Findings of a new analysis of long-term follow-up data from the Phase III JAVELIN Bladder 100 trial (NCT02603432) reinforce the proven survival benefits of avelumab (Bavencio®**; EMD Serono*/ Pfizer) in the first-line maintenance setting for patients with locally advanced or metastatic urothelial carcinoma (mUC), also called transitional cell carcinoma.

Almost all bladder cancers are urothelial carcinomas. This form of cancer begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs. Bladder cancer is the tenth most common cancer worldwide. [1]

In 2020, there were over half a million new cases of bladder cancer diagnosed, with around 200,000 deaths from the disease globally.[1] In the US, an estimated 83,730 cases of bladder cancer were diagnosed in 2021, with around 10,000 locally advanced or metastatic cases presented annually [2] mUC, which accounts for about 90% of all bladder cancers, [3] becomes harder to treat as it advances, spreading through the layers of the bladder wall.[4]

Today, only 25% to 55% of patients receive any second-line therapy after first-line chemotherapy. [5] In the US and EU5 markets, approximately 40% to 50% of patients receive an immune checkpoint inhibitor in second-line therapy. [2] For patients with advanced UC, the five-year survival rate is 6.4%.[2]

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody which has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated anti-tumor immune response in preclinical models. [6][7][8]

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Trial
The JAVELIN Bladder 100 is a Phase III, multi-center, multinational, randomized, open-label, parallel-arm study investigating first-line maintenance treatment with avelumab plus best supportive care versus best supportive care alone in patients with locally advanced or mUC.

In this study, the primary endpoint was overall survival (OS) in the two primary populations of all patients and patients with PD-L1+ tumors defined by the Ventana SP263 assay. Secondary endpoints included progression-free survival, anti-tumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the co-primary populations. All primary and secondary endpoints are measured from the time of randomization.

Study results
With median follow-up of at least 38 months from randomization, patients who were progression-free following platinum-based chemotherapy who received avelumab first-line maintenance plus best supportive care (BSC) had longer median overall survival (OS) than those who received BSC alone in the maintenance setting. This benefit was seen regardless of whether their initial chemotherapy regimens included cisplatin (Platinol®; Bristol-Myers Squibb)*** or carboplatin (Paraplatin®; Bristol-Myers Squibb) .

This analysis, as well as multiple studies of avelumab in the real-world setting, are being presented at the 2023 American Society of Clinical Oncology (ASCO)’s annual Genitourinary Cancers Symposium, February 16-18, 2023.

“Based on the significant improvement in overall survival demonstrated in the Phase III JAVELIN Bladder 100 study, platinum-based chemotherapy followed by avelumab maintenance treatment in patients without evidence of disease progression, has become a standard of care for advanced urothelial carcinoma,” explained Srikala Sridhar, MD, MSc, FRCPC, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

“The findings presented today reinforce that all patients eligible for platinum-based chemotherapy, either cisplatin or carboplatin, can benefit from avelumab maintenance therapy. These findings reported here provide a reference point for outcomes of ongoing and future clinical trials in advanced bladder cancer,” Sridhar added.

In the overall population, patients who received avelumab plus BSC had a median OS of 29.7 months (95% CI, 25.2-34.0) as measured from the start of first-line chemotherapy, compared with 20.5 months (95% CI, 19.0-23.5) in patients who received best supportive care alone (HR, 0.77; 95% CI, 0.636-0.921). This result further supports the JAVELIN Bladder 100 regimen of avelumab first-line maintenance in patients with advanced UC who are progression-free following first-line platinum-based chemotherapy as standard of care.

The analysis also confirmed that the overall survival of avelumab first-line maintenance were similar regardless of whether patients received cisplatin or carboplatin-based chemotherapy.

  • In patients who received cisplatin plus gemcitabine (Gemzar®; Lilly & Co) (n=389), median OS from start of chemotherapy was 31.0 months (95% CI, 24.9-37.1) in the avelumab plus BSC arm (n=183), compared with 23.0 months (95% CI, 19.2-30.9) for BSC alone (n=206) (HR, 0.79; 95% CI, 0.613-1.024).
  • In patients who received carboplatin plus gemcitabine (n=269), median OS from start of chemotherapy was 25.8 months (95% CI, 22.8-33.3) for avelumab plus BSC (n=147), compared with 17.6 months (95% CI, 14.8-21.3) for BSC alone (n=122) (HR, 0.69; 95% CI, 0.514-0.920).

Safety profile
Long-term safety was similar in both the cisplatin plus gemcitabine and carboplatin plus gemcitabine subgroups, with no new safety concerns identified. Grade 3 or greater treatment-related adverse events were 16 percent and 23 percent for cisplatin and carboplatin cohorts, respectively.

“Avelumab remains the only immunotherapy to show improved overall survival in advanced UC patients in the first-line maintenance setting in a Phase III trial. The large, randomized Phase III JAVELIN Bladder 100 trial established avelumab first-line maintenance treatment following platinum-based chemotherapy as a standard of care, and long-term and real-world data such as these presented at ASCO GU 2023 continue adding to the evidence supporting its benefits for patients with advanced bladder cancer,” noted Tamas Sütö, MD, PhD, Senior Vice President & Head of Medical Unit Oncology, Merck KGaA, Darmstadt, Germany.

Additional data presented at the meeting include updates from real-world studies of patient populations in France, Italy, Germany and the U.S. This includes the first full analysis from the AVENANCE real-world study investigating the efficacy and safety of avelumab first-line maintenance therapy in advanced UC patients in France, and the READY study of real-world data from a compassionate use program in Italy, which supports the findings of JAVELIN Bladder 100 in real-world settings.

