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.
Dear Colleague, I am writing to you with a renewed enthusiasm for the field of immunotherapy in oncology after hosting the World Cutaneous Malignancies Congress this summer! This educational opportunity is an event of which I am proud, as world-renowned experts convene to present the most up-to-date information on the [ Read More ]
Excluding cancers of the skin, breast cancer is the most frequently diagnosed cancer in women.1 An estimated 234,190 new cases of invasive breast cancer (231,840 in women and 2350 in men) are expected to be diagnosed among Americans during 2015.1 Breast cancer ranks second as a cause of cancer death [ Read More ]