Andrea B. Apolo, MD
The investigational anti-PD-L1 antibody avelumab demonstrated antitumor activity with an acceptable safety profile in a phase Ib trial of patients with metastatic urothelial cancer refractory to standard therapy.
Responses to avelumab were reported in patients with visceral metastasis, “a population typically associated with poor prognosis,” said Andrea B. Apolo, MD, at the 2016 Genitourinary Cancers Symposium. “It’s very exciting that we’re seeing clinical activity in patients that otherwise don’t have options for therapy. Metastatic bladder cancer is a devastating disease with very limited treatment options,” she said.
Preliminary data on the use of PD-L1 inhibitors in metastatic urothelial cancer have shown encouraging clinical activity and favorable toxicity in patients with enriched PD-L1 expression, and PD-L1 expression on infiltrating immune cells within the tumor have been associated with higher response rates in this disease, said Apolo, clinical investigator, at the National Cancer Institute.
“We know that bladder cancer is an immunogenic tumor. We have been using immunotherapy for bladder cancer for years, but more in the localized non-muscle invasive setting, so now we’re learning a lot more about how active it is in the metastatic setting,” she said.
The phase Ib study included 44 patients with histologically or cytologically confirmed metastatic urothelial cancer that progressed after at least one platinum-containing regimen for unresectable or recurrent disease as well as patients who were cisplatin-ineligible. They received avelumab at a dose of 10 mg/kg as a 1-hour IV infusion every 2 weeks. Patients were not preselected for PD-L1 expression. Treatment was continued until progression, unacceptable toxicity, or any criterion for withdrawal occurred.
The median duration of treatment was 13 weeks, and the median number of doses administered was 6.5. Median follow-up was 3.5 months. Sixteen patients remained on treatment.
There were seven responses (15.9%) by RECIST criteria, and one of these responses was a complete response. The other six responses were partial responses. The median duration of response was not reached, and six of the seven responses were ongoing at the time of data analysis.
The proportion of patients alive and free of progression at 12 weeks was 47.2%. Eight patients (18.2%) had tumor shrinkage of at least 30%, including in patients with visceral metastasis.
Clinical activity was associated with PD-L1 expression. The objective response rate was 40% (4/10) in PD-L1-positive patients (using a ≥5% cutoff) compared with 9.1% (2/22) in PD-L1-negative patients.
“The median progression-free survival [PFS] wasn’t reached for the PD-L1-positive patients, and for the PD-L1-negative, it was 12 weeks,” said Apolo. “The PFS at 12 weeks was 70% versus 45.5% for the PD-L1-negative. There does seem to be a trend that when you are PD-L1-positive, there is a higher response, but even if they’re PD-L1-negative, these patients are still responding. So it’s not the ideal biomarker yet.”
Avelumab is the third immunotherapy reported to have activity in advanced urothelial carcinoma, the others being atezolizumab and pembrolizumab. The 16% response rate with avelumab is very similar to the 15% response rate observed with atezolizumab in a study of all comers with advanced bladder cancer.
“Avelumab as opposed to the other agents has antibody-dependent, cell-mediated cytotoxicity, so it actually can kill tumor cells themselves, so that also may be contributing to some of the activity we’ve seen,” said Apolo. “It’s very different because none of the other agents has this.”
The most common treatment-emergent adverse events were infusion-related reactions, fatigue, nausea, asthenia, pyrexia, diarrhea, and pruritus. Overall, 59.1% had treatment-emergent adverse events, with most being grade 1 or grade 2.
“We’re expanding this trial to 100 more patients to have more data in terms of the activity, and we’re also going to be starting a randomized study in the maintenance setting in patients that received chemotherapy in the first line,” she said.
Apolo AB, Infante JR, Hamid O, et al. Safety, clinical activity, and PD-L1 expression of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic urothelial carcinoma from the JAVELIN Solid Tumor phase Ib trial. J Clin Oncol. 2016;34 (suppl 2S; abstr 367).
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