2.5.1. JAVELIN Solid Tumor Trial

Avelumab is another fully human mAb that targets PD-L1. In the phase Ib JAVELIN clinical trial [33], avelumab was studied in 249 patients with metastatic bladder cancer previously treated with platinum-containing chemotherapy. PD-L1 expression was assessed using the Dako PD-L1 IHC 28-8 pharm Dx assay. The scoring system was similar to the Dako 28-8 assay used for nivolumab. Notably, scoring only accounted for PD-L1 expression on tumor cells only. At 6 months follow-up, the ORR was 17% (95% CI, 11–24%). In PD-L1-positive (≥5% of tumor cells) patients, the ORR was 24% (95% CI, 14–36%). In patients whose tumors had a PD-L1 status of <5% tumor cells, the ORR was 13% (95% CI, 7–23%). The median DOR for all patients was not reached (95% CI, 42.1 weeks to not estimable). Median OS was 6.5 (95% CI, 4.8–9.5) months in all patients. Patients in the PD-L1 status ≥5% and <5% subgroups, the median OS values were 11.9 (6.1–18.0) and 6.1 (5.9–8.0) months, respectively.

#### 2.5.2. JAVELIN Bladder 100 Trial

This was followed with the phase III JAVELIN Bladder 100 trial that evaluated 700 patients given gemcitabine with either first-line cisplatin or carboplatin with and without maintenance avelumab plus best supportive care (BSC; *n* = 350) or BSC alone (*n* = 350) [32]. At the median follow-up time of approximately 19 months, avelumab plus BSC significantly prolonged OS versus BSC alone. The median OS for avelumab plus BSC was 21.4 months compared to 14.3 months for BSC alone. Of note, patients with PD-L1-positive tumors had a median OS that was not reached versus 17.1 months for BSC alone. The ORR of 17% and 24.1% in all patients and PD-L1 ≥5% ICs, respectively, obtained from the phase Ib study is the only available ORR (Table 1) as no ORR for the phase III study has been reported as of submission of our findings. Nonetheless, avelumab has thus far reached its primary objective in a large-scale randomized trial. Based on these results, the FDA approved avelumab on

June 20, 2020 for the treatment of patients with locally advanced or metastatic bladder cancer that has not progressed with first-line platinum-containing chemotherapy [53].

Avelumab is currently being studied in the GCISAVE trial (NCT03324282) that will assess the effectiveness of avelumab in combination with gemcitabine/cisplatin in the first-line treatment of locally advanced metastatic bladder cancer. Avelumab is also currently being evaluated in combination with Bacille Calmette-Guerin in patients with non-muscle invasive bladder cancer (NCT03892642), radiation (NCT03747419), and KHK2455 (a indoleamine 2,3-dioxygenase inhibitor; NCT03915405) in patients with advanced bladder cancer. These findings indicate that avelumab is very promising as maintenance therapy in patients who respond after receiving first-line platinum-containing chemotherapy. In addition, we look forward to ORR results from the Bladder 100 trial and the results of the multiple combination strategies currently being evaluated in the clinic.

