Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial

Abstract

BackgroundThe ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy.Patients and methodsIn 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.ResultsA 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.ConclusionsATLAS 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.Trial registration numberNCT01599754

Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives

“…The ATLAS trial compared axitinib versus placebo in patients with ≥pT2 and/or N+, any Fuhrman grade RCC with primary end‐point DFS with a subanalysis of DFS highest‐risk subpopulation (pT3, Fuhrman grade ≥3 or pT4 and/or N+, any T, any Fuhrman grade); 724 patients (363 axitinib vs 361 placebo) were randomized, and the trial was stopped due to futility. There was no significant difference in DFS (HR 0.87, 95% CI 0.660–1.147, P = 0.321) overall, although in the highest‐risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR, 95% CI) was observed per investigator ( P = 0.005) …”

“…There was no significant difference in DFS (HR 0.87, 95% CI 0.660-1.147, P = 0.321) overall, although in the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR, 95% CI) was observed per investigator (P = 0.005). 27 Two additional adjuvant clinical trials utilizing targeted molecular agents have closed, but the findings are not in the peer-reviewed literature. The SORCE trial randomized 1655 patients with intermediate-to high-risk localized RCC (clear and non-clear cell histology) to the TKI sorafenib or placebo.…”

Adjuvant therapy in renal cell carcinoma

“…These VEGFR TKIs showed significant antitumor activity in metastatic disease ( Fig. [27][28][29][30] [22][23][24][25][26] Four large randomized trials evaluating the efficacy of VEGFR TKIs in the adjuvant setting are discussed below (Table 4).…”

“…[27][28][29][30] This raises the question of whether the improvement in DFS observed in S-TRAC was because of the enrollment of patients who were at high risk of recurrence and thus benefited from adjuvant sunitinib. [27][28][29][30] This raises the question of whether the improvement in DFS observed in S-TRAC was because of the enrollment of patients who were at high risk of recurrence and thus benefited from adjuvant sunitinib.…”

Editorial Comment to Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives

“…Although adjuvant therapy for renal cell carcinoma (RCC) has been much anticipated, previous studies were unable to show prolonged survival of patients. The ASSURE (sunitinib or sorafenib vs placebo), PROTECT (pazopanib vs placebo) and ATLAS (axitinb vs placebo) studies failed to show prolongation of disease‐free survival (DFS) in high‐risk patients after nephrectomy. In the S‐TRAC study (sunitinib vs placebo) in patients with locally advanced RCC (pT3 and pT4), although prolongation of DFS was reported, the efficacy for prolonging overall survival was not proved .…”