Extending Overall Survival in Patients with Advanced Urothelial Carcinoma

BAVENCIO^® (avelumab) in the first-line maintenance setting is a standard of care for patients with advanced urothelial carcinoma (UC) who did not progress after 4-6 cycles of first-line platinum-containing chemotherapy.¹

Primary results from the pivotal JAVELIN Bladder 100 trial – a phase 3, randomized, open-label, multicenter study – demonstrated that patients with unresectable, locally advanced or metastatic UC who did not progress with first-line platinum-containing chemotherapy (N=700) lived significantly longer with BAVENCIO plus best supportive care (BSC) compared to BSC alone.² BAVENCIO was the first³ – and as of June 2023, the only⁴ – immunotherapy to demonstrate a statistically significant improvement in overall survival (OS) as a first-line maintenance treatment for patients with advanced UC in a Phase 3 trial.

Median OS measured from randomization after chemotherapy and start of maintenance therapy was 21.4 months (95% CI, 18.9 to 26.1) for patients who received BAVENCIO plus BSC vs 14.3 months (95% CI, 12.9 to 17.9) for patients who received BSC alone (HR 0.69; 95% CI, 0.56 to 0.86; P=0.001).²

A recently presented exploratory, post hoc analysis from the JAVELIN Bladder 100 trial examined median OS from the start of first-line platinum-containing chemotherapy instead of from the start of maintenance treatment for the first time.⁵ Learn more below about this analysis, which includes first-line chemotherapy treatment as well as the treatment free interval in the OS measurement.

Select Safety Information

BAVENCIO can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody, including after discontinuation of treatment.

Results of Follow-up OS Analysis

Following the initial primary analysis from the JAVELIN Bladder 100 trial, an exploratory analysis was conducted with 19 additional months of follow-up data.⁶

LIMITATIONS: Although the follow-up OS analysis was prespecified, no formal hypothesis testing was performed given that the OS endpoint was met in the initial interim analysis. Therefore, no conclusions can be drawn from the follow-up OS analysis.⁶

With a median follow-up of 38 months (95% CI, 36.1 to 40.5) in the BAVENCIO+ BSC arm and 39.6 months (95% CI, 36.2 to 41.7) in the BSC alone arm, the median OS was 23.8 months (95% CI, 19.9 to 28.8) and 15.0 months (95% CI, 13.5 to 18.2) respectively. Median OS was measured form randomization after chemotherapy and treatment-free interval.⁶

Results of the Recent Exploratory Analysis Measuring OS From Start of Chemotherapy

Previous primary and follow-up results from the JAVELIN Bladder 100 trial measured OS post-randomization, and the median OS numbers did not include the time in which patients received multiple cycles of platinum-containing chemotherapy or the treatment-free interval. A recent exploratory analysis from the trial explored median OS from the start of first-line platinum-containing chemotherapy in all randomized patients.⁵

There are LIMITATIONS to this analysis, including:

• This is an exploratory, post hoc analysis of OS data, calculated from the start of chemotherapy (based on investigator-reported data) to death⁵
• This analysis only includes patients who did not progress on first-line platinum-containing chemotherapy and subsequently enrolled in the JAVELIN Bladder 100 trial⁵
• Safety data are not available pre-randomization⁵
• This analysis is inclusive of platinum-containing chemotherapy (patients were treated with platinum-containing chemotherapy for 4 to 6 cycles), treatment-free interval (the treatment-free interval was 4 to 10 weeks, per trial protocol), randomized study treatment with BAVENCIO plus BSC or BSC alone, and subsequent therapy⁵
• Therefore, no conclusions can be drawn from the following OS analysis⁵

When measured from the start of first-line platinum-containing chemotherapy, median OS for patients treated with BAVENCIO plus BSC was 29.7 months (95% CI, 25.2-34.0), and 20.5 months (95% CI, 19.0-23.5) for patients receiving BSC alone.⁵

Select Safety Information

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

BAVENCIO Has an Established Safety Profile

The WARNINGS AND PRECAUTIONS for BAVENCIO were established based on data from over 1,700 patients treated with BAVENCIO 10 mg/kg across multiple tumor types, the majority of whom were treated with BAVENCIO monotherapy.⁷

Safety information from the JAVELIN Bladder 100 Trial includes:

• A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving BAVENCIO + BSC⁷

The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%).

Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphatase increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase (ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), serum amylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%).

• Patients received premedication with an antihistamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 10% of patients treated with BAVENCIO + BSC (Grade 3: 0.9%)⁷

For more information, please review the full Important Safety Information (ISI) below.

Important Safety Information and Indications

BAVENCIO can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody, including after discontinuation of treatment.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

No dose reduction for BAVENCIO is recommended. For immune-mediated adverse reactions, withhold or permanently discontinue BAVENCIO depending on severity. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (eg, endocrinopathies and dermatologic reactions) are discussed in subsequent sections.

