An exploratory analysis of the phase 3 JAVELIN Bladder 100 trial shows that the overall survival benefit of frontline maintenance avelumab is sustained in patients with advanced urothelial cancer.
Maintenance therapy with avelumab (Bavencio) plus best supportive care (BSC in the frontline setting of metastatic urothelial cancer showed continued improvement in overall survival (OS) compared with BSC alone in patients who receive first-line chemotherapy, according to updated findings from an exploratory analysis of the phase 3 JAVELIN Bladder 100 trial (NCT02603432).1
With an additional 19 months of follow-up, the median OS with avelumab plus BSC was 23.8 months (95% CI, 19.9-28.8) compared with 15.0 months (95% CI, 13.5-18.2) with BSC alone (hazard ratio [HR], 0.76; 95% CI, 0.631-0.915; P = .0036). The 2- and 3-year OS rates with avelumab/BSC were 49.8% and 36.0%, respectively; these rates were 38.4% and 29.8%, respectively, in the BSC-alone arm.
Additional data, which were presented during the 2022 Genitourinary Cancers Symposium, showed that the investigator-assessed progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.2) with avelumab/BSC and 2.1 months (95% CI, 1.9-3.0) with BSC alone, translating to a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.457-0.645; P <.0001). The 2- and 3-year PFS rates were 23.4% and 15.9%, respectively, with avelumab/BSC, and 7.1% and 5.3%, respectively, with BSC alone.
Lead study author Thomas Powles, MBBS, MRCP, MD, explained in a poster presentation during the meeting that no new safety signals were identified with the combination.
“In summary, these data show this consistent survival signal, a HR of 0.76 remains clinically meaningful, and this remains the standard of care for those patients with metastatic urothelial cancer who receive first-line chemotherapy, sequencing maintenance avelumab remains attractive for these patients, across broad subgroups of patients, with no new safety signals,” Powles, who is director of Barts Cancer Institute, said.
Earlier data from JAVELIN Bladder 100 led to the FDA approval of frontline maintenance avelumab plus BSC in June 2020 for use in patients with advanced urothelial cancer that did not progress on frontline platinum-based chemotherapy. At the earlier analysis, the median OS was 21.4 months (95% CI, 18.9-26.1) with the addition of avelumab and 14.3 months (95% CI, 12.9-17.9) with BSC alone, leading to a 31% reduction in the risk of death (HR, 0.69; 95% CI; 0.56-0.86; 1-sided P = .0005).2
In the phase 3 JAVELIN Bladder 100 trial, 700 patients with unresectable locally advanced or metastatic urothelial cancer were randomized 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350) until disease progression, unacceptable toxicity, or withdrawal. A total of 358 patients had PD-L1–positive disease.
To be eligible for participation, patients must have had a complete response (CR), partial response (PR), or stable disease (SD) with standard frontline chemotherapy with either cisplatin/gemcitabine or carboplatin/gemcitabine for 4 to 6 cycles.
Stratification factors included best response to frontline chemotherapy (CR or PR vs SD) and metastatic site (visceral vs nonvisceral) when initiating frontline chemotherapy.
The primary end point of the trial was OS in all randomized patients and in the PD-L1–positive population; secondary end points included PFS, objective response per RECIST v1.1 criteria, and safety.
The updated analysis includes at least 2 years of follow-up in all patients, bringing it to a median follow-up of 38 months. The data cutoff date was June 4, 2021.
Further findings showed that the OS benefit was observed across most prespecified subgroups and was found irrespective of site of metastases (visceral: HR, 0.91; 95% CI, 0.713-1.163; non-visceral: HR, 0.60; 95% CI, 0.451-0.798) and type of chemotherapy used (gemcitabine/cisplatin: HR, 0.78; 95% CI, 0.607-1.008; gemcitabine/carboplatin: HR, 0.70; 95% CI, 0.523-0.929; gemcitabine/carboplatin/cisplatin: HR, 0.69; 95% CI, 0.294-1.639). The benefit was not seen in those from Australia (HR, 1.29; 95% CI, 0.697-2.398) and those with liver lesions at baseline (HR, 0.95; 95% CI, 0.585-1.541).
It was also reported that more patients in the BSC-alone arm received subsequent anticancer therapy. Of all patients (n = 700), 52.9% of patients in the avelumab/BSC arm discontinued and received subsequent therapy with a PD-1/PD-L1 inhibitor (11.4%), FGFR inhibitor (2.9%), or another drug (50.6%). In the BSC-alone arm, 72.0% of patients discontinued treatment and went onto a PD-1/PD-L1 inhibitor (53.1%), FGFR inhibitor (3.7%), or another drug (44.6%). Moreover, 12.3% and 2.9% of patients in the investigative and control arms, respectively, were still receiving study treatment.
Of the subgroups who received subsequent therapy (n = 437), 21.6% of those on the avelumab arm (n = 185) were treated with a PD-1/PD-L1 inhibitor, 5.4% a FGFR inhibitor, and 95.7% another drug; these rates were 73.8%, 5.2%, and 61.9%, respectively, in the BSC-alone arm (n = 252).
For patients who discontinued study treatment due to progressive disease (n = 484), 75.6% of those on avelumab/BSC (n = 209) discontinued and received subsequent treatment with a PD-1/PD-L1 inhibitor (12.9%), FGFR inhibitor (4.8%), or another drug (72.2%). Of those in this subgroup who were treated with BSC alone (n = 275), 81.8% of patients discontinued and received subsequent therapy with a PD-1/PD-L1 inhibitor (60.4%), FGFR inhibitor (4.0%), or another drug (50.5%).
Regarding safety, Powles noted that the long-term safety profile with avelumab, which was analyzed in patients receiving the combination for at least 12 months, was consistent with prior studies of the single-agent checkpoint inhibitor. All-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs) that occurred after at least 12 months of treatment were reported in 86.4% of patients who received avelumab/BSC (n = 118) and 47.5% were grade 3 or higher; these effects occurred with onset at any time (n = 344) in 98.3% of patients; 53.8% of patients had grade 3 or higher TEAEs with onset at any time.
Additionally, any-grade and grade 3 or higher treatment-related AEs (TRAEs) occurring after at least 12 months of treatment occurred in 50.0% and 11.9% of patients; these rates were 78.2% and 19.5%, respectively, at any time.
Also, as onset after at least 12 months of treatment, serious TEAEs occurred in 23.7% of patients and serious TRAEs were reported in 5.1% of patients; 36.4% experienced TEAEs that led to interruption of avelumab and 11.0% had TEAEs that led to discontinuation. TEAEs and TRAEs that led to death occurred in 2.5% and 0.8% of patients, respectively. All-grade infusion-related reactions were reported in 3.4% of patients.
For onset of AEs that occurred at any time, serious TEAEs occurred in 30.5% and serious TRAEs were reported in 10.2% of patients; 45.3% of patients had TEAEs that led to avelumab interruption and 14.2% had TEAEs that led to discontinuation. TEAEs and TRAEs that led to death occurred in 2.0% and 0.6% of patients, respectively. All-grade infusion-related reactions were reported in 21.8% of patients.
The most common TEAEs with onset at this time point was urinary tract infection and diarrhea (n = 15; 12.7% each). One patient did experience a TRAE of immune-mediated nephritis after at least 1 year of the combination that led to death.
1. 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. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487
2. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Eng J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788