Axitinib for Advanced Renal Cell Carcinoma
Axitinib for Advanced Renal Cell Carcinoma
Abstract & Commentary
By Gary Shapiro, MD, Director of Medical Oncology, Cancer Center of Western Wisconsin. Dr. Shapiro reports no financial relationships relevant to this field of study.
Synopsis:This randomized, controlled, open-label, multicenter Phase 3 trial compared axitinib with sorafenib as second-line therapy for metastatic renal clear-cell cancer. The results showed that axitinib extended progression-free survival by 2 months more than sorafenib (6.7 months vs 4.7 months), and had a superior objective response rate (19.4% vs 9.4%).
Source: Rini BI, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomized phase 3 trial. Lancet 2011;378:1931-1939.
In this 175-center international study (the AXIS trial), 723 patients with advanced renal clear-cell cancer, who had failed one previous therapy (sunitinib 54%, cytokines 35%, bevacizumab 8%, temsirolimus 3%), were randomly assigned to receive either oral axitinib (5 mg twice daily) or oral sorafenib (400 mg twice daily).
The median progression-free survival (PFS, the primary endpoint of the study) was 6.7 months with axitinib compared to 4.7 months with sorafenib (hazard ratio 0.665; 95% confidence interval [CI] 0.544-0.812; one-sided P < 0.0001). The objective response rate for axitinib also was superior to sorafenib (19.4% vs 9.4%). Patients received axitinib for a median duration of 6.4 months (range 0.03-22 months) and sorafenib for 5.0 months (range 0.03-20 months). Treatment was discontinued due to toxic effects in 14 (4%) of the 359 patients treated with axitinib and 29 (8%) of the 355 patients treated with sorafenib. The most common adverse events leading to discontinuation of axitinib were fatigue (4, 1%) and transient ischemic attack (3, < 1%), and in the sorafenib group, hand-foot syndrome (4, 1%), diarrhea (3, < 1%), and asthenia (3, < 1%).
The most common adverse events were diarrhea, hypertension, fatigue, decreased appetite, and nausea. Higher rates of gastrointestinal events, fatigue, asthenia, hypertension, hypothyroidism, and dysphonia were observed with axitinib than with sorafenib. However, axitinib had lower rates of dermatologic adverse events and anemia than sorafenib.
Nonfatal serious adverse events occurred in 34.8% of patients in the axitinib group and 32.7% in the sorafenib group. More treatment-related deaths occurred with axitinib than with sorafenib (2.5% vs 1.1%).
Commentary
In recent years, treatment options for patients with advanced renal cell cancer have expanded with the approval of several new targeted agents. These fall into two major groups based on their mode of action. Drugs that target vascular endothelial growth-factor receptors (VEGFR) include sorafenib, sunitinib, and pazopanib, and the VEGF antibody bevacizumab, temsirolimus, and everolimus target rapamycin (mTOR).
Axitinib, a new small-molecule tyrosine kinase inhibitor that targets VEGF receptors 1, 2, and 3, is an appealing alternative to the less potent and less selective first-generation VEGFR inhibitors. On January 27, 2012, the FDA approved axitinib as the seventh drug since 2005 for the treatment of advanced kidney cell cancer, based solely on the Pfizer-funded AXIS trial.1 Although the AXIS data are compelling, it will be up to clinicians, patients, their families, and those bearing the cost of this new treatment to answer (what may well be in fact) the million dollar question: In the absence of overall survival data, is a statistically significant additional 2 months of PFS really all that significant?
In patients previously treated with cytokines, median PFS was 12.1 months for axitinib and 6.5 months for sorafenib. Results in the sunitinib-refractory subgroup also favor axitinib, but with a reduced median PFS (4.8 months for axitinib and 3.4 months for sorafenib). This suggests that even after failure of VEGFR targeted therapy, metastatic renal cell cancer remains sensitive to VEGFR inhibition; or one could simply conclude that the impact of drugs that target the VEGFR is greatest the first time around, and that second-line targeted therapy is relatively ineffective in those patients who already received VEGFR inhibition therapy.
The AXIS study did include one very important outcome parameter that is frequently overlooked in cancer treatment studies a quality-of-life assessment. Using self-reported patient data from the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI)2 questionnaire, the authors added "symptom worsening" as an outcome variable. The primary endpoint was time to "symptom deterioration," a composite endpoint of death, progression, or symptom worsening. Axitinib was associated with a 17% reduction in risk for symptom deterioration compared with sorafenib. How these patients would have fared without any specific antitumor therapy is not known, and we are left to infer benefit from a 2008 Phase 3 study that showed improved PFS in advanced renal cell cancer patients treated with second-line sorafenib compared to placebo-treated patients.3
As in the AXIS trial, the sorafenib vs placebo study used the FKSI questionnaire to assess quality-of-life outcomes. Sorafenib treatment delayed the time (approximately 37 days) to self-reported health status deterioration. The quality of life of placebo-treated patients deteriorated more quickly than that of sorafenib-treated patients. In addition, sorafenib-treated patients maintained or improved their quality of life at a later stage in therapy than placebo-treated patients.
Although these quality-of-life data are interesting, it is hard to put the axitinib vs sorafenib "17% reduction in risk for symptom deterioration" into perspective when one considers the differences found between sorafenib and placebo-treated patients, especially without information about overall survival rates in the AXIS trial. Similarly, although there clearly appeared to be a time to progression advantage for axitinib vs sorafenib (especially in those VEGFR inhibitor therapy naive), we don't know the true cost effectiveness of these marginal improvements. The safety profile for axitinib was different but not necessarily better than that of sorafenib, though these differences may be important for clinicians who want to switch from one drug to another in a patient having problems with one drug.
The AXIS trial authors promise to "elucidate the utility of axitinib vs sorafenib" when the data are mature enough to report overall survival rates. Only then will we know if the treatment of patients with advanced renal cell caner is truly improved by this intriguing, and expensive, new VEGFR inhibitor.
References
1. FDA Drug Approvals and Databases. Last modified: January 27, 2012. Available at: www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289439.htm. Accessed Feb. 16, 2012.
2. Cella D. Development and validation of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). J Support Oncol 2006;4:191-199.
3. Eisen T. Sorafenib for older patients with renal cell carcinoma: Subset analysis from a randomized trial. J Natl Cancer Inst 2008;100:1454-1463.
This randomized, controlled, open-label, multicenter Phase 3 trial compared axitinib with sorafenib as second-line therapy for metastatic renal clear-cell cancer. The results showed that axitinib extended progression-free survival by 2 months more than sorafenib (6.7 months vs 4.7 months), and had a superior objective response rate (19.4% vs 9.4%).Subscribe Now for Access
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