The phase III open-label AXIS trial comparing axitinib (Inlyta) vs sorafenib (Nexavar) as second-line treatment for metastatic renal cell carcinoma showed significantly prolonged independent radiology committee–assessed progression-free survival with axitinib treatment (hazard ratio [HR] = 0.665, P < .0001), leading to approval of axitinib for second-line treatment of advanced renal cell carcinoma.1 AXIS was the first phase III trial to compare an investigational targeted agent with an approved targeted agent in renal cell carcinoma.
As recently reported in Lancet Oncology by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues, overall survival, a secondary outcome measure of the trial, did not differ between treatments.2 The updated analysis showed a continued, investigator-judged, prolongation of progression-free survival with axitinib treatment.
In the trial, 723 patients with clear cell metastatic renal cell carcinoma and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had disease progression after systemic therapy received axitinib at 5 mg twice daily (n = 361) or sorafenib at 400 mg twice daily (n = 362). Baseline characteristics were similar between the two groups. Overall, 91% of patients had prior nephrectomy. Prior first-line therapy consisted of sunitinib (Sutent) in 54% of patients, cytokines in 35%, bevacizumab (Avastin) plus interferon alfa in 8%, and temsirolimus (Torisel) in 3%.
Overall Survival Analysis
As of the cutoff date for the overall survival analysis (November 1, 2011), median overall survival was 20.1 months in the axitinib group and 19.2 months in the sorafenib group (hazard ratio [HR] = 0.969, P = .374). There were no significant differences between the axitinib group and the sorafenib group in median overall survival according to first-line treatment with sunitinib (15.2 vs 16.5 months, HR = 0.997, P = .490) or cytokines (29.4 vs 27.8 months, HR = 0.813, P = .1435) or in the smaller patient subgroups who previously received bevacizumab plus interferon alfa (14.7 vs 19.8 months, HR = 1.825, P = .965), or temsirolimus (14.0 vs 8.5 months, HR = 0.459, P = .064).
After discontinuation of study treatment, 54% of the axitinib group and 57% of the sorafenib group received subsequent systemic treatment, including mammalian target of rapamycin (mTOR) inhibitors (39% and 41%) and vascular endothelial growth factor (VEGF) inhibitors (33% and 32%).
Median progression-free survival on investigator assessment was 8.3 months in the axitinib group vs 5.7 months in the sorafenib group (HR = 0.656, P < .0001). Median progression-free survival was significantly longer with axitinib in patients previously treated with sunitinib (6.5 vs 4.4 months, HR = 0.719, P = .0022) or cytokines (12.2 vs 8.2 months, HR = 0.505, P < .0001). No between-group differences were observed according to prior treatment with bevacizumab plus interferon alfa or temsirolimus. Investigator-assessed objective response rate was higher with axitinib (23% vs 12%, P = .0001)
Factors Associated with Overall Survival
On multivariate analysis, baseline factors significantly associated with overall survival were cytokine vs sunitinib treatment (HR = 0.50), ECOG performance status of 1 vs 0 (HR = 1.45), < 1 year vs ≥ 1 year from diagnosis to study treatment (HR = 1.55), > 1 vs 1 metastatic site (HR = 1.74), liver metastases (HR = 1.30), bone metastases (HR = 1.36), corrected calcium > 10 vs ≤ 10 mg/dL (HR = 2.74), alkaline phosphatase > upper limit of normal vs ≤ upper limit of normal (HR = 1.41), lactate dehydrogenase > 1.5 times upper limit of normal vs ≤ 1.5 times upper limit of normal (HR = 2.68), hemoglobin < lower limit of normal vs ≥ lower limit of normal (HR = 1.69), and neutrophils > upper limit of normal vs ≤ upper limit of normal (HR = 1.69), with P < .05 for all these comparisons.
An analysis of overall survival according to quartile of time to progression on prior sunitinib therapy in patients receiving the agent as first-line treatment suggested a relationship between shorter overall survival and shorter time to progression on sunitinib, with overall survival being lower in axitinib patients in the lower two quartiles and in sorafenib patients in the lowest quartile. As noted by the investigators, these findings “might be indicative of a more aggressive natural history, resistance to VEGF-targeted treatment, or both.”
Hypertension and Overall Survival
A post hoc landmark analysis showed that development of hypertension (diastolic pressure ≥ 90 mm Hg or systolic ≥ 140 mm Hg) within the first 8 and 12 weeks of treatment was independently predictive of overall survival in both treatment groups. For example, median overall survival was 20.7 months in patients developing diastolic pressure ≥ 90 mm Hg by 12 weeks vs 12.9 months in those with diastolic pressure < 90 mm Hg in the axitinib group (P = .012) and 20.2 vs 14.8 months in the sorafenib group (P = .002).
Multivariable analysis including baseline factors showed that among all patients, the hazard ratios for overall survival were 0.63 for diastolic pressure ≥ 90 vs < 90 mm Hg and 0.49 for systolic pressure ≥ 140 vs < 140 mm Hg (both P < .0001). These results are consistent with findings in other studies indicating that the association of treatment-induced hypertension with improved overall survival is a class effect of VEGF inhibitors. There was no significant relationship between development of hypertension and progression-free survival.
The most common treatment-related grade 3 or higher adverse events were hypertension (17%), diarrhea (11%), fatigue (10%), and hand-foot syndrome (6%) in the axitinib group and hand-foot syndrome (17%), hypertension (12%), and diarrhea (8%) in the sorafenib group. Among treatment-related adverse events of any grade, hypertension, nausea, dysphonia, and hypothyroidism were more common in the axitinib group (> 10% difference), whereas hand-foot syndrome, alopecia, and rash were more common in the sorafenib group.
Quality-of-life assessment with the Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-15) and the FKSI–Disease-Related Symptoms subscale showed little change from baseline in either group during treatment. However, quality-of-life scores in both groups decreased at the end of treatment assessment, when patients were coming off study treatment predominantly due to disease progression.
With regard to the longer overall survival observed in the subset of patients in both groups who received cytokines as first-line treatment, the investigators noted that median duration of first-line treatment was longer in those receiving sunitinib (9.5–10.1 months) than in those receiving cytokines (6.0–6.6 months). As they stated, “[T]his difference could have translated into a lead-time benefit for patients previously treated with cytokines. Additionally, patients in the prior cytokine subgroup had their first exposure to VEGF-targeted therapy during [the study] and thus did not have previous resistance to this class of agents. Patients previously treated with sunitinib, however, had already shown clinical resistance to VEGF-targeted therapy and might have had shorter overall survival after treatment with either agent.”
The investigators concluded, “Although overall survival … did not differ between the two groups, investigator-assessed [progression-free survival] remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic [renal cell carcinoma].” ■
Disclosure: The study was funded by Pfizer Inc.
References
1. Rini BI, Escudier B, Tomcak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomized phase 3 trial. Lancet 378:1931-1939, 2011.
2. Motzer RJ, Escudier B, Tomczak P, et al: Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: Overall survival analysis and updated results from a randomized phase 3 trial. Lancet Oncol 14:552-562, 2013.
