Background: Traditional progression definitions based on the RECIST 1.1 criteria may lead to a premature declaration of progression due to tumor flare or pseudo-progression effects associated with I/O drugs, especially among patients with solid tumors (such as RCC). This analysis compared the Q-TWiST between nivolumab and everolimus, using both traditional and novel I/O-relevant definitions of progression. Methods: Using Checkmate 025 data at ≤45 months (m) of follow up, overall survival (OS) was partitioned into 3 health states: TWiST (time without symptoms of disease progression or toxicity), TOX (time with grade ≥3 toxicity after randomization but before progression), and REL (time after progression). The following REL definitions were considered to declare progression: 1) RECIST 1.1 criteria (i.e., traditional Q-TWiST); 2) increase in tumor burden of ≥25% from nadir; 3) treatment discontinuation; 4) ≥2-point reduction from baseline in Functional Assessment of Cancer Therapy-Kidney Cancer Index-Diseases related Symptoms (FKSI-DRS) score; and 5) any combination of ≥2 out of 3 criteria (traditional progression, treatment discontinuation, FKSI-DRS reduction of ≥2-points from baseline). Mean Q-TWiST was calculated by weighting the restricted mean time spent in each health state by a utility of 1.0 for TWiST and 0.5 for TOX and REL. Relative Q-TWiST gain (Q-TWIST difference divided by mean everolimus OS) was calculated. Results: Compared to everolimus, nivolumab patients had statistically significant improvements in Q-TWiST based on all definitions: 1) traditional Q-TWiST: 3.3 m (relative gain:14.4%); 2) 3.5 m (relative gain: 15.3%); 3) 4.3 m (relative gain: 18.7%), 4) 4.8 m (relative gain: 20.9%); and 5) 4.8 m (relative gain: 20.9%). Conclusions: Regardless of progression definition, nivolumab resulted in a statistically significant and clinically important gain in quality adjusted OS vs. everolimus. These gains were greater when using progression definitions that incorporate more I/O-relevant response definitions and/or treatment discontinuation information. Clinical trial information: NCT01668784