Long-term Outcomes From JAVELIN Bladder 100 Solidify Maintenance Avelumab as SOC in Metastatic Urothelial Carcinoma

A long-term post-hoc analysis from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) demonstrated that first-line maintenance avelumab (Bavencio) elicited similar overall survival (OS) and progression-free survival (PFS) benefits vs best supportive care (BSC) alone in patients with advanced urothelial carcinoma, irrespective of choice of platinum-based chemotherapy, further supporting the use of avelumab as maintenance therapy in patients who do not progress on frontline chemotherapy, according to Srikala Sridhar, MD, MSc, FRCPC.¹

In June 2020, the FDA approved avelumab as maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy.² The regulatory decision was supported by previously reported data from JAVELIN Bladder 100.

Data from post-hoc analyses presented at the 2023 Genitourinary Cancers Symposium showed that at a median follow-up of at least 38 months, patients treated with cisplatin plus gemcitabine who were randomly assigned to receive avelumab experienced a median OS of 25.1 months (95% CI, 19.3-30.9), compared with 17.5 months (95% CI, 13.7-24.2) for those randomly assigned to BSC alone (HR, 0.79; 95% CI, 0.611-1.020).¹ The median PFS among this subgroup was 5.7 months (95% CI, 4.6-7.5) in the avelumab arm vs 2.0 months (95% CI, 1.9-3.6) in the BSC arm (HR, 0.56; 95% CI, 0.446-0.713).

Among patients who received carboplatin plus gemcitabine as first-line chemotherapy who were randomly assigned to avelumab, the median OS was 20.8 months (95% CI, 17.9-28.7), compared with 13.0 months (95% CI, 9.4-16.1) for those given BSC alone (HR, 0.69; 95% CI, 0.516-0.925). The median PFS was 3.7 months (95% CI, 3.6-5.6) for the avelumab arm vs 2.0 months (95% CI, 1.9-3.0) for the BSC arm (HR, 0.48; 95% CI, 0.362-0.640).

“The JAVELIN Bladder 100 study has established a new approach to treating patients with metastatic urothelial cancer [in the frontline setting],” Sridhar said.

In an interview with OncLive^®, Sridhar discussed the results of the long-term post-hoc analysis of JAVELIN Bladder 100 and highlighted how the backbone of avelumab maintenance is informing additional research in the frontline setting for patients with metastatic urothelial cancer. Sridhar is a clinician investigator in the Cancer Clinical Research Unit at Princess Margaret Cancer Center, a professor in the Department of Medicine at the University of Toronto, chair of the Genitourinary Medical Oncologists of Canada, and vice chair of the Medical Advisory Board of Bladder Cancer Canada in Toronto.

OncLive: Could you expand on the background and previously reported findings from JAVELIN Bladder 100?

The JAVELIN Bladder 100 study was published [in 2020] in the New England Journal of Medicine. In this study, we [evaluated] patients with metastatic urothelial carcinoma who had received frontline platinum-based chemotherapy [with] either gemcitabine and cisplatin or gemcitabine and carboplatin. As long [patients] had a response, which was either having stable disease, a partial response, or complete response, they were then enrolled on the study and randomly assigned to receive either maintenance avelumab [plus BSC] or BSC [alone].

The primary end point on this study was median OS [in] all patients and in those who were PD-L1 positive. This was a positive study that ultimately led to FDA approval of [avelumab] for use in the maintenance setting.

What were the key findings from the post-hoc analysis presented at the 2023 Genitourinary Cancers Symposium?

[We presented] a post-hoc analysis looking at outcomes in groups defined by the type of chemotherapy they received: gemcitabine and cisplatin or gemcitabine and carboplatin. Not surprisingly, patients who received gemcitabine and carboplatin tended to be older, have worse performance status, and have worse kidney function.

What we found when we looked at the long-term results after [a median] follow-up [of at least] 38 months was that avelumab maintenance had a benefit regardless of whether patients received gemcitabine and cisplatin or gemcitabine and carboplatin. If we look at the [data], we can see that the OS in the group that received the [cisplatin and] gemcitabine plus avelumab was [25.1] months compared with [17.5] months in the group that received [cisplatin and gemcitabine plus] BSC.

If we look at the group that received gemcitabine and carboplatin, those numbers are slightly lower, [which is] perhaps what we would have expected, at [20.8] months in the group receiving avelumab maintenance compared with 13.0 months in the group that received BSC.

The message here is twofold. First, regardless of whether a patient received gemcitabine and cisplatin or gemcitabine and carboplatin, there was a benefit with the use of maintenance avelumab. Looking at the numbers, potentially, gemcitabine and cisplatin did do a bit better than gemcitabine and carboplatin. Typically, in my practice, I try to give cisplatin to patients, if possible. I ensure that they’re well hydrated, and I may go down a bit on the creatinine clearance cutoff [of at least 60 ml/min] from the Galsky criteria [for cisplatin] to try to ensure that patients do get access to cisplatin and, subsequently, avelumab maintenance.

What was found in the analysis of OS from the start of first-line chemotherapy?

We were curious to know [about] patients’ OS from the beginning of frontline chemotherapy. In the patients who received avelumab, the [median] OS [from the start of chemotherapy] was 29.7 months compared with 20.5 months in those who received BSC. It’s important to remember that [these findings] do not represent all patients who get frontline chemotherapy, but rather those who had disease response to frontline [chemotherapy] and were subsequently enrolled on this study.

However, it goes to show us that we are making inroads in this disease. Patients are definitely living longer. Up until recently, these OS data were in the range of just [around 12 to 18 months]. [These data] tell us that we are making good progress.

Were there any notable safety findings with the updated analysis?

The other thing we looked at was long-term safety, and there were no new safety signals, meaning what we had seen originally held up over the long term. This is encouraging, as well.

How could avelumab maintenance inform additional research in the frontline setting for patients with metastatic urothelial cancer?

Looking forward, there are a number of studies building upon this backbone [of avelumab maintenance], where we are adding different drugs and different targeted therapies to avelumab to see if we can push survival even longer. It will be interesting to see how this plays out.

There are also a number of other important studies looking at the frontline setting, comparing current standard of care with some new approaches, combining antibody-drug conjugates and immunotherapy. We are still waiting for those results. For now, the standard of care is chemotherapy with platinum-based agents, followed by avelumab in patients who do not have any evidence of disease progression.

References

1. Sridhar SS, Powles T, Gupta S, et al. 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. J Clin Oncol. 2023;41(suppl 6):508. doi:10.1200/JCO.2023.41.6_suppl.508.
2. FDA approves avelumab for urothelial carcinoma maintenance treatment. News release. FDA. June 30, 2020. Accessed April 20, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/