Avelumab Safety Profile Remains Consistent in Long-Term JAVELIN Bladder 100 Post Hoc Analysis

Joaquim Bellmunt, MD, PhD

In a post-hoc analysis of the phase 3 JAVELIN Bladder 100 trial (NCT02603432), frontline treatment with maintenance avelumab (Bavencio) plus best supportive care (BSC) was associated with a tolerable safety profile. Findings were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

At a median follow-up of 38.0 months (95% CI, 36.1-40.5), any-grade treatment-related adverse effects (TRAEs) occurred at any time in 78.2% (n = 269) of patients who received avelumab plus BSC (n = 344) and after at least 12 months of avelumab treatment (n = 118) in 50.0% (n = 59) of patients in this population. Grade 3 or greater TRAEs occurred in 19.5% (n = 67) of patients in the avelumab plus BSC arm at any time and in 11.9% (n = 14) of these patients after at least 12 months of avelumab treatment. The median duration of avelumab treatment was 5.8 months (range, 0.5-49.7), and the median number of infusions was 11.5 (range, 1.0-106.0).¹

“Post hoc analyses of JAVELIN Bladder 100 confirm the tolerable and manageable long-term safety profile of avelumab first-line maintenance,” Joaquim Bellmunt, MD, PhD, the director of the Bladder Cancer Center at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, said in a presentation on the data.

JAVELIN Bladder 100 enrolled patients with unresectable locally advanced or metastatic urothelial carcinoma who had achieved a complete response, partial response, or stable disease with 4 to 6 cycles of standard gemcitabine with either cisplatin or carboplatin.

A total of 700 patients were randomly assigned 1:1 to receive either avelumab plus BSC (n = 350) or BSC alone (n = 350) until disease progression, unacceptable toxicity, or patient withdrawal. Patients were stratified by best response to first-line chemotherapy and site of metastatic disease when initiating first-line chemotherapy.

The primary end point of this trial was overall survival (OS), with key secondary end points of progression-free survival (PFS) per RECIST v1.1 and safety. The primary analysis populations included all randomly assigned patients and the patients with PD-L1–positive disease.

Previously reported findings from JAVELIN Bladder 100 showed that at a median follow-up of at least 38 months, avelumab maintenance elicited a significantly longer median OS compared with BSC alone, at 23.8 months (95% CI, 19.9-28.8) vs 15.0 months (95% CI, 13.5-18.2) in patients who did not progress after first-line platinum-based chemotherapy (HR, 0.76; 95% CI, 0.631-0.915; P = .0036). The 30-month OS rates were 43.7% (95% CI, 38.2%-49.0%) and 33.5% (95% CI, 28.4%-38.7%) in the avelumab and BSC alone arms, respectively. In addition, the median PFS was 5.5 months (95% CI, 4.2-7.2) with avelumab vs 2.1 months (95% CI, 1.9-3.0) in the BSC alone arm (HR, 0.54; 95% CI, 0.457-0.645; P < .0001), and the 30-month PFS rates were 19.3% (15.0%-24.0%) and 6.3% (95% CI, 3.8%-9.5%), respectively.²

Furthermore, the safety profile of first-line avelumab maintenance therapy was consistent with that seen in prior studies with avelumab monotherapy, and the investigators identified no new safety signals with the agent. In primary findings from JAVELIN Bladder 100, any-grade adverse effects (AEs) were observed in 98.0% of patients in the avelumab group and 77.7% of patients in the BSC alone group. Additionally, grade 3 or higher AEs occurred in 47.4% and 25.2% of patients in the avelumab and BSC alone arms, respectively.³

At the 2023 ASCO Annual Meeting, investigators reported findings from long-term safety analyses of JAVELIN Bladder 100 that were conducted in all patients who received avelumab plus BSC, as well as in a subgroup of patients who were treated for at least 12 months.¹

In these analyses, the most common grade 3 or higher TRAEs that occurred at any time were increased lipase (3.5%) and increased amylase (2.3%). The most common grade 3 or higher TRAE that occurred after at least 12 months of avelumab treatment was increased lipase (1.7%).

