The updated data from the ongoing Phase 1 NAVIGATOR trial support Blueprint Medicines' plans to submit a New Drug Application (NDA) in the first half of 2019 to the U.S. Food and Drug Administration (FDA) for the treatment of PDGFRA Exon 18 mutant GIST, which primarily includes patients with the D842V mutation, and fourth-line GIST. There are currently no approved or effective therapies in these patient populations. In patients with PDGFRα D842V-driven GIST, avapritinib demonstrated an objective response rate (ORR) of 84 percent and a 12-month duration of response (DoR) of 76 percent. In heavily pre-treated patients with fourth-line or later GIST, avapritinib demonstrated an ORR of 20 percent, tumor reductions in 60 percent of patients and a median DoR of 7.3 months. ORR and DoR per central radiographic review will be the primary endpoints for the NDA submission, consistent with regulatory precedent for accelerated approvals based on single-arm oncology studies. In addition, avapritinib demonstrated an ORR of 26 percent in regorafenib-naïve third- and fourth-line GIST and an ORR of 25 percent in second-line GIST. Patients with PDGFRα D842V-driven GIST were excluded from both of these populations.
"With an increased understanding of molecular drivers of GIST over the last decade, it is encouraging to see an investigational drug, like avapritinib, bring a precision therapy approach to GIST," said Michael Heinrich, M.D., Professor of Medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial. "Avapritinib has the potential to be a significant therapeutic advance in GIST, a rare cancer with high medical needs across lines of treatment. In particular, the updated data demonstrate the broad clinical impact of avapritinib for patients with PDGFRα D842V-driven GIST and fourth-line GIST, where there are currently no effective therapies. In addition, the data strongly support clinical development of avapritinib in early lines, including second- and third-line treatment."
"These data highlight the potential of avapritinib, a potent and highly selective inhibitor of KIT and PDGFRA mutant kinases, to be a cornerstone precision therapy in GIST," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "The results validate Blueprint Medicines' approach to designing precision therapies that specifically target genetic drivers of disease, with the goals of delivering transformative benefit to patients and enabling rapid progress toward registration. Avapritinib's highly potent anti-tumor activity in PDGFRα D842V-driven GIST, combined with differentiated activity across treatment lines in KIT-driven GIST, reflect its promise as a potentially foundational treatment option across multiple GIST populations. We are committed to advancing a comprehensive and scientifically driven clinical development program with the goal of improving the lives of GIST patients."
Data Highlights from the Ongoing Phase 1 NAVIGATOR Clinical Trial
As of the data cutoff date of October 15, 2018, 231 patients were treated with avapritinib in the dose escalation and expansion portions of the Phase 1 clinical trial at eight dose levels, ranging from 30 mg once daily (QD) to 600 mg QD. This population consisted of 167 patients with KIT-driven GIST, 56 patients with PDGFRα D842V-driven GIST and eight patients with other PDGFRA mutations. Patients in the expansion portion of the clinical trial were treated at the recommended Phase 2 dose of 300 mg QD.
As of the data cutoff date, avapritinib was well-tolerated, and most AEs reported by investigators were Grade 1 or 2. Across all doses, 20 patients (8.7 percent) discontinued treatment with avapritinib due to treatment-related AEs.
Across all grades, the most common treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (≥20 percent) included nausea (61 percent), fatigue (55 percent), anemia (46 percent), periorbital edema (40 percent), diarrhea (39 percent), vomiting (38 percent), decreased appetite (35 percent), peripheral edema (33 percent), increased lacrimation (31 percent), memory impairment (26 percent), constipation (23 percent), face edema (23 percent), hair color changes (21 percent) and dizziness (20 percent).
Investigator-reported Grade 3 or 4 treatment-related AEs (≥2 percent) included anemia, fatigue, hypophosphatemia, increased bilirubin, decreased white blood count/neutropenia and diarrhea.
Clinical Activity Data
As of the data cutoff date, the following patients were evaluable for response assessments: 56 patients with PDGFRα D842V-driven GIST, 109 patients with fourth-line or later GIST, 23 patients with third- or fourth-line GIST who did not receive prior regorafenib (which is comparable to the VOYAGER trial population) and do not harbor the PDGFRα D842V mutation, and 20 patients with second-line GIST who do not harbor the PDGFRα D842V mutation. Patients were evaluable if they had at least one centrally reviewed radiographic scan, and data are based on modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1 criteria) for GIST.
Across multiple lines of therapy, avapritinib demonstrated important clinical activity in patients with PDGFRA- and KIT-driven GIST.
Clinical Benefit Rate
Fourth-line or laterb,c
Notes: (a) Treated at all doses; (b) Treated at doses of 300 or 400 mg QD; (c) Included patients with the PDGFRα D842V mutation, whose proportion was consistent with the known mutational prevalence in this GIST population; (d) Did not include patients with the PDGFRα D842V mutation, whose proportion was greater than the known mutational prevalence in this GIST population; (e) Treated at doses up to and including 300 or 400 mg QD; (f) Four PR pending confirmation; (g) One PR pending confirmation; (h) Three PR pending confirmation; (i) NR, not reported, as data are too early to estimate.
Additional Data Support Clinical Development Strategy in Earlier Lines of Therapy
Third- and Fourth-Line GIST
Preliminary data showed robust clinical activity in regorafenib-naïve third- and fourth-line GIST patients lacking the PDGFRα D842V mutation. As of the data cutoff date, the ORR was 26 percent, tumor reductions were demonstrated in 78 percent of patients, and the median PFS was 8.6 months per central radiographic review and 10.2 months per investigator review. In contrast, historical data showed a 5 percent ORR and a median PFS of 4.8 months for regorafenib, the current standard-of-care treatment in third-line GIST.
In regorafenib-naive patients with PDGFRα D842V-driven third- or fourth-line GIST, the ORR was 80 percent (eight out of 10 evaluable patients, with one response pending confirmation). Blueprint Medicines' ongoing Phase 3 VOYAGER trial of avapritinib versus regorafenib in third- or fourth-line GIST permits enrollment of patients with both KIT- and PDGFRA-driven GIST, including patients with the PDGFRα D842V mutation. Blueprint Medicines anticipates completing enrollment of the VOYAGER trial in the second half of 2019.
Preliminary data showed a 25 percent ORR in second-line GIST, excluding patients with the PDGFRα D842V mutation. In patients with second-line PDGFRα D842V-driven GIST, the ORR was 94 percent (15 out of 16 evaluable patients, with two responses pending confirmation).
In addition, analyses of circulating tumor DNA (ctDNA) from the NAVIGATOR trial across all lines showed increased activity for avapritinib in patients without the secondary KIT V654A or T670I mutations, which are estimated to occur in about 20 to 25 percent of GIST patients following treatment with imatinib (second-line or later). Independently published data for sunitinib, the current standard of care therapy for second-line GIST, have shown activity against these mutations.
Based on the totality of data, Blueprint Medicines believes a precision medicine approach has the potential to optimize patient outcomes in second-line GIST. The company plans to initiate the registration-enabling Phase 3 COMPASS-2L clinical trial in the second half of 2019 using a ctDNA-guided patient selection strategy. The planned trial will select patients with PDGFRA- and KIT-driven second-line GIST who do not have the KIT V654A or T670I mutations, and randomize them to receive avapritinib or sunitinib with an anticipated primary endpoint of PFS.
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