Axitinib Versus Placebo as an Adjuvant Treatment of Renal Cell Carcinoma

Results From the Phase III, Randomized ATLAS Trial

M. Gross-Goupil; T. G. Kwon; M. Eto; D. Ye; H. Miyake; S. I. Seo; S.-S. Byun; J. L. Lee; V. Master; J. Jin; R. DeBenedetto; R. Linke; M. Casey; B. Rosbrook; M. Lechuga; O. Valota; E. Grande; D. I. Quinn


Ann Oncol. 2018;29(12):2371-2378. 

In This Article

Abstract and Introduction


Background: The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy.

Patients and methods: In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted.

Results: A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660–1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468–0.879; P = 0.0051), and by IRC (0.735; 0.525–1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo.

Conclusions: ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported.


Renal cell carcinoma (RCC) is the most common form of kidney cancer; approximately 80% of RCCs are clear-cell tumors.[1] The 5-year survival rates by American Joint Committee on Cancer (AJCC) tumor, lymph nodes, and metastasis (TNM) staging system are 81%, 74%, 53%, and 8% for stages I, II, III, and IV, respectively.[2] Some patients with locoregional RCC have a relapse risk of up to 40%, increasing to up to 80% in patients considered to be at high risk for recurrence, and could therefore benefit from adjuvant treatment.[3,4] The success of targeted therapies in the metastatic RCC setting led to increased interest in testing these agents in the adjuvant setting. Overall five additional trials assessed the utility of targeted therapy in the adjuvant RCC setting. Of the three completed trials (ASSURE, S-TRAC, and PROTECT),[5–7] only S-TRAC met its primary end point.

S-TRAC included patients with resected ≥T3 and/or N+ clear-cell RCC at high risk for tumor recurrence after nephrectomy. Results showed that disease-free survival (DFS) was significantly longer with sunitinib treatment versus placebo: hazard ratio (HR) = 0.76; 95% confidence interval (CI) = 0.59–0.98; P = 0.03; medians, 6.8 and 5.6 years, respectively.[7] Based on S-TRAC outcomes, the US Food and Drug Administration extended sunitinib's indication to include the treatment of patients at high risk for recurrence after nephrectomy.

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. In the phase III AXIS trial in the second-line setting of metastatic RCC, significantly longer progression-free survival and higher objective response rate were reported for axitinib versus sorafenib; however, the safety profiles were similar and manageable.[8] Consequently, axitinib is approved for the treatment of advanced RCC after failure of one prior systemic therapy. Additionally, in various clinical trials, antitumor activity was observed with axitinib, both as a single agent and in combination with immunotherapy, in the first-line treatment of metastatic RCC.[9–11] Here, we report the efficacy and safety of adjuvant axitinib versus placebo in patients with ≥pT2 and/or N+ RCC from the Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients (ATLAS) trial.