A total of 11.6% (n = 40) of patients experienced TRAEs leading to avelumab discontinuation, the most common being infusion-related reaction (1.2%) at any time and interstitial lung disease (1.7%) after at least 12 months of avelumab treatment.

Any-grade immune-related AEs occurred in 32.3% (n = 111) of patients at any time, the most common being thyroid disorders (12.8%), immune-related rash (10.8%), immune-related nephritis/renal dysfunction (2.3%), immune-related pneumonitis (2.0%), immune-related colitis (1.7%), immune-related hepatitis (1.5%), type 1 diabetes (1.2%), and other immune-related AEs (2.9%). Any-grade immune-related AEs occurred in 22.9% (n = 27) of patients after at least 12 months of avelumab treatment, the most common being immune-related rash (10.2%), immune-related nephritis/renal dysfunction (3.4%), thyroid disorders (1.7%), immune-related pneumonitis (1.7%), immune-related colitis (1.7%), type 1 diabetes (0.8%), and other immune-related AEs (3.4%).

Grade 3 or higher immune-related AEs occurred in 7.6% (n = 26) and 4.2% (n = 5) of patients at any time and after at least 12 months of avelumab treatment, respectively. The most common grade 3 or higher immune-related AEs that occurred at any time were immune-related rash (1.5%), immune-related hepatitis (1.5%), immune-related colitis (0.9%), type 1 diabetes (0.9%), immune-related nephritis/renal dysfunction (0.6%), immune-related pneumonitis (0.3%), thyroid disorders (0.3%), and other immune-related AEs (0.3%). No category of grade 3 or higher immune-related AE occurred in more than 1 patient after at least 12 months of avelumab treatment. Immune-related rash, immune-related nephritis/renal dysfunction, immune-related colitis, and type 1 diabetes occurred in 1 patient each.

Immune-related AEs that occurred at any time led to avelumab discontinuation in 6.1% (n = 21) of patients, the most common being immune-related hepatitis (1.2%) and immune-related nephritis/renal dysfunction (1.2%). Immune-related AEs that occurred after at least 12 months of avelumab treatment led to avelumab discontinuation in 4.2% (n = 5) of patients, the most common being immune-related pneumonitis (1.7%) and immune-related nephritis/renal dysfunction (1.7%), from which 1 patient died.

In all patients who received avelumab, 1, 2, 3, and at least 4 immune-related AEs occurred in 17.7%, 8.7%, 3.2%, and 2.6%, respectively. In the patients who had received at least 12 months of avelumab treatment, 1, 2, 3, and at least 4 immune-related AEs occurred in 15.3%, 3.4%, 2.5%, and 1.7%, respectively.

“These results further support the use of avelumab first-line maintenance until disease progression as standard of care for patients with advanced urothelial carcinoma that have not progressed with first-line platinum-based chemotherapy,” Bellmunt concluded.

Disclosures: Dr Bellmunt reports stock and other ownership interests with Rainier Therapeutics; honoraria from UpToDate; consulting or advisory roles with Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Merck, Novartis, Pfizer, Pierre Fabre; research funding from Millennium (Inst), Pfizer/EMD Serono (Inst), and Sanofi (Inst); patents, royalties, or other intellectual property from UpToDate Bladder Cancer; and travel, accommodations, or expenses from Ipsen, MSD Oncology, and Pfizer.

1. References
2. Bellmunt J, Aragon-Ching JB, Climent MA, et al. Long-term safety of avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC) in the JAVELIN Bladder 100 trial. J Clin Oncol. 2023;41(suppl 16):4516. doi:10.1200/JCO.2023.41.16_suppl.4516
3. 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. J Clin Oncol. 2023;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487
4. 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. doi:10.1056/NEJMoa2002788