Tivozanib Could Be Evaluated in Combination Regimens for Renal Cell Carcinoma
May 20, 2020 04:00am
By Vivek Subbiah, MD
Cabozantinib achieved improvements in the progression-free survival, overall survival, and objective response rate in patients with previously treated advanced renal cell carcinoma compared with everolimus, according to data from the phase III METEOR study.
Cabozantinib (Cabometyx) achieved improvements in the progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with previously treated advanced renal cell carcinoma (RCC) compared with everolimus (Afinitor), according to data from the phase III METEOR study (NCT01865747).
PFS, OS, and ORR were improved across 3 age groups as well, including patients under the age of 65 years, 65 to 74 years, and 75 years or older. There were no significant differences, however, between the age groups.
“Overall, the incidence of baseline characteristics associated with prognosis, such as prior nephrectomy, IMDC risk group and presence of bone metastases, was similar across the age subgroups in this study, although a higher proportion of patients with more favorable ECOG PS was observed in the younger age subgroups,” wrote the study authors led by Frede Donskov of Aarhus University Hospital in AarhusDenmark. “The consistency of these results across subgroups supports efficacy for cabozantinib in each age group.”
The median PFS was 7.4 months with cabozantinib compared with 3.8 months in the control arm for patients below the age of 65 years (HR, 0.53; 95% CI, 0.41-0.68). Among patients between the age of 65 and 74, the median PFS was 8.1 months versus 3.9 months with cabozantinib versus control (HR, 0.53; 95% CI, 0.37-0.77), and the median PFS was 9.4 versus 4.4 months in patients of 75 years or older, respectively (HR, 0.38; 95% CI, 0.18-0.79).
The ORR was 15% with cabozantinib (95% CI, 11-21) versus5% with everolimus (95% CI, 2-8) in the <65 years category, 21% (95% CI, 13-29) versus 2% (95% CI, 0-7) in the 64 to 74 year category, and 19% (95% CI, 6-38) versus 0 for the ≥75 years category, respectively. Overall, a higher ORR was observed with cabozantinib compared with everolimus.
The median OS was 21.4 months versus 17.1 months with cabozantinib versus everolimus (HR, 0.72; 95% CI, 0.54-0.95) for patients 65 years or younger. Median OS was not reached with cabozantinib in the 65 to 74 years arm while everolimus included a median OS of 18.0 months (HR, 0.66; 95% CI, 0.44-0.99). The median OS in the oldest group of patients was 18.4 months with cabozantinib versus 14.0 months with everolimus (HR, 0.57; 95% CI, 0.28-1.14).
Overall, 57% of patients in the cabozantinib arm versus 61% in the control arm received systemic anticancer therapy in the <65 years arm, while 36% versus 48% in the 65 to 74 years arm and 52% versus 44% of the 75 years and older arm received systemic anticancer therapy, respectively.
The median duration of exposure to cabozantinib was 7.5 months, 11.1 months, and 5.6 months in the <65, 65 to 74, and ≥75 years arms, compared with 5.4 months, 3.9 months, and 3.7 months on everolimus, respectively. Dose reductions were needed in 60% versus 22% in the <65 arm, 61% versus27% in the 65 to 74 arm, and 85% versus 36% in the 75 and over arm with cabozantinib versus everolimus, respectively. Treatment discontinuation due to adverse events (AEs) was also more common in the older patients. More patients in the oldest group discontinued cabozantinib due to either fatigue or asthenia than the younger groups.
Grade 3/4 AEs were observed in 134 of the 197 (68%) patients versus 116 of 193 (60%) patients <65 years, 80 of 107 (75%) patients versus 56 of93patients 65 to 74 years, and 21 of 27 (78%) patients versus 21 of 36 patients ≥75 years in the cabozantinib arms versus everolimus arms, respectively.
Grade 3/4 AEs differing by ≥10% between at least 2 age groups for patients treated with cabozantinib were hypertension (26 [13%] in the youngest group, 16 [15%] in the middle ages group and 7 [26%] in the oldest group), fatigue (16 [8%] in the youngest group, 12 [11%] in the middle ages group and 8 [30%] in the oldest group), asthenia (6 [3%] in the oldest group, 5 [5%] in the middle ages group and 4 [15%] in the oldest group) and hyponatremia (4 [2%] in the youngest group, 6 [6%] in the middle ages group, and 5 [19%] in the oldest group).
In the international, open-label METEOR trial, patients were randomized 1:1 to receive either cabozantinib at 60 mg once daily or everolimus at 10 mg once daily. The primary end point of the study was PFS, and secondary end points include OS, ORR, and safety.
Patients were required to have advanced or metastatic clear cell RCC and measurable disease per RECIST criteria. Patients also had to have previous treatment with at least 1 VEGFR tyrosine kinase inhibitor and have progressed within 6 months of their most recent VEGFR TKI therapy, as well as within 6 months of randomization. Patients also had to have a Karnofsky performance status of at least 70% and adequate organ function. Patients with clinically significant cardiovascular, gastrointestinal, or infectious comorbidities were ineligible to participate in the trial.
“Treatment with cabozantinib improved PFS, OS,and ORR in patients with advanced RCC compared with everolimus in all age subgroups in this retrospective analysis, supporting the use of cabozantinib in all age categories. However, older patients more frequently discontinued or required dose reductions due to AEs. Older patients may benefit from proactive dose modification and supportive care to mitigate AEs while retaining efficacy,” the study authors concluded.
Donskov F, Motzer RJ, Voog, et al. Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma [Published Online].European Journal of Cancer. DOI: 10.1016/j.ejca.2019.10.032.