TY - JOUR
T1 - Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS)
T2 - a double-blind, randomised, placebo-controlled, phase 3 trial
AU - Blay, Jean Yves
AU - Serrano, César
AU - Heinrich, Michael C.
AU - Zalcberg, John
AU - Bauer, Sebastian
AU - Gelderblom, Hans
AU - Schöffski, Patrick
AU - Jones, Robin L.
AU - Attia, Steven
AU - D'Amato, Gina
AU - Chi, Ping
AU - Reichardt, Peter
AU - Meade, Julie
AU - Shi, Kelvin
AU - Ruiz-Soto, Rodrigo
AU - George, Suzanne
AU - von Mehren, Margaret
N1 - Funding Information:
J-YB reports grants and personal fees from Deciphera Pharmaceuticals during the study; grants and personal fees from Novartis, Pfizer, and Bayer; and grants from Blueprint Medicines, outside the submitted work. CS reports grants (laboratory research) and personal fees (advisory board) from Deciphera Pharmaceuticals during the study; grants (laboratory research grant), personal fees (lectures), and financial support (travel grant) from Bayer AG; grants (laboratory research grant) and financial support (travel grant) from Pfizer; personal fees (lecture; advisory role) from Blueprint medicines; and financial support (travel grants) from Pharmamar, Novartis, and Lilly, outside the submitted work. MCH reports grants and personal fees from Deciphera Pharmaceuticals during the study; personal fees (consulting) and equity interest from MolecularMD; personal fees from Novartis (consulting, expert testimony); and grants and personal fees (consulting) from Blueprint Medicines, outside the submitted work. MCH also has a patent “Treatment of gastrointestinal stromal tumors” licensed to Novartis. JZ reports stock from GW Pharmaceuticals, Aimmune, Vertex, Bluebird Bio, Alnylam, Biomarin, Sage Therapeutics, Dova Pharmaceuticals, Therapeutics MD, Juno Therapeutics, Kite Pharma, Kiadis Pharma, CSL Limited, Cochlear, QURE, Sangamo Therapeutics, and Frequency Therapeutics; grants (to institution) and honoraria, consulting and advisory role from Pfizer; grants (to institution) and honoraria, consulting and advisory role, and travel and accommodation support from Merck Serono; grants (to institution) and honoraria from Specialized Therapeutics; honoraria and a consulting and advisory role from Targovax and Halozyme; honoraria from Gilead Sciences and Quantium HealthCare; grants (to institution) and consulting and advisory role, and travel and accommodation support from Merck; consulting and advisory role for Sirtex Medical, Lipotek, and 1GlobalHealth; grants (to institution) from Bayer, Roche, Bristol-Myers Squibb, Baxalta and Shire, and Lilly; grants (to institution) and travel and accommodation support from AstraZeneca; and travel and accommodation support from Deciphera Pharmaceuticals, outside the submitted work. SB reports personal fees (advisory board) from Deciphera Pharmaceuticals; grants (research support) from Incyte; grants (research support) and personal fees (advisory board) from Blueprint Medicines; personal fees (Continuing Medical Education-honoraria, travel support) from Pharmamar, personal fees (advisory board) from ADC Therapeutics, Nanobiotix, Bayer, Exelixis, Daiichi-Sankyo, and Roche, personal fees (advisory board, Continuing Medical Education-honoraria) from Lilly, grants (research support) and personal fees (Continuing Medical Education, advisory board) from Novartis, outside the submitted work. HG reports participation in sponsored studies and fees for an advisory role paid to institution from Deciphera Pharmaceuticals, during the study. PS reports personal fees from Deciphera Pharmaceuticals, during the study; and institutional support from Exelixis, Plexxikon, Eisai, Loxo, Lilly, Blueprint Medicines, Ellipses Pharma, Deciphera Pharmaceuticals, Merck, Servier, Genmab, Adaptimmune, Intellisphere, Transgene, Exelixis, outside the submitted work. RLJ reports having a consultant role for Adaptimmune, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daichii, Deciphera Pharmaceuticals, Immunedesign, Lilly, Merck, Pharmamar, Tracon, and UpToDate; and grants from GlaxoSmithKline and Merck, outside the submitted work. SA reports grants from Deciphera Pharmaceuticals, during the study; grants from Desmoid Tumor Research Foundation, research funding to institution from AB Science, TRACON Pharma, CytRx Corporation, Bayer, Novartis, Daiichi Sankyo, Lilly, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera Pharmaceuticals, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics; and personal fees and research funding to institution from Immune Design, outside the submitted work. GD reports advisory board participation for Bayer, Epizyme, and Blueprint Medicines, outside the submitted work. PC reports funding for clinical trials and personal fees (advisory role) from Deciphera Pharmaceuticals, during the study; personal fees (advisory role) from Exelixis; funding for clinical trial from Array Biopharma; and funding for clinical trial from Plexxikon, outside the submitted work. PR reports grants and personal fees from Novartis; personal fees from Pfizer, Bayer, Pharmamar, Clinigen, Lilly, Deciphera Pharmaceuticals, Roche, Merck, and Amgen, outside the submitted work. JM is a full-time employee and receives stock from Deciphera Pharmaceuticals. KS is an employee of Deciphera Pharmaceuticals. RR-S is a full-time employee of Deciphera Pharmaceuticals. SG reports grants (research clinical trial agreement with institution, advisory board) from Deciphera Pharmaceuticals, during the study; grants, personal fees, and non-financial support from Deciphera Pharmaceuticals; grants, personal fees, and non-financial support from Blueprint Medicines; grants and non-financial support from Daiichi Sankyo; personal fees from Exelixis and Eli Lilly; grants and personal fees from Bayer; grants from Pfizer and ARIAD; personal fees from UpToDate, Research To Practice, and MORE Health; equity from Abbott Laboratories and Allergan, outside the submitted work. MvM reports clinical trial support to institution from, personal fees (advisory board member) from, and travel for advisory board and investigator meeting participation for Deciphera Pharmaceuticals, during the study; personal fees (advisory board member) from, clinical research support to institution from, and travel for advisory board and investigator meeting participation from Blueprint, clinical research support to institution from Arog Pharmaceuticals, and personal fees (advisory board participation) from Exelixis, outside the submitted work.
Funding Information:
The INVICTUS study was funded by Deciphera Pharmaceuticals. We thank the patients and their families and caregivers, the investigators, the investigational site staff of the INVICTUS study, Oliver Rosen (formerly of Deciphera Pharmaceuticals, now SQZ Biotech, Watertown, MA, USA), and the medical writing assistance of Laura Jung of ETHOS Health Communications (Yardley, PA, USA) which was supported financially by Deciphera Pharmaceuticals, in compliance with international good publication practice guidelines.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
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U2 - 10.1016/S1470-2045(20)30168-6
DO - 10.1016/S1470-2045(20)30168-6
M3 - Article
C2 - 32511981
AN - SCOPUS:85086649923
VL - 21
SP - 923
EP - 934
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 7
ER -