MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.
The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.
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Dr. Margitta Retz
The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.
However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.
SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.
In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.
A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.
After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.
For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.
Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.
An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).
In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).
A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.
In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.
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Dr. Michael Staehler
Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.
He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.
The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.