Best Supportive Care (BSC) vs BSC Alone with 1L Chemotherapy for Advanced Urothelial Carcinoma
(UroToday.com) Advanced urothelial carcinoma has among the worst prognosis for tumors treated by genitourinary oncologists. Standard of care dictates that patients receive platinum-based induction chemotherapy. However, even with this treatment, rates of recurrence and disease progression are high and overall survival is quite short due to the development of chemotherapy resistance. In the JAVELIN Bladder 100 study which was reported at ASCO 2020 Virtual Annual Meeting, the addition of avelumab, a PD-L1 directed therapy, as first-line maintenance to best supportive care demonstrated improvements in overall survival for patients who did not have disease progression during their initial cytotoxic chemotherapy induction.
Published September 18, 2020
ESMO Virtual Congress 2020: The Landscape is Moving in Metastatic Urothelial Carcinoma - Invited Discussant
(UroToday.com) Dr. Juergen Gschwend summarized the three important abstracts in the setting of metastatic urothelial carcinoma (mUC) that were presented at the European Society of Medical Oncology (ESMO) 2020 Virtual Congress:
- LBA24 - TROPHY-U-01 Cohort 1 Final Results: A Phase 2 Study of Sacituzumab Govitecan (SG) in Metastatic Urothelial Cancer (mUC) That Has Progressed After Platinum (PLT) and Checkpoint Inhibitors (CPI) – Presented by Dr. Yohann Loriot (Villejuif, France)
- 698O - Patient-reported outcomes (PROs) from IMvigor130: a global, randomised, partially blinded Phase III study of atezolizumab (atezo) + platinum-based chemotherapy (PBC) vs. placebo (PBO) + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC) – presented by Dr. Aristotelis Bamias (Athens, Attiki, Greece)
- 699O- Avelumab first-line (1L) maintenance + best supportive care (BSC) vs. BSC alone for advanced urothelial carcinoma (UC): association between clinical outcomes and exploratory biomarkers. Presented by Dr. Srikala Sridhar (Toronto, Canada).
Published September 20, 2020
ESMO Virtual Congress 2020: Unresectable or Metastatic Urothelial Carcinoma and Advanced Urothelial Carcinoma - Invited Discussant
(UroToday.com) Dr. Kilian Gust began his discussion of three abstracts in unresectable, metastatic urothelial carcinoma, and advanced urothelial carcinoma with a discussion on historical efficacy rates of platinum therapy as first-line treatment for advanced urothelial carcinoma. Cisplatin-based regimens have an objective response rate (ORR) of 50% and median overall survival of 15 months, whereas carboplatin-based regimens have an ORR of 36% with a median overall survival (OS) of 9 months.
Published September 20, 2020
ESMO Virtual Congress 2020: What is the Future of Immunotherapy in Urothelial Cancer?

(UroToday.com) At this year’s European Society of Medical Oncology (ESMO) 2020 Virtual Congress, following a number of abstracts assessing the role of immunotherapy in advanced urothelial carcinoma, Dr. Kilian Gust provided an invited discussion regarding the future of immunotherapy in this disease with a focus on how to combine and sequence therapies.

Published September 18, 2020
SES AUA 2021: Avelumab First-Line Maintenance + Best Supportive Care (BSC) vs BSC Alone with 1L Chemotherapy for Advanced Urothelial Carcinoma: JAVELIN Bladder 100 Subgroup Analyses
(UroToday.com) Advanced urothelial carcinoma carries among the worst prognoses for tumors treated by genitourinary oncologists. Standard of care dictates that patients receive platinum-based induction chemotherapy. However, even with this treatment, rates of recurrence and disease progression are high and overall survival is quite short due to the development of chemotherapy resistance. In the JAVELIN Bladder 100 study which was reported at ASCO 2020 Virtual Annual Meeting and subsequently published in the New England Journal of Medicine, the addition of avelumab, a PD-L1 directed therapy, maintenance to best supportive care following induction chemotherapy demonstrated improvements in overall survival for patients who did no have disease progression during their initial cytotoxic chemotherapy induction.
Published April 23, 2021
SIU Virtual Congress 2020: Benefits of MDT Approach for Patients Receiving Treatment with Anti PD Agents, and the Role of Anti-PD1 Agents in the Management of Locally Advanced and Metastatic Bladder Cancer
(UroToday.com) The multidisciplinary team approach to the treatment of urothelial carcinoma in the age of anti-PD1 agents instructional course was chaired by Dr. Shaheen Alanee and included Dr. Petros Grivas who provided a lecture on the benefits of a multidisciplinary team approach for patients receiving treatment with anti PD agents, specifically for patients with locally advanced and metastatic bladder cancer.

