CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.
Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.
Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.
Lower Dose, Less Toxicity
A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.
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Dr. Richard J. Lee
In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.
The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.
Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.
Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.
Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.
Activity and Toxicity Persist at 100 mg
Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.
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Dr. Matthew R. Smith
Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.
The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.
Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.
Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.
Randomized Trials Started
Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.