In results of a phase II study, cabozantinib (Cabometyx) showed signs of activity in patients with progressive glioblastoma who were naïve to antiangiogenic therapy, despite the predefined statistical target for success not being met.
Patrick Y. Wen, MD
In results of a phase II study, cabozantinib (Cabometyx) showed signs of activity in patients with progressive glioblastoma (GBM) who were naïve to antiangiogenic therapy, despite the predefined statistical target for success not being met.
The phase II multicenter, open-label, single-agent, non-comparator trial explored 2 dose levels of cabozantinib in patients with recurrent or refractory GBM.
A total of 151 patients enrolled in the study had measurable disease at baseline. A subgroup analysis by cabozantinib starting dose demonstrated an objective response rate (ORR) of 17.6% (95% CI, 6.8%34.5%) in patients who received 140 mg/day and 14.5% (95% CI, 8.7%–22.2%) in those who received 100 mg/day, all of which were partial respones. The results for ORR did not meet the predefined statistical target for success.
The median duration of response was 5.9 months (range, 1.912.8) in the 140 mg/day group and 8.5 months (range, 1.0–9.3) in the 100 mg/day group. Overall, 90% of patients with measurable disease at baseline and ≥1 evaluable post-baseline assessment had a decrease in their tumor volume. The median follow-up for scans was 3.6 months (range, 0.03–25.0) in the 140 mg/day group and 3.6 months (range, 0.03–17.5) in the 100 mg/day group.
“Although the predefined statistical target for success was not met, cabozantinib showed evidence of clinical activity in patients with refractory or recurrent GBM who had not received prior antiangiogenic therapy. Further assessment of activity and tolerability at a lower starting dose would be necessary to better evaluate cabozantinib in this patient population,” lead investigator Patrick Y. Wen, MD, of Dana-Farber Cancer Institute, et al, concluded in their study.
A total of 222 patients were enrolled on the study between June 2008 and June 2012, with 152 patients (68%) naïve to prior antiangiogenic therapy. The patients initially received oral cabozantinib 140 mg/day (freebase weight). Due to high rates of dose reduction and interruption at the initial dose, a protocol amendment added another cohort at a reduced starting dose of 100 mg/day to allow qualitative assessment of the safety of the dose, with 15 planned antiangiogenic treatment-naïve patients. This dose was deemed appropriate based on the median average daily dose of the first cohort enrolled and initial assessments suggested continued efficacy at doses ≤100 mg/day. A second protocol amendment added an additional cohort to be enrolled at the 100 mg/day starting dose, with 80 antiangiogenic treatment-naïve patients planned. Treatment was continued until documented disease progression or unacceptable toxicity.
To be eligible for the study, patients had to be diagnosed with refractory or recurrent GBM in first or second relapse and had to have radiographic evidence of recurrent disease by gadolinium-enhanced MRI scan. Patients also were required to have received prior temozolomide (Temodar) and radiation therapy (required for patients enrolled at the 100 mg/day dose); have a Karnofsky performance status score of ≥60%; and have adequate hematologic, renal, and liver function.
The median age of patients in the 140 mg/day group (n = 34) was 55 (range, 20-73), and the median age of patients in the 100 mg/day group (n = 118) was 56.5 (range, 21-82). The majority of patients in both groups had a Karnofsky performance status of 90 to 10022 patients (64.7%) in the 140 mg/day group and 74 patients (62.7%) in the 100 mg/day group. Eleven patients (32.4%) in the 140 mg/day group and 44 patients (37.3%) in the 100 mg/day group had a performance status of 70 to 80, and 1 patient (2.9%) in the 140 mg/day group had a performance status of ≤60. Approximately one-third of patients received >1 prior systemic therapy before study entry.
The primary endpoint of the study was ORR using the modified Response Assessment in Neuro-Oncology (RANO) criteria as assessed by an independent radiology facility (IRF). Secondary endpoints included duration of response, 6-month and median PFS, OS, and glucocorticoid use.
Adverse events (AE) were generally manageable with dose reductions or dose interruptions. Dose reductions due to an AE were required in 21 patients (61.8%) in the 140 mg/day group and 85 (72.0%) in the 100 mg/day group. AEs resulted in treatment discontinuation in 6 (17.6%) patients in the 140 mg/day group and 22 (18.6%) patients in the 100 mg/day group.
The most common treatment-emergent AEs across both dose levels included fatigue (76.3%), diarrhea (62.5%), decreased appetite (47.4%), palmar-plantar erythrodysesthesia syndrome (39.5%), nausea (38.8%), headache (36.8%), constipation (34.2%), hypertension (32.2%), weight decrease (31.6%), and dysphonia (30.9%).