Atezolizumab demonstrated clinical benefit in patients with metastatic urothelial carcinoma (mUC) who had a poor prognosis after progressing following platinum-based chemotherapy, according to phase II trial results reported at the European Cancer Conference convening in Vienna, Austria, 25 - 29 September, 2015.
Atezolizumab restores immune response by targeting programmed death ligand-1 (PD-L1) and has demonstrated activity in mUC, where there is currently a high, unmet need for viable treatments.
Breakthrough designation was granted for atezolizumab by the US Federal Drug Administration in 2014 for patients with mUC whose tumour expressed PD-L1.
Response had previously been demonstrated in patients with non-small-cell lung cancer where tumour shrinkage was found to be proportional to the degree of PD-L1 expression by the tumour.
Jonathan Rosenberg, Medical Oncology, Memorial Sloan Kettering Cancer Centre, New York, USA, lead investigator of the IMvigor study, reported findings from an international multicentre phase II trial of atezolizumab in patients with locally-advanced or metastatic mUC.
IMvigor 210 enrolled 316 patients who had progressed during or following platinum-based chemotherapy. Atezolizumab was administered at 1200 mg intravenously on the first day of each 21-day cycle until no further clinical benefit was demonstrated. Median treatment duration was 12 weeks (range: 0 to 46 weeks).
The co-primary study endpoints were overall response rate (ORR), as assessed by central review (RECIST v1.1) and ORR assessed by the investigators using modified RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety.
Tumour tissue was prospectively assessed centrally for PD-L1 expression using the SP142 immunohistochemistry (IHC) assay. PD-L1 status was assessed on tumor cells and immune cells (IC) using an SP142 antibody-based immunohistochemistry assay; however, both the patients and investigators were blinded as to PD-L1 status.
Response to atezolizumab parallels PD-L1 expression
By data cut-off of May 5, 2015, data from 311 patients were evaluable for efficacy and safety. Baseline characteristics showed ECOG PS 1 in 62% of patients, median patient age was 66 years, 78% were male, and 31% of patients had metastasis to the liver. The patients had been heavily pre-treated; 40% of patients had undergone ≥2 prior systemic regimens in the metastatic setting and 74% of patients had received cisplatin-based chemotherapy.
Results were evaluated according to the degree of PD-L1 expression on immune cells and on all comers showing significant ORR improvements across all groups that increased with higher PD-L1 expression. ORR by RECIST 1.1 was 15% (p = 0.0058) in all comers, 18% (p = 0.0004) in IC1/2/3 (PD-L1 expression ≥1%) compared to ORR 27% (p = 0.0001) in the IC2/3 subgroup with PD-L1 expression ≥5%.
Overall, 12 patients achieved complete response (CR), and 35 achieved partial response (PR). In addition, 15 additional unconfirmed RECIST v1.1 CR/PRs were seen. Median PFS at a median follow-up of 24 weeks was 2.1 months across all groups.
The median DoR had not been reached at the time of cut off, however, at a minimum follow-up of 24 weeks, 92% (43 of 47) of responding patients maintained response. OS data are not yet mature but prolonged OS was demonstrated in patients with higher PD-L1 expression.
Treatment-related adverse events (AEs) of any grade occurred in 66% of patients, with 15% of patients experiencing grades 3/4 treatment-related AEs consisting most often of fatigue in 6 (2%) patients. AEs leading to treatment discontinuation were reported in 3% of patients.
Prof. Ronald de Wit of the Erasmus MC, University Medical Center Rotterdam, The Netherlands, who discussed the study results, said that classical chemotherapy is not very effective in second-line treatment of metastatic bladder cancer. In US most widely used agent is docetaxel, while in EU vinflunine is used in some countries.
Perspective second-line therapies are atezolizumab that targets PD-L1, pembrolizumab that targets PD-1, and docetaxel/ramucirumab that targets VEGFR-2.IMvigor 210 enrolled an all-comer population. VENTANA PD-L1 (SP142) CDx Assay was used to prospectively measure tumour-infiltrating immune cells, PD-L1 expression was based on 3 IHC scoring levels.
The study data are promising, but it is needed to await phase III studies results (IMvigor and Keynote trials amongst others). It is also important to identify patients who may benefit (most) and Prof. De Wit questioned if IHC could eventually help in that regard.
The investigators state that IMvigor 210 is the first phase II study of a PD-L1/PD-1–targeted agent in mUC. They also noted that studies in treatment naive, platinum ineligible patients are ongoing, as is a phase III trial of atezolizumab versus chemotherapy.
This trial met the primary endpoints, including durable responses in platinum-pretreated patients and preliminary data suggest higher PDL1 expression on immune cells associated with higher overall response rates and longer survival.
21LBA Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210)
The study was sponsored by Genentech, a member of the Roche group.