‘Encouraging’ Efficacy, Safety For Atezolizumab In Advanced Urothelial Carcinoma

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medwireNews: The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab elicits durable responses and has a favourable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma, shows research published in The Lancet.

“[A]tezolizumab shows promise as a second-line treatment option” for patients who have failed prior platinum-based therapy, say the researchers, who also identified potential biomarkers of response to the immune checkpoint inhibitor.

The phase II trial included 310 urothelial carcinoma patients who were treated with intravenous atezolizumab 1200 mg given on day 1 of a 21-day cycle. Study participants were grouped into three categories according to the percentage of PD-L1–positive tumour infiltrating immune cells (ICs): IC0 (<1%), IC1 (1% to <5%) and IC2/3 (5% and above).

At the primary analysis, atezolizumab therapy resulted in an independently assessed objective response rate (ORR), as per the RECIST 1.1 criteria, of 27% for the 100 patients in the IC2/3 group, 18% for the 207 patients in the IC1 plus IC2/3 group and 15% for the entire study cohort. These rates were significantly higher than the historical control ORR of 10%.

The responses were durable, with 84% of the 45 patients who responded to treatment still doing so almost a year later.

Overall survival (OS) was a median of 11.4 months in the IC2/3 group, 8.8 months in the IC1 plus IC2/3 group and 7.9 months for all patients, with corresponding 1-year survival rates of 48%, 39% and 36%.

Noting that “higher levels of PD-L1 immunohistochemistry expression on immune cells were associated with a higher response rate to atezolizumab and longer [OS]”, the study authors suggest that “PD-L1 expression on immune cells is a potential biomarker for the selection of patients for treatment with atezolizumab.”

In addition, they also found that the tumour molecular subtype as per The Cancer Genome Atlas (TCGA) analysis and the mutational load independently predicted response to atezolizumab. Specifically, the ORR was significantly higher for the luminal cluster II subtype than for the other subtypes, at 34% versus 10% for subtype I, 16% for subtype III and 20% for subtype IV. And the median mutational load was significantly higher in patients who responded than in those who did not respond to treatment (12.4 vs 6.4 per Mb).

“Additional data and larger sample sizes are needed to allow the formal construction of a multi-biomarker classifier, and continued consideration of all three biomarkers is warranted in next-generation companion diagnostics”, sayJonathan Rosenberg, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-researchers.

In a linked comment, George Netto, from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, describes the results as “encouraging”, but points out that the “incremental” ORR improvement and “modest” median OS in the overall cohort highlight “the importance of future efforts to identify, validate, and standardise biomarkers of response.”

Atezolizumab was well tolerated in this patient population, with 16% of participants experiencing a grade 3 or 4 treatment-related side effect and 5% a grade 3 or 4 immune-mediated adverse event.

References

Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.Lancet 2016; Advance online publication 4 March. doi: http://dx.doi.org/10.1016/S0140-6736(16)00561-4

Netto GJ. Role for anti-PD-L1 immune checkpoint inhibitor in advanced urothelial carcinoma.Lancet 2016; Advance online publication 4 March. doi: http://dx.doi.org/10.1016/S0140-6736(16)00654-1

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