Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial

Summary

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.

Introduction

Oncogenic mutations in the genes encoding receptor tyrosine kinases KIT and PDGFRA are the driver mutations in more than 85% of gastrointestinal stromal tumours, the most common sarcoma of the gastrointestinal tract.1, 2 Targeting of KIT or PDGFRA with imatinib revolutionised treatment for patients with metastatic or unresectable gastrointestinal stromal tumours, changing a uniformly fatal cancer to a manageable disease with durable responses and improved overall survival.³ However, imatinib and other approved agents do not target PDGFRA Asp842Val (D842V), which is the primary driver mutation in 5–6% of gastrointestinal stromal tumours.4, 5, 6, 7 Patients with advanced D842V-mutant gastrointestinal stromal tumours have a poor prognosis, similar to that of all patients with gastrointestinal stromal tumours in the pre-imatinib era, because approved agents provide essentially no objective responses, and median progression-free survival and overall survival are only 3–5 months and approximately 15 months, respectively.8, 9, 10

The D842V mutation occurs in the region of the gene encoding the PDGFRA activation loop (exon 18) and shifts the kinase into the active conformation, which drives oncogenic signalling and renders the kinase largely resistant to imatinib and other type 2 tyrosine kinase inhibitors that preferentially bind to the inactive conformation.11, 12 Avapritinib (also known as BLU-285) was designed to potently and selectively target the active conformation of KIT and PDGFRA via a type 1 inhibition mechanism.12, 13 In preclinical studies, avapritinib demonstrated notable selectivity within the kinome for KIT and PDGFRA, potent biochemical activity against KIT and PDGFRA, including PDGFRA D842V (half maximal inhibitory concentration [IC₅₀]=0·2 nM), and in-vivo efficacy against gastrointestinal stromal tumour xenografts that were resistant to imatinib.¹³

We aimed to evaluate the safety, tolerability, and antitumour activity of avapritinib in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours.