PFS Not Significantly Better With First-Line Axitinib Versus Sorafenib in mRCC

Thomas E. Hutson, DO, PharmD

As first-line therapy for patients with metastatic renal cell carcinoma (mRCC), axitinib did not demonstrate superiority over sorafenib on the endpoint of progression-free survival (PFS) in an open-label phase III trial. Although the median PFS was 3.6 months longer with axitinib, when adjusted for performance status, the difference between the two treatment groups failed to reach statistical significance, said Thomas E. Hutson, DO, PharmD, at the 2013 Genitourinary Cancers Symposium held February 14-16 in Orlando, Florida.

In the multicenter, randomized trial, 288 patients with untreated measurable, clear-cell mRCC, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomly assigned in a 2:1 ratio to axitinib, 5 mg twice daily, or sorafenib, 400 mg twice daily, as first-line therapy. Patients assigned to axitinib had their dosage titrated to 7 mg and then 10 mg twice daily if they did not have grade 3 or 4 axitinib-related adverse events for a consecutive 2-week period. Randomization was stratified by ECOG performance status. The primary endpoint was PFS as determined by an independent radiology committee.

The portion of the trial comparing the two agents as first-line therapy was added to an ongoing phase III trial of axitinib and sorafenib as second-line therapy.

The median PFS was 10.1 months in those assigned to axitinib versus 6.5 months in those assigned to sorafenib. The hazard ratio (HR) adjusted for performance status was 0.767, with a 95% CI, 0.56-1.05, rendering it not significant. The statistical design had a high bar, requiring an HR of 0.56, noted Hutson, Director of Genitourinary Oncology at the Baylor Charles A. Sammons Cancer Center in Dallas, Texas.

A significant difference in PFS between groups was observed in two subgroups.

• In patients with nephrectomy, median PFS was 10.3 months in the axitinib group versus 6.4 months in the sorafenib group (unstratified HR = 0.67; P = .009).
• In patients with a ECOG performance status of 0, median PFS was 13.7 months versus 6.6 months in favor of axitinib (unstratified HR = 0.64; P = .022).

In patients with ECOG performance status of 1, the median PFS with axitinib versus sorafenib was 6.5 versus 6.4 months, respectively (HR = 0.931; P = .38). Ninety percent of the patients enrolled were not from the United States, possibly influencing assessment of ECOG performance status, said Hutson.

The objective response rates (ORR) were 32.3% with axitinib and 14.6% with sorafenib (P = .0006 adjusted for performance status). Researchers are awaiting mature overall survival data.

Dose interruption occurred in 72% of the axitinib group and 78.1% of the sorafenib group. Treatment was interrupted due to adverse events in 49.7% assigned to axitinib and 45.8% assigned to sorafenib.

“Seventy percent of patients were able to dose titrate in the axitinib arm based upon protocol guideline. This resulted in a median daily dose of 12.7 mg…yielding a dose intensity of almost 125%,” noted Hutson. The relative dose intensity of sorafenib was 98% (starting dose: 800 mg daily; median total daily dose: 797.8 mg).

‘Hypertension and diarrhea were notably more frequent with axitinib, while hand-foot syndrome was more prominent with sorafenib,” he said.

All-cause adverse events (≥20%) with axitinib versus sorafenib were diarrhea (50% vs 40%), hypertension (49% vs 29%), weight loss (37% vs 24%), fatigue (33% vs 26%), decreased appetite (29% vs 19%), palmar-plantar erythrodysesthesia (26% vs 39%), dysphonia (23% vs 10%), asthenia (21% vs 16%), and hypothyroidism (21% vs 7%).

Grade ≥3 laboratory abnormalities were uncommon in both treatment groups.

The researchers noted that while the study did not achieve statistical significance for its primary endpoint, axitinib demonstrated longer median PFS and significantly higher ORR compared with sorafenib and had an acceptable safety profile when given as first-line therapy for mRCC.

Hutson TE, Gallardo J, Lesovoy V, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal cell carcinoma (mRCC). Presented at: 4th Annual Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract LBA348.

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