Background: Higher SUN exposure is associated with better outcomes. Patients (pts) with minimum toxicity on the standard schedule do worse than pts needing dosing changes for toxicity. Methods: It was hypothesized that toxicity-driven dose/schedule individualization would improve the primary endpoint (PFS) from 8.5 (EFFECT trial) to 14 months (mo), with 99 pts required to detect this with 90% power and 2-sided alpha = 0.05. In a prospective phase II study (eligibility as EFFECT) pts start on 50 mg/day (d) for 28 d with treatment (Rx) breaks reduced to 7 d. If grade-2 toxicity develops before d 28, pts stay on a 50 mg on the next cycle with the number of d on Rx individualized aiming for ≤ grade-2 toxicity. Dose is reduced to 37.5 mg and then 25 mg if pts do not tolerate a 50 mg or 37.5 mg dose respectively for at least 7 d. Pts with minimum toxicity on d 28 are escalated to 62.5 mg and then 75 mg. Results: 117 pts were enrolled in 12 centers. Nine non-evaluable pts came off early due to toxicity (5), non-compliance (2) and global deterioration (2). Of 108 pts evaluable for response (IMDC favorable 31.5%, intermediate 58.3%, poor 10.2%. Bone mets 19%, Nephrect 83%), 10 are still on Rx. Dose was escalated in 20 pts (18.5%) to 62.5 mg (12 pts) and then to 75 mg (8 pts). In 49 pts (45.4%) eligible for dose reduction by standard criteria, a 50 mg dose was maintained but for 7 - 24 d, while 7 pts (6.5%) stayed on a 28 d schedule. Dose was reduced to 37.5 mg in 22 pts (20.4% vs. 36 - 63% in 4 large SUN trials) and to 25 mg in 10 pts (9.3% vs. 27 - 43% in 4 trials). Rx was stopped due to toxicity in 10/117 pts (9.3% vs. 15 - 19% in 4 trials). See table for response (ORR, 108 pts) and survival (117 pts) data vs. EFFECT (146 pts). The median followup is 15.5 mo (0.6 -37.9) for PFS and 24.5 mo (4.4 - 47.7) for OS. Conclusions: The null hypothesis of the PFS being 8.5 mo can be rejected with a p < 0.001. Individualized dosing is safe and feasible in a multicenter setting and associated with improved dose intensity and one of the best ORR, PFS and OS reported for a TKI. Clinical trial information: NCT01499121