Blueprint Medicines Aims For Genomically Defined GIST Indication With Avapritinib NDA
Executive Summary
Kinome-focused Blueprint Medicines plans to follow up its first NDA, for all lines of therapy in patients with exon 18 mutant GIST or fourth-line use in non-genomically selected patients, with submissions for third-line GIST and advanced systemic mastocytosis in 2020.
Blueprint Medicines Corp.’s recent submission of its first new drug application for its lead candidate avapritinib could be followed by four more filings in the next 18 months, chief executive officer Jeffrey Albers told a 17 June 2019 conference call. Three of those planned filings include an indication with a breakthrough therapy designation.
The NDA for avapritinib, a highly selective KIT and platelet-derived growth factor receptor alpha (PDGFRA) inhibitor, seeks approval in two populations: adults with exon 18 mutant gastrointestinal stromal tumors regardless of prior therapy and fourth-line GIST. Avapritinib holds a breakthrough therapy designation for treatment of unresectable or metastatic GIST harboring a specific exon 18 mutation known as D842V.
The D842V mutation is associated with resistance to Novartis AG’s Gleevec (imatinib) and Pfizer Inc.’s Sutent (sunitinib). Expert guidelines already recommend some genomic profiling for patients with GIST, a sarcoma of the GI tract, Blueprint observed. Mutational testing will be “critical to tailor therapy to the underlying disease driver.”
Blueprint acknowledged the plethora of kinase-targeting drugs on the market, while seeing ample room to grow. “The function of the majority of the kinome is still unknown, and small molecule drugs approved by the FDA target less than 5% of the 518 kinases,” according to Blueprint investor materials. “Many of the approved drugs are multi‑kinase inhibitors that are not selective for disease drivers.”
Blueprint describes itself as a precision therapy company developing highly selective kinase inhibitors in selective patient populations. The company expressed hope that that it would be able to seek accelerated approval for GIST patients with a PDGFRA D842V mutation – a group that includes only about 500 people across the major markets – on the basis of Phase I data back in 2017. (Also see "Blueprint Lays Out Path To Early Approval In Small GIST Population" - Scrip, 7 Jun, 2017.)
“If approved, avapritinib will represent the first treatment innovation in GIST since 2013,” Albers said.
Blueprint announced data from the pivotal study for the NDA, the Phase I NAVIGATOR trial in unresectable or metastatic GIST, at the American Society for Clinical Oncology meeting on 1 June. Objective response rate (ORR) and duration of response (DOR) assessed by central radiographic review are the primary registrational endpoints, the company noted. The 43 evaluable patients with PDGFRA Exon 18 mutant GIST (including 38 with D842V-driven disease) across all lines of therapy had an ORR of 86%, Blueprint reported. Median DOR was not reached; 78% of patients remained in response as of the data cutoff date.
In the 111 evaluable NAVIGATOR patients with fourth-line GIST, the ORR was 22% and the median DOR was 10.2 months.
The company is following up on NAVIGATOR with the Phase III VOYAGER trial, which compares avapritinib with Bayer AG’s Stivarga (regorafenib) in 460 patients with third-line or fourth-line GIST patients who progressed following first-line Gleevec and one or two additional therapies.
An sNDA filing is planned for third-line GIST based on VOYAGER, with support from third-line GIST patients in NAVIGATOR, in 2020.
A randomized precision medicine trial, the Phase III COMPASS-2L trial, is slated to start in the second half of 2019. The study will test avapritinib against Pfizer’s Sutent (sunitinib) in second-line GIST patients with specified disease genotypes.
Systemic Mastocytosis Submission In Sight
Blueprint plans to move avapritinib rapidly into its next potential market: systemic mastocytosis, “a mast cell disorder encompassing a spectrum of diseases,” Blueprint chief medical officer Anthony Boral told the teleconference. Nonetheless, “nearly all cases across all subtypes are driven by the KIT D816V mutation.” Avapritinib “was specifically designed by our scientists to potently target D816V mutant KIT,” he noted.
At the European Hematology Association meeting in Amsterdam on 15 June, “we shared for the first time a confirmed overall response rate based on central review by a panel of SM clinical experts,” Albers stated. Those assessments of the full data from the EXPLORER Phase I study “will form the foundation of our planned NDA” in the first quarter 2020 for advanced SM, supported by initial data from the Phase II PATHFINDER trial.
“The data continue to be highly supportive of an expedited development approach,” Albers said. Avapritinib holds a BTD for the treatment of advanced SM, including the subtypes of aggressive systemic mastocytosis (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL).
Blueprint found a confirmed overall response rate of 77% in 39 advanced SM patients in EXPLORER, assessed by central review. “One the most important aspects of this updated data set is the transition to blinded central review of pathology and radiology as well as overall response assessments by a panel of SM clinical experts,” Boral said. The central review “involves a rigorous and consistent evaluation of both baseline diagnoses and response assessments, including the bone morrow, pathology and imaging as well as clinical evaluations that are components of the IWG response criteria.”
