July 2015, Special ASCO Edition
Early Data for ANTI–PD-L1 in Urothelial Bladder Cancer
The programmed death-1 ligand 1 (PD-L1) inhibitor atezolizumab (formerly MPDL3280A) had encouraging activity in a cohort of heavily pretreated patients with metastatic urothelial bladder cancer (UBC). PD-L1 status as measured by an SP142 assay appears to be predictive of the benefit of atezolizumab in UBC, but it is not predictive of survival.
“Survival is encouraging, and responses are clinically meaningful in this phase 1a study,” said Daniel P. Petrylak, MD, Yale Cancer Center, New Haven, CT.
Patients who were the higher expressors of PD-L1 (ie, immunohistochemistry [IHC]2 and IHC3) had 1-year overall survival (OS) rates of 57% and 38%, respectively.
UBC is a disease of high mutational complexity and immunogenicity, Petrylak explained. Atezolizumab was designed to restore T-cell–mediated antitumor activity and enhance T-cell priming. Metastatic UBC is associated with poor outcomes. There are no FDA-approved therapies for relapse after platinum-based therapy, and OS is 5 to 7 months in the second-line setting.
“Since PD-L1 is expressed in many tumors, we were justified in doing a phase 1 trial in many solid tumors. These included triple-negative breast cancer, melanoma, non–small cell lung cancer, renal carcinoma, and UBC. At first, the phase 1 study enrolled only PD-L1 expressors, and then we took all comers,” he said.
He reported results from an ongoing dose-expansion phase of the study that included 205 patients who were screened using the highly specific SP142 assay to measure PD-L1 using 4 IHC scoring levels. Twenty-seven percent of patients had IHC2/3 expression (high levels).
In the UBC cohort (85 patients), median age was 66 years, 79% had visceral metastases, and 37% had liver metastases. Adverse events were generally well tolerated with no treatment-related deaths. Five percent of patients had immune-mediated grade 3/4 events. Overall, 40% had a grade 3/4 adverse event of any cause.
The overall response rate (ORR) was 50% for IHC2/3 patients. Patients with low levels of PD-L1 had an ORR of 17%. Responders included patients with visceral metastases at baseline, with an ORR of 32%. A waterfall plot showed that 44 of UBC patients (55%) had reduced tumor burden.
Median duration of treatment has not yet been reached in IHC2/3 patients.
“We see long-term responses in both low and high expressors of PD-L1,” Petrylak said.
Median time to response was 62 days. Median OS is between 10 and 14 months, Petrylak said.
Formal discussant of this trial, Noah M. Hahn, MD, Johns Hopkins University School of Medicine, Baltimore, MD, said that the ORR of 34% for the entire population of this poor-prognosis, heavily pretreated cohort is “independent of marker status and impressive.”
PD-L1 is not panning out as a biomarker for atezolizumab. “For right now, we have no marker for treatment selection,” Hahn said.
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