Alternating Pazopanib, Everolimus Not Supported In Metastatic Clear Cell RCC

Single-agent vascular endothelial growth factor inhibitor therapy remains the optimal choice in the first-line setting of metastatic clear cell renal cell carcinoma

medwireNews: A rotating regimen of pazopanib and everolimus does not improve outcomes or quality of life, or reduce toxicity, relative to continuous pazopanib in patients with treatment-naïve metastatic clear cell renal cell carcinoma (RCC), finds a Dutch research team.

“First-line treatment with single-agent vascular endothelial growth factor inhibitor until progression remains the first choice” in this patient population, say Emile Voest, from the Netherlands Cancer Institute in Amsterdam, and colleagues.

At the 1-year mark, the primary endpoint of survival until first progression or death was achieved by 45% of 52 patients randomly allocated to receive an alternating schedule of pazopanib 800 mg/day for 8 weeks followed by everolimus 10 mg/day for 8 weeks.

This did not vary significantly from the 32% progression-free survival (PFS) rate observed for the 49 participants given the vascular endothelial growth factor inhibitor pazopanib at a dose of 800 mg/day continuously.

As reported in JAMA Oncology, the median PFS durations were likewise comparable, at 7.4 and 9.4 months, respectively.

After disease progression, patients in the rotating arm switched to either pazopanib or everolimus whereas those in the control arm were given everolimus as the second-line regimen. The groups were also comparable with respect to PFS at the time of second progression or death. The ROPETAR (Rotating Pazopanib and Everolimus to Avoid Resistance) investigators note that the difference in median PFS at this time was “relatively large”, at 20.2 versus 14.5 months for the rotating and control treatment arms, but it was not significant.

Furthermore, as assessed by the EORTC Quality of Life Questionnaire Core 30 version 3.0 and the Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease-Related Symptoms questionnaire, quality of life did not vary significantly between groups.

And neither did the alternating regimen lead to fewer adverse events, with mucositis (35 vs 8%, anorexia (39 vs 22%) and dizziness (16 vs 2%) occurring more frequently in the rotating versus control groups.

Emile Voest et al say that prior clinical and preclinical studies have supported the hypothesis that acquired resistance to targeted agents such as pazopanib can be reversed in many patients with drug withdrawal, thus providing a rationale to explore an alternating treatment schedule. They also expected a rotating regimen to have a favourable effect on tolerability and improve quality of life.

However, “[t]his study failed to translate these findings to an active treatment regimen with 8-week rotations of different targeted agents”, the study authors write.

The team believes that several questions remain unanswered, such as: “Is an interval of 2 months as chosen in the ROPETAR study optimal to reverse evolving resistance and activate an alternative resistance pathway?”


Cirkel GA, Hamberg P, Sleijfer S, et al. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer. The ROPETAR randomized clinical trial. JAMA Oncol; Advance online publication 1 December 2016. doi:10.1001/jamaoncol.2016.5202

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