Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma.

Abstract

286 Background: Anti-PD-L1 immunotherapy has shown promising clinical activity in urothelial carcinoma (UC). We report on a planned update of efficacy and follow-up in patients (pts) receiving durvalumab for the treatment of locally advanced or metastatic UC. Methods: Pts received durvalumab 10 mg/kg Q2W up to 12 months (mo), unacceptable toxicity or confirmed progressive disease. Tumor PD-L1 expression was assessed using the validated Ventana SP263 assay (PD-L1 high = TC ≥ 25% or IC ≥ 25%). Primary endpoints were confirmed ORR by RECIST v1.1 with blinded independent central review (BICR) and safety. Duration of response (DoR) and overall survival (OS) were key secondary endpoints. Results: As of July 24, 2016 (data cutoff [DCO]), the primary efficacy population included 103 pts who were followed for at least 13 weeks (median duration of follow up 7.3 mo); 37% had ≥ 2 prior regimens; 97% had prior platinum treatment; 95% had visceral metastases; and 49% had liver metastases at baseline. As of the DCO, 21 pts (20.4%) had a confirmed response per BICR (including 5 pts [4.9%] with a complete response) and an additional 3 pts had an unconfirmed response. Responses were seen in both PD-L1 high and PD-L1 low/negative subgroups (Table). Responses occurred early (median time to response 1.4 mo) and were durable. Median DoR has not been reached. Of the 21 confirmed responders, 18 pts had an ongoing response, 16 pts had DoR ≥ 6 mo and 7 pts had DoR ≥ 9 mo. Treatment-related Grade 3/4 AE rates were low (5.2%; as treated population, n = 191); Grade 3/4 immune-mediated AEs (imAEs) occurred in 3 pts, and 1 pt discontinued treatment due to an imAE of acute kidney injury. Conclusions: Durvalumab administered at 10 mg/kg Q2W showed clinical activity and an excellent safety profile in pts with locally advanced or metastatic UC. Clinical trial information: NCT01693562. [Table: see text]

Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…Grade 3 or 4 treatment-related AEs occurred in 5.2% of treated patients and 3 patients had a grade 3 or 4 immune-mediated AE. 99 Avelumab is another PD-L1 inhibitor currently in clinical trials to evaluate its activity in the treatment of bladder cancer. Results from the phase 1b trial for 44 patients with platinum-refractory disease demonstrated an ORR of 18.2% that consisted of 5 CRs and 3 partial responses following treatment with avelumab.…”

A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma

“…There are currently no recommended dosage modifications for patients with renal or hepatic impairment, defined as mild to moderate renal impairment (creatinine clearance [CrCl] 30–89 ml/min) and mild hepatic impairment (bilirubin level ≤ ULN and AST level > ULN, or bilirubin level > 1.0–1.5 times ULN and any AST level), respectively. However, the effect of severe renal impairment or moderate to severe hepatic impairment on pharmacokinetics is unknown . Recommendations for withholding and/or discontinuing therapy are outlined in Table…”

“…However, the effect of severe renal impairment or moderate to severe hepatic impairment on pharmacokinetics is unknown. 10,15,16 Recommendations for withholding and/or discontinuing therapy are outlined in Table 1. 10 Avelumab On May 9, 2017, the FDA granted accelerated approval to avelumab for patients with locally advanced or metastatic UC whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.…”

Which Checkpoint Inhibitor? An Embarrassment of Riches for Bladder Cancer

“…Of those, partial or complete responses were seen in nearly a third (ORR 31.1%). Interestingly, only 2 of 39 patients in the PD-L1 negative responded to durvalumab, but both obtained complete response [4]. Durvalumab, and avelumab are still unapproved and while they may receive accelerated approval, there are no Phase III trials in the salvage setting.…”

“…Following this landmark trial, PD-1 inhibitors: pembrolizumab and nivolumab and PD-L1 inhibitors: durvalumab and avelumab, all showed clinically significant objective response rates (ORR) and progression-free survival in the second-line setting after progression on platinum-based chemotherapy (Table 1) [2][3][4][5]. Nivolumab was recently granted accelerated approval in February 2017.…”