BAVENCIO can cause immune-mediated pneumonitis. Withhold BAVENCIO for Grade 2, and permanently discontinue for Grade 3 or Grade 4 pneumonitis. Immune-mediated pneumonitis occurred in 1.2% (21/1738) of patients, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%), and Grade 2 (0.6%) adverse reactions. Systemic corticosteroids were required in all (21/21) patients with pneumonitis.

BAVENCIO can cause immune-mediated colitis. The primary component of immune-mediated colitis consisted of diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 colitis. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including Grade 3 (0.4%) and Grade 2 (0.7%) adverse reactions. Systemic corticosteroids were required in all (26/26) patients with colitis.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis. Withhold or permanently discontinue BAVENCIO based on tumor involvement of the liver and severity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% (16/1738) of patients, including fatal (0.1%), Grade 3 (0.6%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in all (16/16) patients with hepatitis.

BAVENCIO can cause primary or secondary immune-mediated adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated adrenal insufficiency occurred in 0.5% (8/1738) of patients, including Grade 3 (0.1%) and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in all (8/8) patients with adrenal insufficiency.

BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated pituitary disorders occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction.

BAVENCIO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Thyroiditis occurred in 0.2% (4/1738) of patients, including Grade 2 (0.1%) adverse reactions. Hyperthyroidism occurred in 0.4% (7/1738) of patients, including Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 29% (2/7) of patients with hyperthyroidism. Hypothyroidism occurred in 5% (90/1738) of patients, including Grade 3 (0.2%) and Grade 2 (3.7%) adverse reactions. Systemic corticosteroids were required in 7% (6/90) of patients with hypothyroidism.

BAVENCIO can cause immune-mediated type I diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated type I diabetes mellitus occurred in 0.1% (2/1738) of patients, including Grade 3 (0.1%) adverse reactions.

BAVENCIO can cause immune-mediated nephritis with renal dysfunction. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 increased blood creatinine. Immune-mediated nephritis with renal dysfunction occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction. Systemic corticosteroids were required in this patient.

BAVENCIO can cause immune-mediated dermatologic adverse reactions, including rash or dermatitis. Exfoliative dermatitis including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold BAVENCIO for suspected and permanently discontinue for confirmed SJS, TEN, or DRESS. Immune-mediated dermatologic adverse reactions occurred in 5% (90/1738) of patients, including Grade 3 (0.1%) and Grade 2 (2.0%) adverse reactions. Systemic corticosteroids were required in 29% (26/90) of patients with dermatologic adverse reactions.

BAVENCIO can result in other immune-mediated adverse reactions. Other clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies. For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4. For neurological toxicities, withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 infusion-related reactions. Permanently discontinue BAVENCIO for Grade 3 or Grade 4 infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Eleven (92%) of the 12 patients with Grade ≥3 reactions were treated with intravenous corticosteroids.

Fatal and other serious complications of allogeneic hematopoietic stem cell transplantation (HSCT) can occur in patients who receive HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient with locally advanced or metastatic urothelial carcinoma (UC) receiving BAVENCIO + best supportive care (BSC) as first-line maintenance treatment. In patients with previously treated locally advanced or metastatic UC, fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%). In patients with previously treated locally advanced or metastatic UC receiving BAVENCIO, the most common adverse reactions (all grades, ≥20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphatase increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase (ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), serum amylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%).

Indication

First-line maintenance treatment of urothelial carcinoma (UC)

• BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy

Please see full Prescribing Information and Medication Guide.

To learn more about how BAVENCIO can benefit patients, visit: https://www.bavencio.com/en_US/hcp/uc-home.html

¹ NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer v1. 2023. https://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Accessed 3 May 2023.

² Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230.

³ EMD Serono. 9 April 2020. EMD Serono and Pfizer Receive US FDA Breakthrough Therapy Designation and Submit Application for BAVENCIO® for First-Line Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma - News | EMD Serono. Accessed 21 March 2023.

⁴ EMD Serono. 13 February 2023. New Analyses Reinforce Survival Benefit of BAVENCIO - News | EMD Serono. Accessed 21 March 2023.

⁵ Sridhar S et al. JAVELIN Bladder 100 trial in subgroups defined by 1L chemotherapy regimen and analysis of overall survival (OS) from start of 1L chemotherapy. ASCO Genitourinary Cancers Symposium 2023. Program Guide – ASCO Meeting Program Guide. Accessed 21 March 2023.

⁶ Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow up results from the JAVELIN Bladder 100 trial. Presented at ASCO GU 2022.

⁷ BAVENCIO Prescribing Information.

©2023 Merck KGaA, Darmstadt, Germany or its affiliates. All rights reserved. EMD Serono is the Healthcare business of Merck KGaA, Darmstadt, Germany in the U.S. and Canada. BAVENCIO is a registered trademark of Merck KGaA, Darmstadt, Germany or its affiliates.

US-AVE-01227 06/2023