Alternating therapy in renal cell carcinoma fails to show an advantage

There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.

The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.

Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.

Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).

Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).

There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.

Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.

Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.

Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.

The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.

There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.

The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.

Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.

Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).

Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).

There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.

Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.

Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.

Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.

The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.

There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.

The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.

Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.

Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).

Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).

There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.

Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.

Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.

Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.

The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.