TY - JOUR
T1 - Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR)
T2 - a multicentre, open-label, phase 1 trial
AU - Heinrich, Michael C.
AU - Jones, Robin L.
AU - von Mehren, Margaret
AU - Schöffski, Patrick
AU - Serrano, César
AU - Kang, Yoon Koo
AU - Cassier, Philippe A.
AU - Mir, Olivier
AU - Eskens, Ferry
AU - Tap, William D.
AU - Rutkowski, Piotr
AU - Chawla, Sant P.
AU - Trent, Jonathan
AU - Tugnait, Meera
AU - Evans, Erica K.
AU - Lauz, Tamieka
AU - Zhou, Teresa
AU - Roche, Maria
AU - Wolf, Beni B.
AU - Bauer, Sebastian
AU - George, Suzanne
N1 - Funding Information:
MCH owns stock in MolecularMD; has received honoraria from Novartis; has served in advisory or consultancy roles for MolecularMD, Novartis, Blueprint Medicines, and Deciphera; has provided expert testimony for Novartis; has a patent Activating Mutations of PDGFRA ; and his institution receives royalties for a patent Treatment of Gastrointestinal Stromal Tumors licensed by Novartis. RLJ has served in advisory or consultancy roles for Blueprint Medicines, Athenex, Lilly, Immune Design, Merck Serono, Adaptimmune, Daiichi Sankyo, Helsinn, Eisai, TRACON Pharmaceuticals, Deciphera, PharmaMar, Clinigen Group, Epizyme, and UpToDate; and has received institutional research funding from Merck Sharp & Dohme. MvM reports a leadership position with the US National Comprehensive Cancer Network (chair of the Soft Tissue Sarcoma panel); has served in advisory or consultancy roles for Blueprint Medicines, Deciphera, Arog, and Exelexis; and has received research funding from Blueprint Medicines, Deciphera, Arog, and Novartis. PS has served in an advisory or consultancy role for Exelixis (honoraria provided to PS) as well as Plexxikon, Eisai, Loxo Oncology, Lilly, Blueprint Medicines, Ellipses Pharma, Deciphera, Merck, SERVIER, Genmab, Adaptimmune, Intellisphere, and Transgene (honoraria provided to institution); and received institutional research funding from Blueprint Medicines, Boehringer Ingelheim, CoBioRes NV, Eisai, Lilly, Excelixis, G1 Therapeutics, Novartis, PharmaMar, and Plexxikon. CS has received honoraria from Bayer; served in advisory or consultancy roles for Deciphera and Blueprint Medicines; received research funding from Deciphera, Bayer, and Pfizer; and received travel and accommodation funding from Novartis, Lilly, PharmaMar, Pfizer, and Bayer. Y-KK has served in advisory or consultancy roles for Lilly/ImClone, Taiho Pharmaceutical, Roche/Genentech, Merck Serono, Dae Hwa Pharmaceutical, Bristol-Myers Squibb, Astellas Pharma, and LSK BioPharma; and received research funding from LSK BioPharma and Dae Hwa Pharmaceutical. PAC has received honoraria from Novartis, Roche/Genentech, Blueprint Medicines, and Amgen; has received institutional research funding from Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Taiho Pharmaceutical, Toray Industries, Transgene, Loxo Oncology, GlaxoSmithKline, Innate Pharma, and Janssen; and travel and accommodation funding from Roche, Amgen, Novartis, Bristol-Myers Squibb, and Merck Sharp & Dohme. OM owns stock in Transgene; has received honoraria from Roche; has served in advisory or consultancy roles for AstraZeneca, Amgen, Bayer, Lilly, GlaxoSmithKline, Novartis, Pfizer, Roche, Servier, and Vifor Pharma; has served on speakers' bureaus for Lilly and Roche; and has received travel and accommodation funding from Roche, Pfizer, and PharmaMar. FE has served in advisory or consultancy roles for Merck Serono, Roche, Eisai, and Ipsen; and received travel and accommodation funding from Pfizer. WDT has served in leadership roles at and owns stock in Certis Oncology Solutions and Atropos; served in advisory or consultancy roles for EMD Serono, Janssen, Lilly, Daiichi Sankyo, Novartis, Eisai, Immune Design, Blueprint Medicines, Loxo Oncology, Agios, GlaxoSmithKline, and Nanocell Therapy; received research funding from Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, and Deciphera; and reports a patent and royalty for companion diagnostics for CDK4 inhibitors (14/854,329). PR has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Lilly, and Pfizer; served in advisory or consultancy roles for Novartis, Blueprint Medicines, Bristol-Myers Squibb, Pierre Fabre, Merck Sharp & Dohme, and Amgen; served on speakers' bureaus for Pfizer, Novartis, and Lilly; received research funding from Novartis, Roche, and Bristol-Myers Squibb; and received travel and accommodation funding from Orphan Europe and Pierre Fabre. SPC has received honoraria from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration, and Janssen; has served in advisory or consultancy roles for Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration, and Janssen; has served on speakers' bureaus for Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration, and Janssen; and has received research funding from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration, and Janssen. JT has received honoraria from GlaxoSmithKline and has served in advisory or consultancy roles for Novartis, Lilly, and Janssen. MT is an employee of Blueprint Medicines. EKE is an employee of Blueprint Medicines, and owns equity and has stock options with Blueprint Medicines. TL is an employee of Blueprint Medicines. TZ is an employee of Blueprint Medicines. MR is an employee of Blueprint Medicines. BBW was an employee of Blueprint Medicines at the time the study was done and owns stock in Blueprint Medicines. SB has received honoraria from Novartis, Pfizer, Bayer, PharmaMar, and GlaxoSmithKline; served in advisory or consultancy roles for Blueprint Medicines, Bayer, Lilly, Deciphera, Exelixis, Janssen-Cilag, Plexxikon, and Nanobiotix; received institutional research funding from Blueprint Medicines, Novartis, and Incyte; and received travel and accommodation funding from PharmaMar. SG owns stock in Abbott Laboratories and Allergan; has served in advisory or consultancy roles for Blueprint Medicines, Deciphera, Bayer, Eli Lilly, Exelixis, Daiichi Sankyo, UpToDate, Research to Practice, and MORE Health; has received institutional research funding from Pfizer, Novartis, Bayer, ARIAD, Blueprint Medicines, and Deciphera; receives royalties from UpToDate; has provided expert testimony for Bayer; and also reports a relationship with Research to Practice.
Funding Information:
This study was funded by Blueprint Medicines, Cambridge, MA, USA. We thank all patients who participated in this clinical trial and their families. We acknowledge the clinical research staff who assisted in patient care and data collection. We also thank Khalid Mamlouk (Epizyme, Cambridge, MA, USA) for his assistance. Beth Kamp (Epizyme) and Meredith Kalish (Ashfield Healthcare Communications, New York, NY, USA), part of UDG Healthcare, provided medical writing support under the direction of the authors, which was funded by Blueprint Medicines in accordance with Good Publications Practice (GPP3) guidelines .
PY - 2020/7
Y1 - 2020/7
N2 - Background: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). Methods: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. Findings: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Interpretation: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Funding: Blueprint Medicines.
AB - Background: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). Methods: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. Findings: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Interpretation: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Funding: Blueprint Medicines.
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U2 - 10.1016/S1470-2045(20)30269-2
DO - 10.1016/S1470-2045(20)30269-2
M3 - Article
C2 - 32615108
AN - SCOPUS:85085472073
VL - 21
SP - 935
EP - 946
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 7
ER -