Abstract 1286
Background
Axitinib (AXI) is approved for second-line treatment of advanced RCC. This Phase 3, randomized, double-blind trial compared the efficacy and safety of adjuvant AXI vs placebo (PBO) in patients (pts) at high risk of recurrent RCC.
Methods
Pts had undergone nephrectomy; >50% clear-cell RCC; no evidence of macroscopic residual or metastatic disease (independent review committee [IRC] confirmed). The intent-to-treat (ITT) population (pop) was all randomized pts ≥pT2 and/or N1 with any Fuhrman grade (FG) and ECOG PS 0-1. Pts (stratified by risk group and country) received (1:1) oral AXI 5 mg twice daily (BID) or PBO for up to 3 y, with min 1 y until recurrence, evidence of a second primary malignancy, significant toxicity, or consent withdrawal. Max dose increases to 10 mg BID and decreases to 1 mg BID were allowed. The primary endpoint was disease-free survival (DFS; IRC). Secondary endpoints were overall survival (OS) and safety.
Results
724 pts were included: 363 AXI and 361 PBO. Most pts were Asian (73.3%), median age 58.0 y and highest risk (56.5%; defined as pT3 with FG ≥ 3 or pT4 and/or N1 with any FG). The study was stopped due to futility at a preplanned interim analysis at 203 DFS (IRC) events. DFS in the ITT pop and highest and lower risk subpops are shown in the table. OS data were not mature (deaths: 7.7% AXI and 7.2% PBO). Median (range) treatment duration was 19.9 (0.1-37.0) mo for AXI and 21.9 (0.0-36.9) mo for PBO. More adverse events (AEs; 98.6% vs 92.5%), serious AEs (19.4% vs 14.5%), grade 3-4 AEs (61.2% vs 30.1%), dose reductions (56.2% vs 8.4%), interruptions (51.4% vs 21.7%) and discontinuations due to AEs (23.3% vs 11.1%) were reported for AXI vs PBO. The most common AE was hypertension: 64.3% and 24.5%, respectively.Table: 863O
Summary of disease-free survival
| ITT popa | Axitinib (N = 363) | Placebo (N = 361) |
|---|---|---|
| Based on IRC | ||
| Median (95% CI), y | NR (4.1-NR) | NR (4.1-NR) |
| HR (95% CI) | 0.870 (0.660-1.147) | |
| P value | 0.3211 | |
| Based on investigator assessment | ||
| Median (95% CI), y | NR (3.6-NR) | NR (4.1-NR) |
| HR (95% CI) | 0.776 (0.599-1.005) | |
| P value | 0.0536 | |
| Highest risk popb | Axitinib (N = 209) | Placebo (N = 200) |
| Based on IRC | ||
| Median (95% CI), y | NR (3.5-NR) | NR (2.5-NR) |
| HR (95% CI) | 0.735 (0.525-1.028) | |
| P value | 0.0704 | |
| Based on investigator assessment | ||
| Median (95% CI), y | 4.4 (3.4-NR) | 2.8 (1.5-NR) |
| HR (95% CI) | 0.641 (0.468-0.879) | |
| P value | 0.0051 | |
| Lower risk popb | Axitinib (N = 146) | Placebo (N = 149) |
| Based on IRC | ||
| Median (95% CI), y | NR (NR-NR) | NR (NR-NR) |
| HR (95% CI) | 1.016 (0.620-1.666) | |
| P value | 0.9483 | |
| Based on investigator assessment | ||
| Median (95% CI), y | NR (NR-NR) | NR (NR-NR) |
| HR (95% CI) | 1.048 (0.654-1.681) | |
| P value | 0.8445 |
CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Score; HR, hazard ratio; IRC, independent review committee; ITT, intent-to-treat; NR, not reached aHR and its CIs are obtained from the Cox proportional hazards model stratified by risk group. Two-sided P values based on the log-rank test stratified by risk group. bHR and its CIs are obtained from an unstratified Cox proportional hazards model. Two-sided P values based on an unstratified log-rank test. ITT pop included all randomized pts ≥pT2 and/or N1 with any Fuhrman grade and ECOG PS 0-1. The highest risk pop had pT3 with Fuhrman grade ≥3 or pT4 and/or N1 with any Fuhrman grade. The lower risk pop had pT2 or pT3 with Fuhrman grade ≤2.
Conclusions
In ATLAS, there were no significant differences between AXI and PBO for DFS in the ITT pop and lower risk subpop, whereas a significant difference for DFS per investigator was seen in the highest risk subpop. No new safety signals were seen in pts at high risk of recurrent RCC.
Clinical trial identification
NCT01599754.
Legal entity responsible for the study
SFJ Pharma and Pfizer.
Funding
SFJ Pharma and Pfizer.
Editorial Acknowledgement
Medical writing support was provided by Anne Marie McGonigal, PhD, of Engage Scientific Solutions, and funded by Pfizer.
Disclosure
M. Gross-Goupil: BMS, Ipsen, Novartis, Pfizer, Roche. R. Debenedetto, R. Linke: Employee of SFJ Pharmaceuticals. M. Casey, B. Rosbrook, M.J. Lechuga Frean, O. Valota: Employee of Pfizer Inc. E. Grande: Advisory board services and honoraria: Pfizer, BMS, Roche, EUSA Pharma, Astra Zeneca. D.I. Quinn: Advisory board services and honoraria: Pfizer, Bayer, Novartis, BMS, Merck, Exelixis, Genentech, Roche, Janssen, Astra Zeneca, Astellas. All other authors have declared no conflicts of interest.