Frontline Maintenance Avelumab Plus Sacituzumab Govitecan Extends PFS in Urothelial Cancer

First-line switch maintenance treatment with avelumab (Bavencio) plus sacituzumab govitecan-hziy (Trodelvy) improved progression-free survival (PFS) vs single-agent avelumab in patients with locally advanced or metastatic urothelial carcinoma without progression after frontline platinum-based chemotherapy, according to data from the phase 2 JAVELIN Bladder Medley trial (NCT05327530).¹

The results, which were published in Annals of Oncology, indicated that the median investigator-assessed PFS with the doublet (n = 74) was 11.17 months (95% CI, 7.43-not evaluable [NE]) vs 3.75 months (95% CI, 3.32-6.77) with the monotherapy (n = 74), translating to a 51% reduction in the risk of disease progression or death (HR, 0.49; 95% CI, 0.31-0.76). A PFS benefit with the combination vs the single agent was reported across several subgroups.

“The JAVELIN Bladder Medley trial reconfirmed the efficacy and safety of avelumab [first-line] maintenance treatment…,” Jeannie Hoffman-Censits, MD, of the Department of Medical Oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, in Baltimore, MD, and colleagues, wrote in the paper. “Combining avelumab with anti-Trop2 antibody-drug conjugates may be a promising strategy to improve patient outcomes in locally advanced/metastatic urothelial carcinoma.”

Jumping Into JAVELIN Bladder Medley: Trial Design and Objectives

The international, open-label, parallel-arm, phase 2 study enrolled patients with unresectable locally advanced or metastatic urothelial carcinoma without progressive disease after 4 to 6 cycles of first-line chemotherapy comprised of cisplatin and/or carboplatin plus gemcitabine. Patients were at least 18 years of age and had an ECOG performance status of 0 or 1.

Following a 4- to 10-week interval from their last chemotherapy dose, participants in these arms of the trial were randomized 2:1 to receive 800 mg of avelumab every 2 weeks alone or in combination with 10 mg/kg of sacituzumab govitecan on days 1 and 8 of 21-day cycles. Treatment continued until progressive disease, intolerable toxicity, withdrawal of consent, initiation of new anticancer treatment, or any other reason for permanent discontinuation.

The primary end points were investigator-assessed PFS and safety. Secondary end points included overall survival (OS), objective response, and duration of response (DOR).

“For analyses of PFS and OS, data in the avelumab monotherapy arm [control arm] were extended per protocol using propensity score-weighted data from the avelumab plus [best-supportive-care (BSC)] arm of the JAVELIN Bladder 100 trial [NCT02603432],” the study authors wrote. “Specifically, all patients from the avelumab-plus-BSC arm of JAVELIN Bladder 100 who met the inclusion and exclusion criteria of the JAVELIN Bladder Medley trial were included in the analyses.”

To account for population differences, data from individual patients were weighted leveraging propensity scores based on predefined characteristics at baseline. Additionally, the propensity score-weighted data from JAVELIN Bladder 100 was down-weighted so that the overall weight of the JAVELIN Bladder 100 data was 37 patients, which corresponds to the number of those randomized to the control arm of the JAVELIN Bladder Medley trial. Investigator-assessed data from the JAVELIN Bladder 100 trial were leveraged for the PFS analysis.

What Came Before

Data from JAVELIN Bladder 100 showed that with 2 years or more of follow-up in all patients, the median OS from the start of switch-maintenance with avelumab plus BSC (n = 350) was 23.8 months (95% CI, 19.9-28.8) vs 15.0 months (95% CI, 13.5-18.2) with BSC alone (n = 350; HR, 0.76; 95% CI, 0.63-0.91; 2-sided P = .0036).² The median PFS was 5.5 months (95% CI, 4.2-7.2) with avelumab by investigator assessment vs 2.1 months (95% CI, 1.9-3.0) without (HR, 0.54; 95% CI, 0.46-0.64; 2-sided P < .0001).

Current Analysis: A Closer Look at Patient Population

The median patient age in the avelumab/sacituzumab govitecan arm was 70 years (range, 42-85) vs 67 years (range, 53-89) in the avelumab monotherapy arm. Most patients were male (82.4% vs 75.7%), had a primary tumor location of the bladder (75.7% vs 70.3%), PD-L1–negative status (68.9% vs 59.5%), and did not have liver (73.0% vs 75.7%) or lung (77.0% vs 70.3%) lesions at randomization. About half of the patients were from Europe (51.4% vs 59.5%).

