cantly reduced at doses equal to or greater than 1 mg/kg/day (5-fold of human AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.
Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at plasma exposures (AUC) approximately 0.5-fold (males) and <0.1-fold (females) of those expected in humans at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately 9-fold of human AUC at the recommended dose) exhibited ovarian necrosis.
14 CLINICAL STUDIES
Study 1 was a randomized (1:1), open-label, multicenter study of CABOMETYX versus everolimus conducted in patients with advanced RCC who had received at least 1 prior anti-angiogenic therapy. Patients had to have a Karnofsky Performance Score (KPS) ≥ 70%. Patients were stratified by the number of prior VEGFR tyrosine kinase inhibitors and Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group.
Patients (N=658) were randomized to receive CABOMETYX (N=330) administered orally at 60 mg daily or everolimus (N=328) administered orally at 10 mg daily. The majority of the patients were male (75%), with a median age of 62 years. Sixty-nine percent (69%) received only one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 46% favorable (0 risk factors), 42% intermediate (1 risk factor), and 13% poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%).
The main efficacy outcome measure was progression-free survival (PFS) assessed by a blinded independent radiology review committee among the first 375 subjects randomized. Other efficacy endpoints were objective response rate (ORR) and overall survival (OS) in the Intent-to-Treat (ITT) population. Tumor assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter. Patients received treatment until disease progression or experiencing unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator.
Statistically significant improvements in PFS, OS, and ORR were demonstrated for CABOMETYX compared to everolimus (FIGURE 1 and 2 and TABLE 4 and 5).
Figure 1: Progression-Free Survival in Study 1 (First 375 Randomized)
image of Progression-Free Survival in Study 1 (First 375 Randomized)
Table 4: Progression-Free Survival in Study 1 (First 375 Randomized)
Endpoint CABOMETYX Everolimus
N = 187 N = 188
* stratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs 2 or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs 1 vs 2 or 3) as stratification factors (per IVRS data)
Median PFS (95% CI), months 7.4 (5.6, 9.1) 3.8 (3.7, 5.4)
HR (95% CI), p-value* 0.58 (0.45, 0.74), p<0.0001
Figure 2: Overall Survival in Study 1 (ITT)
image of Overall Survival in Study 1 (ITT)
Table 5. Overall Survival and Objective Response Rate in Study 1 (ITT)
Endpoint CABOMETYX Everolimus
N = 330 N = 328
* stratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs 2 or more |