Published October 12, 2020
SUO 2020: Navigating Novelty in Advanced Disease: Current Evidence and Adaptive Strategies for Sequencing Immune Checkpoint Inhibitors, FGFR Inhibitors, and Antibody-Drug Conjugates
(UroToday.com) At the 2020 Society of Urologic Oncology (SUO) Annual Virtual Meeting, Dr. Neal Shore chaired a session examining the use of newer and emerging agents in bladder cancer, which highlighted a presentation by medical oncologist Dr. Robert Dreicer discussing novel treatment options for patients with advanced bladder cancer. Dr. Dreicer notes that in 1993 cisplatin chemotherapy was approved for the treatment of advanced disease, followed by a long drought for other systematic therapy options until the last few years. Currently, the standards of care for initial therapy in advanced urothelial cancer are summarized in the following table:

Patients that are unfit for cisplatin-based chemotherapy represent 40-60% of patients with advanced urothelial cancer, however, there are widely accepted definitions for who is truly unfit, including (i) ECOG of 2 or greater, (ii) creatinine clearance ≤ 60 ml/min, (iii) grade 2 or greater peripheral neuropathy/hearing loss, (iv) NYHA class III heart failure. Taking into consideration all lines of therapy for standard of care for advanced urothelial carcinoma, the current landscape is as follows:

The KEYNOTE-052 trial was a multicenter, single-arm, Phase II study that assessed pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic disease.¹ Dr. Dreicer highlights that 11% of these patients were ≥ 85 years of age, 42% had ECOG performance status 2, and 85% had visceral disease. Among 370 patients, the objective response rate was 29% (95% confidence interval [CI] 25-34%), including 7% (95% CI 25-34%) of patients with complete response, and 22% (95% CI 18-27%) with partial response.

First presented at the 2019 European Society of Medical Oncology (ESMO 2019) Annual Meeting, the IMvigor130 trial is a Phase III trial assessing atezolizumab as monotherapy or combined with platinum-based chemotherapy vs placebo + platinum-based chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. This trial enrolled 1,213 platinum-based chemotherapy-eligible patients with metastatic urothelial carcinoma. Patients were randomized 1:1:1 to Arm A (atezolizumab + platinum-based chemotherapy [gemcitabine + either cisplatin or carboplatin]), Arm B (atezolizumab) or Arm C (placebo + platinum-based chemotherapy). The co-primary efficacy endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS) (Arm A vs C) and OS (Arm B vs C) per RECIST 1.1. The IMvigor130 trial design is as follows:

With a median follow-up of 11.8 months, the median PFS was 8.2 months in Arm A vs 6.3 months in Arm C (hazard ratio [HR] 0.82, 95% CI 0.70-0.96; p = 0.007). The PFS benefit of combination therapy was also robust across most subgroups. The comparison of OS did not cross the prespecified interim efficacy boundary, with a median of 16.0 months in Arm A and 13.4 months in Arm C (HR 0.83, 95% CI 0.69-1.00; p = 0.027). For Arm B vs C, the median OS was 15.7 months and 13.1 months, respectively (HR 1.02, 95% CI 0.83-1.24), for ITT patients and not estimable and 17.8 months, respectively (HR 0.68, 95% CI 0.43-1.08), for PD-L1 IC2/3 patients.

The KEYNOTE-361 trial was recently presented at the ESMO 2020 virtual meeting, a Phase III trial randomizing patients with advanced or metastatic disease 1:1:1 to pembrolizumab + gemcitabine + cisplatin or carboplatin versus pembrolizumab versus gemcitabine + cisplatin or carboplatin. The dual primary endpoints for this trial were PFS per RECIST v1.1 by blinded review and overall survival. Overall survival in the intention to treat population was 17.0 months (95% CI 14.5-19.5) in the pembrolizumab plus chemotherapy arm versus 14.3 months (95% CI 12.3-16.7) in the chemotherapy arm (HR 0.86, 95% CI 0.72-1.02, p=0.0407).

