Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) is continuously evolving, with several new first-line (1L) and second-line (2L) treatment options. In the AXIS trial, axitinib resulted in significantly longer progression-free survival (PFS) vs sorafenib in the 2L treatment of mRCC. In these post-hoc exploratory analyses of AXIS, possible key drivers for successful 2L treatment with axitinib after sunitinib were evaluated. Methods: AXIS was an open-label, randomized, phase III trial (NCT00678392) in patients (pts) with mRCC who failed 1 prior systemic therapy. Univariate and multivariate analyses evaluated potential predictive factors for improved PFS (investigator-assessed) and overall survival (OS) with axitinib. PFS (independent review), OS and objective response rate (ORR) for axitinib vs sorafenib according to these predictive factors were assessed. Results: In all, 389 pts received 1L sunitinib: 194 and 195 pts received 2L axitinib and sorafenib, respectively. Based on multivariate analyses of PFS and OS, predictive factors favoring 2L axitinib treatment were identified as: non-bulky disease (sum of the longest diameter < 98 mm), favorable/intermediate (Fav/Int) risk (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), no bone and no liver metastases. Thus, pts were grouped according to these factors. In pts with favorable risk factors (n = 86), a significantly longer median (95% confidence interval [CI]) PFS was observed in axitinib (n = 39; 13.9 [7.8–17.7] mo) vs sorafenib pts (n = 47; 4.7 [3.5–6.7] mo; hazard ratio [HR] 0.476 [95% CI 0.263–0.863]; P= 0.0126). Median (95% CI) OS (32.4 [23.8–not evaluable] mo vs 35.0 [23.9–35.0] mo; HR 0.902 [95% CI 0.457–1.780]; P= 0.7661) and ORR (both 12.8%) were similar between the 2 groups. More pts had stable disease ≥20 weeks with axitinib (38.5%) vs sorafenib (21.3%). Conclusions: In the continuously changing treatment landscape for mRCC, axitinib remains a suitable 2L treatment option, particularly in pts with non-bulky disease, Fav/Int risk and no bone nor liver metastases, characterized by an impressive PFS. Clinical trial information: NCT00678392