The phase III open-label AXIS trial comparing axitinib (Inlyta) vs sorafenib (Nexavar) as second-line treatment for metastatic renal cell carcinoma has shown a significant difference in median progression-free survival (8.3 months in the axitinib group vs 5.7 months in the sorafenib group; hazard ration [HR] = 0.656, P < .0001), which is sustained in the 2013 report of long-term follow-up.1 (Click here to see the June 10, 2013 issue of The ASCO Post for prior coverage of the AXIS trial.) However, neither the initial report2 nor the updated report1 was able to demonstrate a statistically significant difference in median overall survival between the two arms.
‘Triumphant Results’ for New Treatments
Rather than comparing survival in the two arms, it is important to look at the absolute survival numbers for both. In fact, both arms have generated median survivals of nearly 2 years (20.1 months in the axitinib group and 19.2 months in the sorafenib group; HR = 0.969, P = .374). This is actually a triumphant result for these new treatments for renal cell carcinoma, with the numerical median survivals amounting to a doubling of the historical median survival for patients with renal cell carcinoma as described in clinical reports and textbooks during the decades prior to the development of the antiangiogenic targeted therapies for renal cell carcinoma.
Granted, in this study of patients treated in second line, the population is a bit skewed by entering patients who are still eligible for a clinical trial after progressing on their first-line therapy. However, by the Memorial Sloan-Kettering Cancer Center definition of risk group, this study of over 700 patients showed 264 patients with intermediate risk characteristics, and 201 and 238 patients with favorable and poor risk characteristics, respectively. So, again, the average and median risk remains intermediate, with a historical survival on therapy of 10 months.
In this particular trial, the survival improvement over historical data appears to reflect the development of multiple active therapies, including cytokines, antiangiogenic tyrosine kinase inhibitors, and mTOR inhibitors, which are now being used in sequence, and which all appear to have an additional level of activity against renal cell carcinoma when used in a sequential fashion.
Difference in Survival Less Surprising, More Promising
In the AXIS trial, patients who were treated with axitinib had improved progression-free survival compared with sorafenib whether their prior therapy was a cytokine or another antiangiogenic agent, demonstrating some ability to respond again to inhibition of angiogenesis with a subsequent agent after a “treatment break.” Additionally, those with the longest duration of progression-free survival on their first agent had the longest progression-free survival with either axitinib or sorafenib—again demonstrating continued sensitivity to antiangiogenic therapy in some patients.
Thus, having no difference in survival between the two arms of the AXIS trial is less surprising and more promising than might appear at first glance—patients were treated with active agents on both arms, and more than half of patients on each arm went on to subsequent therapy, also with active agents. Additionally, the learning curve for managing patients on antiangiogenic agents has improved and patients are able to stay on such agents with adequate management of toxicity for longer periods of time, thereby adding to drug-related benefit.
Finally, the study pointed out an as yet hypothetical but potentially important concept: that the development of hypertension may be a biomarker of prolonged survival in patients treated with antiangiogenic tyrosine kinase inhibitors. Prospective analysis of this hypothesis is warranted in future studies.
Overall, the expectation of demonstrating a survival difference when comparing new antiangiogenic agents in renal cell carcinoma in this era of multiple active, commercially available agents may be unrealistic. We and our patients should be grateful that we can safely sequence these agents and provide continued treatment after study drugs are discontinued, leading to prolonged survival for both groups. ■
Dr. Dutcher is Associate Director, Cancer Research Foundation, and Immediate Past-Chair of the ECOG-ACRIN Renal Cancer Subcommittee.
Disclosure: Dr. Dutcher is a speaker for Pfizer, Novartis, Prometheus, and GlaxoSmithKline, an advisor for Pfizer, Prometheus, and Novartis, and serves on Data Safety and Monitoring Committees for Bristol-Myers Squibb and Merck.
References
1. 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.
2. Rini BI, Escudier B, Tomczak 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.
