Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with carboplatin/gemcitabine (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy (

Associació per a la Recerca Oncologica, Spain
Study Design: 
This is a phase II multicenter, randomized trial evaluating the safety and efficacy of the combination of avelumab plus carboplatin/ gemcitabine versus carboplatin/ gemcitabine alone in patients with metastatic UC who have not received prior systemic therapy and are cisplatin ineligible. Patients had to have an ECOG status of 0-2 and patients received 6 cycles of carboplatin/gemcitabine with or without avelumab which was given as induction (2 cycles avelumab), concurrent with chemotherapy (6 cycles), and as maintenance in the group that received it with the chemotherapy. Avelumab maintenance was continued until progression, unacceptable toxicity, or treatment discontinuation.
Up to 50% of patients with metastatic urothelial carcinoma (mUC) are not eligible for cisplatin. Carboplatin has activity but not comparable and so this trial evaluates whether Avelumab given as an induction therapy and in combination with carboplatin/ gemcitabine results in superior anti-tumor activity compared to standard chemotherapy in cisplatin-ineligible patients with metastatic UC. Biologically, chemotherapies can induce immunogenic cell death which may enhance the ability of checkpoint inhibitors such as avelumab.
The primary endpoint was overall response rate (ORR) by RECIST criteria. The secondary endpoints included PFS, OS, duration of response (DoR), and safety and tolerability.
Induction immunotherapy followed by chemoimmunotherapy did not significantly improve outcomes in this trial. The trial is different than the findings seen in the Javelin 100 study which demonstrated superior OS in the maintenance arm with avelumab. However, this initial analysis is still immature and further follow-up is needed for definitive conclusions.
The trial enrolled 42 patients in the chemoimmunotherapy arm and 42 patients in the chemotherapy alone arm. In an intention to treat analysis, the overall response rate was 57.1% versus 53.5% respectively, with no significant difference between the arms. Partial and complete responses were 45.2% and 11.9% in the chemoimmunotherapy arm compared with 44.2% and 9.3% in the chemotherapy arm. Median PFS was similar at 6.9 months versus 7.4 months (p=0.1356) in the chemoimmunotherapy versus chemotherapy arms respectively. Median OS was similar at 10.5 months versus 13.2 months (p=0.2642) in the chemoimmunotherapy versus chemotherapy arms respectively. Overall, the drugs were safe and tolerable with their usual expected toxicities.