In the combination arm, 50% had visceral metastases at the start of frontline chemotherapy and 50% had nonvisceral metastases; in the monotherapy arm, these respective rates were 51.4% vs 48.6%. In the combination arm, 55.4% of patients received cisplatin plus gemcitabine as their first-line chemotherapy regimen, and 44.6% received carboplatin plus gemcitabine; 73.0% had a complete response (CR) or partial response (PR) as a best response, and 25.7% had stable disease (SD). In the monotherapy arm, 67.6% received cisplatin plus gemcitabine as their frontline chemotherapy regimen, and 32.4% received carboplatin plus gemcitabine; 78.4% experienced a CR or PR as a best respons,e and 21.6% had SD.

Additional Efficacy

The median follow-up for PFS was 10.94 in the combination arm and 19.25 in the monotherapy arm. At the last follow-up, 70.3% and 73.0% of patients in the respective arms were alive. Findings from a sensitivity analysis that did not include the extended control arm data indicated that the median PFS was 3.56 months (95% CI, 1.91-9.23) with avelumab monotherapy (n = 37), and the hazard ratio for the combination vs the single agent was 0.43 (95% CI, 0.25-0.75).

At the time of data cutoff, the OS data were immature. The median follow-up for OS was 11.40 months and 18.04 months in the combination and monotherapy arms, respectively. The median OS was not reached (95% CI, 15.51-NE) with avelumab with sacituzumab govitecan vs 23.75 (95% CI, 18.79-30.82) without it (HR, 0.79; 95% CI, 0.42-1.50).

Objective response rates were 24.3% (95% CI, 15.1%-35.7%) and 2.7% (95% CI, 0.1%-14.2%) in the combination and monotherapy arms, respectively. The median DORs were 11.9 months (95% CI, 5.7-NE) and NE, respectively. The disease control rates were 68.9% and 43.2%.

Safety Spotlight

Treatment-related adverse effects (TRAEs) were reported in 97.3% of those in the avelumab/sacituzumab govitecan arm vs 63.9% of those in the avelumab monotherapy arm; these cases were grade 3 or higher for 69.9% and 0%, respectively.

The most common any-grade TRAEs reported in the combination (n = 73) and monotherapy (n = 36) arms that were related to avelumab included fatigue (28.8% vs 5.6%), diarrhea (21.9% vs 5.6%), asthenia (16.4% vs 11.1%), pruritus (15.1% vs 16.7%), hypothyroidism (11.0% vs 0%), nausea (9.6% vs 2.8%), infusion-related reaction (8.2% vs 11.1%), rash (8.2% vs 0%).

The most common any-grade TRAEs reported in combination arm that were related to sacituzumab govitecan comprised alopecia (any grade, 58.9%; grade ≥3, 0%), diarrhea (49.3%; 12.3%), neutropenia (47.9%; 39.7%), fatigue (39.7%; 8.2%), nausea (35.6%; 0%), anemia (31.5%; 11.0%), decreased neutrophil count (31.5%; 23.3%), asthenia (23.3%; 0%), decreased appetite (17.8%; 0%), constipation (13.7%; 0%), vomiting (13.7%; 0%), febrile neutropenia (11.0%; 11.0%), pruritus (9.6%; 0%), and thrombocytopenia (8.2%; 0%).

References

1. Hoffman-Censits J, Tsiatas M, Chang PM-H, et al. Avelumab plus sacituzumab govitecan versus avelumab monotherapy as first-line maintenance treatment in patients with advanced urothelial carcinoma: JAVELIN Bladder Medley interim analysis. Ann Oncol. 2025;36(9):1088-1095. doi:10.1016/j.annonc.2025.05.010
2. Powles T, Park SH, Caserta C, et al. Avelumab first-line maintenance for advanced urothelial carcinoma: results from the JAVELIN Bladder 100 trial after ≥2 years of follow-up. J Clin Oncol. 2023;41(19):3486-3492. doi:10.1200/JCO.22.01792