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ASCO: Two hits and a miss against advanced urothelial cancer


 

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CHICAGO – Immunotherapies showed their mettle against advanced urothelial cancers in two clinical trials presented at the annual meeting of the American Society of Clinical Oncology, but the targeted agent lapatinib was a total bust as maintenance therapy following chemotherapy in patients with HER1/HER2-positive metastatic bladder cancers.

Dr. Daniel P. Petrylak Neil Osterweil/Frontline Medical News

Dr. Daniel P. Petrylak

In a phase Ia trial of an investigational monoclonal antibody (atezolizumab; MPDL3280A)) targeted against the programmed death ligand 1 (PD-L1, also targeted by pembrolizumab [Keytruda]), the overall response rate (ORR) among patients with heavily pretreated urothelial bladder cancer whose tumors had high levels of PD-L1 expression was 50%, and the 1-year overall survival (OS) rate was 57%, reported Dr. Daniel P. Petrylak from the Yale Cancer Center in New Haven, Conn.

Dr. Elizabeth Plimack Neil Osterweil/Frontline Medical NEws

Dr. Elizabeth Plimack

In a separate trial, also in a heavily pretreated population, pembrolizumab, which blocks both PD-L1 and PD-L2, was associated with a 28% ORR, a 10% complete response rate (CR), and 1-year overall survival of 50%, said Dr. Elizabeth Plimack from the Fox Chase Cancer Center, Philadelphia.

Dr. Noah N. Hahn Neil Osterweil/Frontline Medical News

Dr. Noah N. Hahn

“I would say we are so far past the end of the old era of cytotoxic, nonselected trials, that we can’t even see it in the rearview mirror anymore,” said Dr. Noah M. Hahn from the Johns Hopkins Medical Institutions, Baltimore, commenting on the immunotherapy abstracts. Dr. Hahn was the invited discussant.

But at the same oral abstract session, results of a phase II/III double-blind, randomized trial comparing maintenance lapatinib (Tykerb) with placebo following chemotherapy for metastatic HER1/HER2-positive bladder cancer showed absolutely no benefit from the drug, no matter how the data were sliced, dissected, or rearranged, reported Dr. Thomas Powles from the Barts Cancer Institute at Queen Mary University of London.

“We desperately need new drugs here,” Dr. Powles said.

Atezolizumab trial

“Metastatic urothelial bladder cancer [UBC] is associated with poor outcomes. There are no FDA-approved therapies for patients who relapse after platinum-based therapy, and the overall survival is approximately 5-7 months. Urothelial bladder cancer has a high mutational load, due to tobacco and environmental carcinogen exposures. In other cancers, high somatic nonsynonomous mutational burden has been associated with durable clinical benefit of PD-L1/PD-1-directed therapy, thus the justification for examining this in urothelial bladder cancer,” Dr. Petrylak said.

He presented data on a cohort of 92 patients with metastatic UBC who were enrolled in a larger trial of atezolizumab against UBC and other cancers. The cohort originally included patients with high levels of PD-L1 expression on immunochemical staining (IC 2/3), but was later expanded to include all comers, the majority of whom had low or no detectable levels of PD-L1 expression (IC 0/1).

The patients received atezolizumab via intravenous administration every 3 weeks at either 15 mg/kg of body weight, or in a 1200-mg flat dose.

Responses to atezolizumab among 87 patients evaluable for efficacy correlated with PD-L1 expression, with the 12 patients in the highest quartile (IC 3) having an ORR of 67%, and 34 patients with IC2 having an ORR of 44%, for a combined ORR of 50%. This included 9 patients with a complete response, and 14 with a partial response.

In contrast, the combined ORR for patients with IC 1 or IC 0 was 17%, with no complete responses, and 7 partial responses.

Among 80 patients with postbaseline tumor assessments, 44 had a reduction in tumor burden. There was also a decrease in circulation C-reactive protein, an inflammatory marker, as well as in the tumor markers carcinoembryonic antigen and cancer antigen 19-9 among patients who had responses to atezolizumab.

Patients generally tolerated the treatment well at a median safety follow-up of 16 weeks, with no treatment-related deaths, and only one discontinuation due to a treatment-related adverse event. Grade 3 or 4 immune-mediated events occurred in 5% of patients, and included an increase in aspartate aminotransferase, increased blood bilirubin, and hypophysitis.

Pembrolizumab trial

Dr. Plimack presented updated results and a biomarker analysis from the KEYNOTE 012 study, a phase I study of pembrolizumab in patients with urothelial tract cancers as well as triple-negative breast cancer, head and neck cancer, and gastric cancer.

In the urothelial cohort, 33 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder, or urethra received pembrolizumab 10 mg/kg IV every other week until either complete response, after which therapy could be discontinued if desired; partial response or stable disease, which could be followed by 24 months of additional therapy or until disease progression or intolerable toxicity; or confirmed disease progression, whereupon treatment would stop.

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