With a new tyrosine kinase inhibitor joining the armamentarium, the question is how to optimize targeted agents for advanced renal cell carcinoma.

The AXIS trial demonstrated strong clinical activity for axitinib, which was superior to second-line sorafenib (Nexavar) and generally appears most similar to sunitinib (Sutent), according to William Oh, MD, of the Tisch Cancer Institute, Mount Sinai School of Medicine, New York.

Relative Treatment Options

“One of the impressive findings in the AXIS trial was that axitinib was clearly well tolerated,” he noted. Median relative dose intensity was higher and treatment-related discontinuations were fewer than with sorafenib. “I think of sorafenib as an ‘easier’ tyrosine kinase inhibitor than sunitinib, but axitinib was even better tolerated,” he observed. While more hypertension and hypothyroidism occurred with axitinib, sorafenib produced more hand-foot syndrome, rash, and alopecia.

The question now is how to position axitinib among the treatment options. In AXIS, the most “dramatic” responses were in patients previously treated with cytokines (35% of the cohort), whose progression-free survival was 12.1 months, vs 6.5 months with sorafenib (P < .0001). “But patients typically no longer receive cytokines; therefore, the more relevant issue is how patients previously treated with sunitinib (54% of the cohort) will respond,” he said. In this subset, median progression-free survival was 4.8 months vs 3.4 months, respectively (P = .011). Those previously treated with bevacizumab (Avastin) or temsirolimus (Torisel) were too few in number for analysis.

New Standard of Care?

Should axitinib become the new second-line standard of care? “Maybe,” he said. Only everolimus is backed by level 1 evidence, after primary tyrosine kinase inhibitor therapy. Should axitinib become FDA-approved, it would also have level 1 evidence support. While both drugs produced strong hazard ratios and progression-free survival rates in clinical trials, the RECORD-1 everolimus (Afinitor) study lacked an active control, and therefore, the drugs’ efficacy cannot be compared. The optimal sequence of tyrosine kinase inhibitor and mTOR inhibitor, therefore, remains unknown.

“So far, the phase III studies have not told us what to do with the typical patient in the second-line setting…. The strongest argument for using axitinib may be its relatively favorable toxicity profile. The progression-free survival benefit was statistically significant. Whether it is clinically significant for your patients remains to be seen,” Dr. Oh concluded. ■