Background: Imatinib (IM) is the standard first-line treatment for advanced GIST and regorafenib (REG) is approved for third line therapy. We studied if an alternating regimen of two tyrosine kinase inhibitors, IM and REG, delays resistance to IM and improves outcomes. Methods: ALT-GIST (NCT02365441) is a randomised non-comparative phase II trial to investigate the efficacy of an alternating regimen (ALT) of 21-25 days of IM 400mg orally daily followed by a 3-7-day gap for washout followed by 21 days of REG 160 mg orally daily and a 7-day gap for washout. The control arm was continuous IM 400mg daily. Delayed recruitment led to revised endpoints of activity and safety. To assess clinical activity, the best objective tumor response (OTR) at 9 months was deemed to be an appropriate endpoint in the revised protocol. Results: Seventy-six eligible patients (ALT 40, IM 36) enrolled from June 2015 to September 2018 were evaluable for the OTR. The patients (pts) were predominately male (n = 51, 67%). Median age was 58 (range, 24-81) in the ALT arm and 65 (range, 35-82) in the IM arm. KIT was mutated in 63, PDGFR in 2, and wildtype in 5 tumors. Relative dose intensity in the ALT arm 102% for IM and 82% for REG and was 93% in the IM arm. Median follow-up time was 19.3 months (range 6.0-40.0).The best responses to the ALT and IM treatments were similar at 9 months, 1 vs 0 pts had complete response, 23 vs 23 partial response, 15 vs 13 stable disease, and the OTR was 60% (95% CI, 45-74%) and 64% (95% CI, 48-78%), respectively. Seven (18%) pts in ALT arm and 10 (28%) in IM arm discontinued treatment due to progressive disease. Seven pts (18%) in the ALT arm stopped protocol therapy due to unacceptable toxicity, and none in the IM arm. Fifteen (38%) pts in the ALT arm and 14 (38%) in the IM arm had serious adverse events, mostly grade 3. Progression free survival (PFS) at 1 year was ALT 0.86 (95%CI:0.69,0.94) and IMI 0.83 (95% CI 0.65-0.92), p logrank = 0.57. Conclusions: There was no meaningful difference in the primary endpoint of OTR and in PFS between the groups in this first analysis of ALT-GIST, and no unexpected safety signals. The study is ongoing and other endpoints will be reported in due course. Clinical trial information: ACTRN12614000950662.