BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor 
tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is 
a clinical challenge for patients with advanced gastrointestinal stromal 
tumours. We compared the efficacy and safety of ripretinib, a switch-control 
tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA 
mutations, with placebo in patients with previously treated, advanced 
gastrointestinal stromal tumours.
METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we 
enrolled adult patients in 29 specialised hospitals in 12 countries. We included 
patients aged 18 years or older who had advanced gastrointestinal stromal 
tumours with progression on at least imatinib, sunitinib, and regorafenib or 
documented intolerance to any of these treatments despite dose modifications, 
and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 
0-2. Eligible patients were randomly assigned (2:1) to receive either oral 
ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo 
group). Randomisation was done via an interactive response system using randomly 
permuted block sizes of six and stratified according to number of previous 
therapies and ECOG performance status. Patients, investigators, research staff, 
and the sponsor study team were masked to a patient's treatment allocation until 
the blinded independent central review (BICR) showed progressive disease for the 
patient. The primary endpoint was progression-free survival, assessed by BICR. 
The primary analysis was done in the intention-to-treat population and safety 
was assessed in patients who received at least one dose of study drug. Patients 
randomly assigned to placebo were permitted to cross over to ripretinib 150 mg 
at the time of disease progression. The INVICTUS study is registered with 
ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical 
Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing.
FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients 
were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At 
data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in 
the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients 
in the ripretinib group and 37 in the placebo group had had progression-free 
survival events. In the double-blind period, median progression-free survival 
was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months 
(0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most 
common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in 
the ripretinib group (n=85) included lipase increase (four [5%]), hypertension 
(three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the 
placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related 
treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), 
diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), 
hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema 
(one [2%]). Treatment-related serious adverse events were reported in eight (9%) 
of 85 patients who received ripretinib and three (7%) of 43 patients who 
received placebo. Treatment-related deaths occurred in one patient in the 
placebo group (septic shock and pulmonary oedema) and one patient in the 
ripretinib group (cause of death unknown; the patient died during sleep).
INTERPRETATION: Ripretinib significantly improved median progression-free 
survival compared with placebo and had an acceptable safety profile in patients 
with advanced gastrointestinal stromal tumours who were resistant to approved 
treatments.
FUNDING: Deciphera Pharmaceuticals.