Presented by: Thomas Powles, MD, PhD, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew’s Hospital, London, UK
An analysis of 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma whose disease did not progress after completion of first-line platinum-containing chemotherapy provides convincing support for the use of maintenance therapy with avelumab. Results of the JAVELIN Bladder 100 study demonstrated that, compared to best supportive care (BSC) alone, avelumab in combination with BSC results in a significantly prolonged OS, both in the overall population and the PD-L1 positive population. In addition to this, the progression-free survival (PFS) was also prolonged when avelumab was added to BSC in this patient population.
Although most patients with advanced urothelial cancer obtain disease control with first-line platinum-based chemotherapy (disease control rate of 65-75%), the PFS and OS for these patients are usually short because of the occurrence of chemotherapy resistance. PD-L1/PD-1 inhibitors, such as avelumab, are currently considered as standard second-line treatment options for patients with disease progression after platinum-based chemotherapy. However, only around 25-55% of the patients receives second-line therapy and only a minority of these patients obtains a durable clinical benefit. Therefore, the JAVELIN Bladder 100 trial investigated avelumab as a first-line maintenance treatment option in patients whose disease had not progressed with first-line platinum-based induction chemotherapy.
The JAVELIN Bladder 100 study is a phase III multicentre, multinational, randomised, open-label study that enrolled 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma whose disease did not progress after completion of four to six cycles of first-line platinum-containing chemotherapy with cisplatin plus gemcitabine or carboplatin plus gemcitabine. After a treatment-free interval of 4-10 weeks, patients were randomly assigned (1:1) to avelumab 10 mg/kg intravenously once every two weeks in combination with best supportive care (BSC) or BSC alone until disease progression, unacceptable toxicity or withdrawal of consent. BSC included the use of antibiotics, nutritional support, hydration, pain management and palliative local radiotherapy when needed. Other systemic anti-tumour therapy was not permitted. Stratification was done based on best response to first-line chemotherapy (complete response, partial response or stable disease) and metastatic site (visceral versus non-visceral). The primary endpoint of the JAVELIN Bladder 100 study was OS in the overall population as well as in the subgroup of PD-L1 positive patients.
The median OS in the avelumab plus BSC care arm was reported at 21.4 months, which was significantly longer than the 14.3 months seen with BSC alone. This represents a statistically significant 31% reduction in the risk of death (HR [95%CI]: 0.69 [0.56-0.86], p< 0.001) for patients treated with avelumab. At 18 months, 61% of the patients in the avelumab plus BSC arm was still alive as compared to 44% in the BSC alone arm. In addition, avelumab plus BSC also significantly prolonged the OS versus BSC alone in the PD-L1 positive population (HR [95%CI]: 0.56 [0.40-0.78]). Subgroup analysis of OS in the overall population indicated that the hazard ratio for OS favoured avelumab plus BSC across all subgroups, irrespective of ECOG performance status, the first-line chemotherapy regimen that was used, the best response to first-line chemotherapy, the site of baseline metastases, the creatinine clearance and the PD-L1 status. PFS, as assessed by blinded independent central review, in the overall population was 3.7 months for patients in the avelumab plus BSC arm, as compared to 2.0 months for patients in the BSC alone arm (HR [95%CI]: 0.62 [0.52-0.75], p< 0.001). Avelumab was well tolerated and its safety profile in the JAVELIN Bladder 100 study was in line with what was observed in previous studies with immune checkpoint inhibitors in urothelial cancer.
JAVELIN Bladder 100 met its primary endpoint by showing a significantly longer OS with avelumab first-line maintenance as compared to BSC, both in the overall population as in the PD-L1 positive patient subgroup. The OS benefit of avelumab was consistent across prespecified subgroups, including first-line chemotherapy regimen (cisplatin- or carboplatin-based) and best response to first-line chemotherapy (complete or partial response versus stable disease). In addition, the safety profile of avelumab as first-line maintenance was manageable and consistent with previous studies of avelumab monotherapy. Overall, based on these results, maintenance avelumab should now be considered a new first-line standard-of-care for advanced urothelial carcinoma patients whose disease did progressed during platinum-based induction therapy.
Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma: JAVELIN Bladder 100 phase III interim analysis. Presented at ASCO 2020; Abstract LBA1.