The modified IWG-MRT-ECNM criteria are a “rigorous method for assessing clinical response in advanced SM patients with regulatory precedent in the US and Europe.” Boral said.
“This rigor is expected by the regulatory authorities and enables the data from our Phase I study to form the foundation of our planned NDA submission next year,” Boral continued.
Another important finding from EXPLORER is that “all reported responses were confirmed,” Boral said. “To put this in perspective, the rigor of the IWG response criteria requires about 6 months of follow-up to identify baseline clinical findings, assessing initial response and confirm the response in subsequent assessments.”
“As of the data cutoff, 69 patients were enrolled, of whom 39 were evaluable based on IWG response criteria, which require a measurable clinical finding or C-finding at baseline” he reported. “The IWG evaluable population is generally less healthy with higher bone marrow mast cell burden and serum tryptase.” Almost half of all the patients had secondary mutations associated with poor prognosis, and about 25% of patients had previously received Novartis’ Rydapt (midostaurin), which was approved by the FDA for ASM, SM-AHN and MCL in April 2017.
“Importantly, central review of the baseline diagnoses identified a number of discrepancies,” Boral reported, resulting in “the reclassification of some patients to SM-AHN and indolent SM. Across the study population, there are now 37 patients with SM-AHN and 15 patients with indolent SM, all of which we confirmed diagnoses.”
“These findings highlight the difficulty in classifying different SM subtypes and the importance of ultimately pursuing a broad SM indication for avapritinib,” Boral said.
With the reclassification of patients, “an unexpected outcome from the EXPLORER trial is that we've ended up getting meaningful experience in patients with indolent systemic mastocytosis and the results are really impressive,” Albers told the teleconference. “The fact that 15 out of the 69 patients were ultimately assessed to have ISM further highlights that there's a true continuum of disease.”
The ISM patients were not evaluable for response under the IWG criteria, but other components of the response criteria, including objective measures of mast cell burden, “would translate into an approximately 80% to 90% response rate in this group of indolent SM patients,” Albers said.
“We’re currently working with clinical experts to explore a supplementary approach to setting a response that would encompass a broad SM population,” he continued. “We plan to present this data at a future scientific meeting.”
Blueprint’s Phase II PIONEER trial is currently enrolling ISM patients. “We look forward to sharing the initial data from the Part 1 of this study in the second half of 2019,” Albers said.
Expediting BLU-667 In RET-Altered Cancers
Blueprint is also looking to bring its second candidate, the selective RET kinase inhibitor BLU-667, to market in the US swiftly, the company indicated during the ASCO meeting. BLU-667 is “specifically designed for highly potent and selective targeting of oncogenic RET alterations,” the company said.
The FDA granted Breakthrough Therapy Designations to BLU-667 for the treatment of RET-fusion positive non-small cell lung cancer (NSCLC) that has progressed following platinum-based chemotherapy and RET-mutation positive medullary thyroid cancer (MTC) that requires systemic treatment and for which there are no acceptable alternative treatments.
“Based on the early achievement of the enrollment target for the RET-fusion NSCLC cohort” in the Phase I ARROW trial, Blueprint Medicines said at the ASCO meeting 3 June that it plans to submit an NDA in the first quarter of 2020 for BLU-667 for the treatment of patients with NSCLC previously treated with platinum-based chemotherapy.
“Blueprint Medicines continues to expect to submit an NDA to the FDA for BLU-667 for the treatment of patients with RET-mutant MTC previously treated with an approved multi-kinase inhibitor in the first half of 2020,” the company added. The MTC indication would also be based on ARROW data.
“Based on encouraging clinical activity in patients with NSCLC naïve to prior systemic therapy and feedback from the FDA,” Blueprint Medicines announced plans to “expand the enrollment target of the ongoing ARROW trial cohort for treatment-naïve patients with RET-fusion NSCLC, with the goal of supporting expedited development in first-line RET-fusion NSCLC.” A Phase III trial in first-line RET-altered NSCLC is planned for the second half of 2019, as is a Phase II combination trial with AstraZeneca PLC’s Tagrisso (osimertinib) in treatment-resistant EGFR-mutant NSCLC harboring an acquired RET alteration.
“In addition, based on the strong data for BLU-667 across RET alteration and tumor types, we plan to continue to work with investigators and global regulatory authorities to bring BLU-667 to the broader population of patients with RET-altered cancers who could potentially benefit.”
The Phase I ARROW trial is designed with seven cohorts of patients with RET-altered advanced solid tumors treated with the recommended Phase II dose of BLU-667:
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RET-fusion NSCLC patients previously treated with a platinum-based chemotherapy,
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RET-fusion NSCLC patients who have not previously received a platinum-based chemotherapy,
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RET-mutant MTC patients previously treated with cabozantinib or vandetanib,
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RET-mutant MTC patients who have not previously received cabozantinib or vandetanib,
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Patients with other RET-fusion tumors,
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Patients with other RET-mutant tumors, and
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RET-altered solid tumor patients previously treated with a selective RET inhibitor.