In arguably one of the most influential trials in the last year, the Phase III JAVELIN Bladder 100 trial showed that avelumab first-line maintenance plus best supportive care significantly prolonged overall survival (primary endpoint) versus best supportive care alone in patients with advanced urothelial carcinoma without disease progression with first-line induction chemotherapy (HR 0.69, 95% CI 0.56-0.86):²

Furthermore, in the PD-L1+ population median OS was not reached for avelumab plus best supportive care (95% CI 20.3 to not reached) versus 17.1 months (95% CI 13.5-23.7) for best supportive care alone (HR 0.56, 95% CI 0.40-0.79).

Shifting gears, Dr. Dreicer also discussed erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor that is approved in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma and susceptible FGFR3/2 alterations following ≥ 1 line of platinum-based chemotherapy. Approval of erdafitinib was based on data from the primary analysis of the pivotal BLC2001 trial in adult patients with previously treated locally advanced or metastatic urothelial carcinoma and FGFR3/2 alterations.³ At the final analysis of the BLC2001 study, among all patients treated with the optimal schedule of erdafitinib, the objective response rate was 40%, median duration of response was 5.98 months, median progression-free survival was 5.5 months, and median overall survival was 11.3 months.

Enfortumab vedotin is an antibody-drug conjugate that is comprised of a fully human monoclonal antibody conjugated to the clinically validated microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. Enfortumab vedotin targets Nectin-4, a transmembrane protein. In EV-101, a Phase I dose-escalation/expansion study n=155), enfortumab vedotin had a confirmed objective response rate of 43%, and duration of response of 7.4 months; median overall survival was 12.3 months, and the overall survival rate at 1 year was 51.8%.³ EV-301 is a global Phase III study of enfortumab vedotin versus physician choice of docetaxel/paclitaxel/vinflunine in patients previously treated with platinum and checkpoint inhibitors. In a press release on September 18, 2020, this trial was stopped early by the DMC as enfortumab vedotin significantly improved overall survival, with a 30% reduction in death (HR 0.70, 95% CI 0.56-0.89, p=0.001).

Dr. Dreicer concluded with several sequencing questions/comments in advanced urothelial cancer therapeutics:
- There is a relative wealth of therapeutic options, which creates challenges
- There is no data to support checkpoint inhibitor/chemotherapy combinations upfront
- The switch maintenance data is compelling
- There is data to support adjuvant therapy for high-risk patients with checkpoint inhibitor therapy
- Next-generation sequencing needs to become part of the management paradigm
- Single-agent “salvage” chemotherapy’s time is gone
- Novel non-chemotherapy combinations for upfront therapy are being evaluated in Phase III trials
Presented by: Robert Dreicer, MD, Section Head, Medical Oncology, Deputy Director, University of Virginia Cancer Center, University of Virginia, Charlottesville, Virginia

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC

References:

1. Balar, Arjun V., Daniel Castellano, Peter H. O'Donnell, Petros Grivas, Jacqueline Vuky, Thomas Powles, Elizabeth R. Plimack 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." The Lancet Oncology 18, no. 11 (2017): 1483-1492.

2. Powles, Thomas, Se Hoon Park, Eric Voog, Claudia Caserta, Begoña P. Valderrama, Howard Gurney, Haralabos Kalofonos et al. "Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma." New England Journal of Medicine 383, no. 13 (2020): 1218-1230.

3. Loriot, Yohann, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert Huddart, Earle Burgess, Mark Fleming et al. "Erdafitinib in locally advanced or metastatic urothelial carcinoma." New England Journal of Medicine 381, no. 4 (2019): 338-348.

4. Rosenberg, Jonathan, Srikala S. Sridhar, Jingsong Zhang, David Smith, Dean Ruether, Thomas W. Flaig, Joaquina Baranda et al. "EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4–Positive Solid Tumors, Including Metastatic Urothelial Carcinoma." Journal of Clinical Oncology 38, no. 10 (2020): 1041.
Published December 4, 2020

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