September 2015, Vol. 2, No. 5
Pembrolizumab in Advanced Urothelial Bladder Cancer
Advanced urothelial bladder cancer (UBC) joins the list of tumor types for which treatment with pembrolizumab, a programmed death-1 (PD-1) inhibitor with dual blockade of its ligands PD-L1 and PD-L2, holds promise.
Updated safety and efficacy data from the phase 1b KEYNOTE 012 study showed an overall response rate (ORR) of 27.6% and a complete response (CR) rate of 10% in a cohort of heavily pretreated patients with advanced UBC. Responses were long-lasting for up to 64 weeks. Median overall survival (OS) of 12.7 months compares favorably with historical trials in this population. About 50% of patients in this cohort were alive at 12 months.
â€śThese results support the further development of pembrolizumab in urothelial bladder cancer and continuing investigation of novel biomarkers,â€ť said lead author Elizabeth Plimack, MD, Director, Bladder Cancer Center, Fox Chase Cancer Center, Philadelphia, PA.
Of 95 patients screened, 62.4% were PD-L1 positive (expression of â‰Ą1% PD-L1â€“positive tumor cells in tumor nests or a PD-L1â€“positive band in stroma by a prototype immunohistochemistry assay), and 33 patients were enrolled. All patients had UBC and PD-L1â€“positive tumors as per the definition above. Brain metastasis was an exclusion criterion. Patients were treated with pembrolizumab 10 mg/kg every 2 weeks until CR, disease progression, or unacceptable toxicity.
Median age was 70 years; patients were predominantly male; the majority had ECOG 1 performance status; 24% had liver metastasis; and 9% had lymph node as the only metastatic site. About one-quarter had no prior therapy; 33% had â‰Ą3 prior therapies.
Eighty-five percent of patients treated with pembrolizumab had only mild or no adverse events. Five patients experienced grade 3/4 treatment-related adverse events. â€śMany of these occurred in more than 1 patient, so the total number of grade 3 and 4 adverse events is higher than 5,â€ť Plimack explained. There was 1 treatment-related discontinuation in the trial.
Immune-related events occurred in a few patients; these included colitis, myositis, rhabdomyolysis, rash, and uveitis.
ORR was 27.6%â€”3 CRs (10%) and 5 partial responses (17.2%); stable disease was seen in 3 patients (10%), progressive disease in 14 (48.3%), and 4 could not be assessed. The disease control rate was 38% (11 patients).
Sixty-four percent of patients had a decrease in target lesions on treatment.
Median duration of follow-up was 15 months. Median time to response was 9 weeks; response duration ranged from 8.1 weeks to 64.1 weeks, and some patients are still in response. Three patients remain on therapy.
Median progression-free survival (PFS) is 2 months. PFS at 12 months is 19.1%. Median OS is 13 months, and 1-year survival is 52.9%.
In an investigative analysis of biomarkers among 18 patients with PD-L1â€“positive tumors in tumor cells only, 33% had tumor shrinkage according to RECIST; in 11 PD-L1â€“negative tumors in tumor cells only, 9% had a response according to RECIST.
When PD-L1 expression was analyzed in both tumor cells and inflammatory cells among 24 PD-L1â€“positive tumors, the response rate was 29%; among 4 PD-L1â€“negative tumors, none had a response.
â€śTo maximize detection of response and minimize false-negative findings, scoring PD-L1 in both tumor cells and tumor-associated inflammatory cells is recommended,â€ť Plimack said.
Four gene expression signatures from melanoma were analyzed in the UBC cohort: interferon-gamma, expanded immune, T-cell receptor signaling, and de novo (33 genes). Of these, only T-cell receptor signaling was associated with improved clinical benefit and prolonged response.
â€śOur findings support the further development of pembrolizumab in UBC and continuing investigation of novel biomarkers,â€ť Plimack said.
Formal discussant of this paper, Noah M. Hahn, MD, Johns Hopkins University School of Medicine, Baltimore, MD, said that the ORR of 28% with pembrolizumab was â€śpretty impressive.â€ť
â€śNearly two-thirds of patients had some response or tumor reduction, and overall survival was also impressive,â€ť Hahn noted.
The response rates to agents over the past 25 years range from 10% to 15%, and median overall survival was 10 months. â€śPembrolizumab more than doubles overall response rate, and the OS of 13 months stacks up nicely against historical treatments post platinum,â€ť Hahn noted.
Pembrolizumab was well tolerated, Hahn continued, with lower rates of grade 3/4 toxicities.
â€śWith new agents like pembrolizumab and atezolizumab, therapeutic options are expanded and outcomes are improving in UBC,â€ť he said.
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