  • In the ongoing (median follow-up 15.2 months) non-interventional AVENANCE study of 593 patients in France with advanced UC that had not progressed with first-line platinum-based chemotherapy who received avelumab as a first-line maintenance treatment, median OS from start of avelumab treatment was 20.7 months (95% CI, 17.1-not estimable) and the 12-month OS rate was 65.4% (95% CI, 61.0-69.4). Median progression-free survival (PFS) was 5.7 months (95% CI, 5.3-7.0).
  • In the READY study of 464 patients in Italy who received BAVENCIO first-line maintenance treatment following platinum-based chemotherapy, median OS was not reached and the 12-month OS rate from the start of avelumab treatment was 69.2% (95% CI, 64.8%-73.7%). The median PFS was 8.1 months (95% CI, 6.1-10.4) with a 12-month PFS rate of 44.3% (95% CI, 39.5-49.1).

Data for avelumab as well as real-world analyses in urothelial cancer, presented at ASCO GU include:

TitleLead Author, Abstract # and Session Details (all times PT)
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up from the JAVELIN Bladder 100 trial in subgroups defined by 1L chemotherapy regimen and analysis of overall survival (OS) from start of 1L chemotherapy

 

SS Sridhar

Abstract #508

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

Full analysis from AVENANCE: A real-world study of avelumab first-line (1L) maintenance treatment in patients (pts) with advanced urothelial carcinoma (aUC)

 

P Barthélémy

Abstract #471

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

Treatment patterns, indicators of receiving systemic treatment, and clinical outcomes in metastatic urothelial carcinoma: a retrospective analysis of real-world data in Germany

 

G Niegisch

Abstract #464

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

Real-world treatment patterns and sequencing in patients with locally advanced or metastatic urothelial cancer (la/mUC) in the USM Kearney

Abstract #572

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

Baseline characteristics from a retrospective, observational, US-based, multicenter, ‘real-world’ (RW) study of avelumab first-line maintenance (1LM) in locally advanced/metastatic urothelial carcinoma (la/mUC) (PATRIOT-II)

 

P Grivas

Abstract #465

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

READY: REAl-world Data from an Italian compassionate use program of avelumab first-line maintenance (1LM) treatment for locallY advanced or metastatic urothelial carcinoma (la/mUC)L Antonuzzo

Abstract #469

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

Assessment of treatment patterns and real-world outcomes following changes in the treatment paradigm for locally advanced/metastatic urothelial carcinoma (la/mUC) in the USM Kirker

Abstract #468

Poster Session B: Prostate Cancer and Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

SPADE: Design of a real-world observational study of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (UC) in the Asia-Pacific (APAC) regionP-J Su

Abstract #TPS577

Trials in Progress Poster Session B: Urothelial Carcinoma

Friday, Feb 17, 2023

12:30-2:00 PM; 5:15-6:15 PM

C-reactive protein (CRP) as a predictive marker for outcomes with avelumab + axitinib (A + Ax) in patients with poor-risk advanced renal cell carcinoma (aRCC): exploratory analysis from JAVELIN Renal 101Y Tomita

Abstract #670

Poster Session C: Renal Cell Cancer; Adrenal, Penile, Urethral and Testicular Cancers

Saturday, Feb 18, 2023

7:00-8:00 AM; 12:30-2:00 PM

A UK real-world observational study of avelumab + axitinib (A + Ax) in advanced renal cell carcinoma (aRCC): 24-month interim resultsP Nathan

Abstract #631

Poster Session C: Renal Cell Cancer; Adrenal, Penile, Urethral and Testicular Cancers

Saturday, Feb 18, 2023

7:00-8:00 AM; 12:30-2:00 PM

 

Note: * EMD Serono is the healthcare business of Merck KGaA, Darmstadt, Germany in the U.S

Note: ** Avelumab is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. Avelumab is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Note: *** This branded product is no longer on the market. Generic alternatives may be available.

Clinical trials
A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100) – NCT02603432
A Non-Interventional Study On Avelumab Use in Patients with Advanced or Metastatic Urothelial Carcinoma (Avenance) – NCT04822350

Highlights of prescribing information
Avelumab (Bavencio®; EMD Serono/Pfizer)[Prescription Information]
Cisplatin (Platinol®; Bristol-Myers Squibb) [Prescription Information]
Carboplatin (Paraplatin®; Bristol-Myers Squibb) [Prescription Information]
Gemcitabine (Gemzar®; Lilly & Co)[Prescription Information]

References
[1] Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021;0:1–41.
[2] SEER. Cancer stat facts: bladder cancer. Online. Last accessed February 2022.
[3] Cancer.net. Bladder cancer: introduction. Online. Last accessed February 2022.
[4] American Cancer Society. What is bladder cancer? Online . Accessed February 2022.
[5] Cheeseman S, et al. Current treatment and outcomes benchmark for locally advanced or metastatic urothelial cancer from a large UK-based single centre. Front Oncol. 2020;10:167.
[6] Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3(10):1148-1157.
[7] Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237.
[8] Dahan R, Sega E, Engelhardt J, et al. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell. 2015;28(3):285-295.

Featured image: San Francisco, CA – 2020 Genitourinary Cancers Symposium Attendees listen to presentations during during Oral Abstract Session B: Urothelial Carcinoma; Penile, Urethral, Testicular, and Adrenal Cancers at the 2020 Genitourinary Cancers Symposium 2020. Photo courtesy: © 2020 ASCO/Todd Buchanan. Used with permission.

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