Berzosertib regimen does not extend PFS in metastatic urothelial cancer
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The addition of berzosertib to cisplatin and gemcitabine did not extend PFS among patients with metastatic urothelial cancer, according to results of a randomized phase 2 trial.
The berzosertib (M6620, Merck) regimen also appeared associated with a significantly higher rate of hematologic toxicities, even though patients in the experimental group received attenuated doses of cisplatin and gemcitabine.
“The finding that berzosertib did not improve PFS was disappointing and quite surprising,” researcher Yung Lyou, MD, assistant clinical professor in the department of medical oncology and therapeutics research at City of Hope, told Healio. “It was unexpected because the preclinical data had suggested that these agents would work synergistically to inhibit urothelial cancer growth.”
Cisplatin with gemcitabine is standard upfront therapy for patients with metastatic urothelial cancer.
Berzosertib is an ataxia telangiectasia and Rad3 (ATR) inhibitor. Preclinical studies suggested targeting ATR may increase the cancer-killing effect of cisplatin-gemcitabine chemotherapy, Lyou said.
“This study tried to answer the question: Does inhibition of ATR by adding berzosertib improve the cytotoxic effects of cisplatin-based chemotherapy for metastatic urothelial cancer?” Lyou said.
The trial included 87 patients (median age, 67 years; range, 32-84; 78% men) from 23 centers in the NCI Experimental Therapeutics Clinical Trials Network.
All patients had confirmed metastatic urothelial cancer, had received no prior cytotoxic therapy for metastatic disease, and had completed perioperative therapy at least 12 months earlier.
Researchers randomly assigned 41 patients to the control regimen, which consisted of 70 mg/m2 cisplatin on day 1 and 1,000 mg/m2 gemcitabine on days 1 and 8 of each 21-day cycle.
They assigned the other 46 patients to the experimental regimen, which consisted of 60 mg/m2 cisplatin on day 1, 875 mg/m2 gemcitabine on days 1 and 8, and 90 mg/m2 berzosertib on days 2 and 9 of each 21-day cycle. Cisplatin and gemcitabine doses in the experimental group were reduced by about 20% to compensate for toxicity from berzosertib.
PFS served as the primary endpoint.
Median follow-up was 18.9 months (interquartile range, 9.9-27.4).
Results showed median PFS of 8 months in both the experimental and control groups (unstratified HR = 1.17; 95% CI, 0.69-1.98; stratified HR incorporating Bajorin risk criteria = 1.22; 95% CI, 0.72-2.08).
Researchers reported shorter median OS among berzosertib-treated patients than those assigned the control regimen (14.4 months vs. 19.8 months; adjusted HR incorporating Bajorin risk criteria = 1.42; 95% CI, 0.76-2.68).
A higher percentage of patients assigned berzosertib experienced grade 3 or grade 4 thrombocytopenia (59% vs. 39%) and neutropenia (37% vs. 27%), resulting in a higher frequency of dose reductions in the experimental group. Median cisplatin dose was significantly lower in the experimental group than the control group (250 mg/m2 vs. 370 mg/m2; P < .001).
“Overall, it appears that the experimental combination had higher amounts of toxicity despite dose-reducing the cisplatin-gemcitabine chemotherapy by 20%,” Lyou told Healio. “The reason for this finding could be that the regimen of cisplatin and gemcitabine is already myelosuppressive, and the addition of berzosertib made it worse despite our mitigation efforts.
“Also, it could be that decreasing the dose of the cisplatin-gemcitabine chemotherapy reduced the overall cytotoxic effects on the urothelial cancer, thus decreasing its eventual clinical benefits for the experimental group,” Lyou added. “An important lesson that we learned from this trial was that excessive attenuation of cisplatin dosing should be avoided whenever feasible.”
Future studies should focus on biomarker-based designs evaluating monotherapy or combinations with less myelosuppression, researchers concluded.
“Although the negative results of this clinical trial were disappointing, we felt it was very important to publish these findings so that other clinical investigators and patients can benefit from this experience,” Lyou said.
For more information:
Yung Lyou, MD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010.
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