Cabometyx Failed to Improve Survival in Advanced Bladder Cancer

While Cabometyx had a favorable side effect profile, it did not lead to a significant survival advantage over placebo in a clinical trial.

Post-chemotherapy Cabometyx (cabozantinib) is a tolerable treatment option for patients with advanced urothelial carcinoma (bladder cancer), though the drug did not have a significant benefit compared to placebo in the phase 2 ATLANTIS clinical trial.

Findings from the trial were presented by first author Robert J. Jones, at the 2022 American Society of Clinical Oncology Annual Meeting.

The ATLANTIS trial included patients with advanced urothelial carcinoma who underwent four to eight cycles of first-line chemotherapy, during which time they were prescreened for tissue-based biomarkers. Patients with ongoing clinical benefit after chemotherapy were offered randomization into one of several substudies based on biomarker status. Patients with a DNA repair deficiency were randomized to Rubraca (rucaparib) compared to placebo, patients who were androgen receptor biomarker-positive were randomized to Xtandi (enzalutamide) compared to placebo, and patients who were “all biomarkers negative” received Cabometyx or placebo.

Patients in the Cabometyx arm received 40 mg once daily vs matching placebo. The main goal of the study was progression-free survival (time from treatment until disease worsens). Secondary end points included overall survival (time from treatment until death of any cause), confirmed response rates and safety and tolerability.

Recruitment was discontinued after 61 patients were randomized due to a United Kingdom-wide recruitment hiatus beginning in March 2020 because of the COVID-19 pandemic, and also due to the presentation of data in June 2020 supporting the use of Bavencio (avelumab) in the maintenance setting.

Jones reported an average progression-free survival of 13.7 weeks with Cabometyx, compared to 15.8 weeks with placebo. Average overall survival was 75.5 weeks with Cabometyx, compared to 82.9 weeks with placebo.

Median duration of treatment was 13 cycles for Cabometyx compared to 10 cycles for placebo. Overall response rate (percentage of patients whose disease shrunk as a result of treatment) was 3.3% for Cabometyx and 6.5% for placebo.

Regarding safety, side effects seen more commonly in patients receiving Cabometyx and placebo included fatigue (56.7% and 32.2%, respectively), hypertension (43.3% and 12.9%), nausea (30% and 19.4%) and diarrhea (40.0% vs 6.5%).

“Notably, 43% of patients receiving (Cabometyx) had to reduce the dose from 40 to 20 mg, although there were no treatment discontinuations due to toxicity,” said Jones, professor of clinical research at the University of Glasgow Institute of Cancer Sciences in Glasgow, Scotland.

In his concluding remarks, Jones said, “Though underpowered, this study does not support further investigation of cabozantinib alone as a maintenance therapy after platinum-based chemotherapy in unselected patients with advanced urothelial cancer.”

Jones added that negative patient selection for DNA repair deficiency and androgen receptor biomarkers may have biased interpretation of the findings.

“Future trials should consider combining novel agents with maintenance immunotherapy,” Jones said.

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