Cabozantinib Bests Everolimus in Outcomes Following Sequential Treatment With VEGFR TKIs, Checkpoint Inhibitors in RCC

Patients with advanced renal cell carcinoma (RCC) who received cabozantinib (Cabometyx) demonstrated improved clinical outcomes compared with patients who received everolimus (Afinitor) in a subgroup analysis of clinical outcomes from the phase III METEOR trial (NCT01865747).

Patients who received cabozantinib had better progression-free survival (PFS) rates, objective response rates (ORRs), and overall survival (OS) rates than patients who received everolimus, regardless of prior treatment with VEGFR tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors. The current subgroup analysis was stratified by prior therapy with sunitinib (Sutent), pazopanib (Votrient), or prior anti—PD-1/PD-L1 therapy.

Although improved survival has been demonstrated in patients with advanced RCC treated with targeted therapies, these treatments are rarely curative and over time can result in the development of resistance. The overall strategy in disease management relies on sequential treatment with VEGF-targeted agents and mTOR inhibitors.

In the study, Powles et al reported that a total of 658 patients were randomized to receive cabozantinib (n = 330) or everolimus (n = 328). Seventy-one percent (n = 235) of patients in the cabozantib arm and 70% (n = 229) of patients in the everolimus arm had received 1 prior VEGFR TKI. In this subpopulation, median PFS was 7.4 months for patients who received cabozantinib versus 3.8 months for patients who received everolimus (HR, 0.52; 95% CI, 0.41-0.66). ORR, as assessed by independent radiology committee, was 17% versus 3%, respectively, and median OS was 21.4 months for cabozantinib versus 16.5 months for everolimus (HR, 0.65; 95% CI, 0.50-0.85).

For patients who received ≥2 VEGFR TKIs, median PFS was 7.4 months for cabozantinib as compared with 4.0 months for everolimus (HR, 0.51; 95% CI, 0.35-0.74). The ORR was 17% versus 4%, respectively, and median OS was 20.8 months versus 17.2 months (HR, 0.73; 95% CI, 0.48-1.10).

When the specific type of VEGFR TKI was considered, 41% (n = 135) of patients in the cabozantinib arm and 40% (n = 132) of patients in the everolimus arm had received sunitinib as the only prior VEGFR TKI. Twenty-seven percent (n = 88) of patients in the cabozantinib arm and 25% (n = 83) of patients in the everolimus arm had received prior pazopanib only. The researchers reported that demographics and baseline characteristics were balanced between treatment groups for patients who had received sunitinib or pazopanib as the only prior VEGFR TKI, although they noted that in the pazopanib group, patients who received cabozantinib had better ECOG performance status compared with the everolimus group (75% vs 59% had ECOG PS 0).

The improved clinical outcomes in favor of cabozantinib continued regardless of specific prior VEGFR TKI, the researchers reported. For patients treated with sunitinib as the only prior VEGFR TKI, median PFS was 9.1 months for cabozantinib versus 3.7 months for everolimus (HR, 0.43; 95% CI, 0.32-0.59). ORR was 16% versus 3% and median OS was 21.4 versus 16.5 months (HR, 0.66; 95% CI, 0.47-0.93), respectively.

Researchers reported that patients who were treated with pazopanib demonstrated a median PFS of 7.4 months for cabozantinib versus 5.1 months for everolimus (HR, 0.67; 95% CI, 0.45-0.99). In this subgroup, ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR, 0.66; 95% CI, 0.42-1.04), respectively.

Thirty-two (4.9%) patients had received prior anti—PD-1/PD-L1 therapy, 18 (5.4%) in the cabozantinib arm and 14 (4.3%) in the everolimus arm. Thirty-one patients received nivolumab (Opdivo) and 1 patient received atezolizumab (Tecentriq). Median OS was not reached for cabozantinib versus 4.1 months for everolimus (HR, 0.22; 95% CI, 0.07-0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR, 0.56; 95% CI, 0.21-1.52), respectively.

In the group who received prior sunitinib therapy, 67% of the cabozantinib-treated group reported grade 3/4 adverse events (AEs), compared with 61% in the everolimus-treated group. For patients who received previous pazopanib therapy, 73% of the cabozantinib-treated group reported grade 3/4 adverse events (AEs), compared with 62% in the everolimus-treated group. In the group previously treated with anti—PD-1/PD-L1 agents, 83% and 64% of patients reported grade 3/4 AEs, respectively.

Powles et al noted that the current subgroup analyses were consistent with results from the overall study population, in which researchers observed improvements in PFS, ORR, and OS for cabozantinib compared with everolimus regardless of prior therapy.

The researchers noted that current guidelines for advanced RCC recommend VEGFR-targeted therapy based on improved OS compared with everolimus in the frontline setting, with cabozantinib and nivolumab in the second-line setting. Further, there is no high-level evidence available regarding subsequent therapy after either agent; the subgroup analyses in this study suggest that cabozantinib is clinically active following sequential therapy with VEGFR TKIs and checkpoint inhibitors.

Reference:

Powles T, Motzer RJ, Escudier B, et al. Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma.Br J Cancer. 2018;119(6):663-669. doi: 10.1038/s41416-018-0164-0.