Avapritinib NDA Being Split in Two, PDGFRA+ GIST Indication Continuing Review

October 28, 2019

The FDA plans to split up the submitted New Drug Application for avapritinib into 2 separate NDAs in the treatment of 2 different populations of patients with gastrointestinal stromal tumors, according to a press release from Blueprint Medicines.

The FDA plans to split up the submitted New Drug Application (NDA) for avapritinib (BLU-285) into 2 separate NDAs in the treatment of 2 different populations of patients with gastrointestinal stromal tumors (GIST), according to a press release from Blueprint Medicines.

The company previously submitted one NDA for avapritinib as a treatment for adult patients withPDGFRAexon 18—mutant GIST, regardless of prior therapy, and in the fourth-line setting for GIST; the NDA was granted a priority review by the FDA. The administrative change would create separate NDAs for the 2 different settings. The agency also requested further topline data from the phase III VOYAGER trial of avapritinib in patients with third- and fourth-line GIST, which are expected to be available in the second quarter of 2020, the request will likely result in an extension of the review period for this part of the NDA. The separate NDA for treating PDGFRAexon 18 mutant GIST is expected to continue.

"Throughout the development of avapritinib, we have had a productive and collaborative dialogue with the FDA about the potential of avapritinib to address important medical needs in subsets of patients with advanced GIST," Jeff Albers, CEO of Blueprint Medicines, said in a statement. "We plan to continue to work closely with the FDA during its review of the separate NDAs forPDGFRAexon 18 mutant GIST and fourth-line GIST, and we plan to submit the requested VOYAGER trial data as expeditiously as possible."

The ongoing open-label, randomized VOYAGER trial is investigating the KIT/PDGFRA inhibitor in comparison with regorafenib (Stivarga) in patients with advanced GIST in the third- or fourth-line setting (NCT03465722). Patient screening has been completed for the trial, but enrollment is continuing through the end of November 2019, according to the company’s press release. Topline data from the trial will released to the FDA in the second quarter of 2020.

Pending an initial approval of avapritinib, the company then plans to submit an NDA for avapritinib as a treatment for third-line GIST in the second half of 2020.

"We are focusing our strategy and resourcing for the avapritinib clinical development program on three core activities: completing the VOYAGER trial and supporting the FDA's review of NDAs forPDGFRAexon 18 mutant GIST and fourth-line GIST, submitting an NDA for advanced systemic mastocytosis in the first quarter of 2020, and submitting an NDA for third-line GIST in the second half of 2020," said Andy Boral, MD, PhD, Chief Medical Officer of Blueprint Medicines. "We remain committed to exploring the potential of avapritinib in patients with second-line GIST and working with the GIST community to advance precision medicine approaches that can transform patient care, both of which may be further enabled by a robust dataset from the VOYAGER trial including nearly 500 patients with third- and fourth-line GIST."

VOYAGER is planning to enroll 460 patients with locally advanced, unresectable or metastatic GIST who have previously received treatment with imatinib (Gleevec) and at least 1 other tyrosine kinase inhibitor (TKI) and have an ECOG performance status of 0 to 1. Exclusion criteria for the trial include patients with significant cardiovascular disease; recent thrombotic or embolic events; recent grade ≥3 hemorrhage or bleeding events; risk of intracranial bleeding; symptomatic wounds, ulcers, perforations, or fractures; metastases to the brain; poor organ function; history of seizure disorder; recent major surgical procedure. Those who have previously received more than 3 different TKIs, concomitantly use a CYP3A4 inhibitor, or are both KITand PDGFRAwild-type were also excluded from the trial.

In the investigational arm, patients will receive 300 mg avapritinib given orally and continuously. In the control arm, patients will receive 160 mg oral regorafenib given daily for 3 weeks of every 4-week cycle.

The primary end point is progression-free survival by modified RECIST criteria and the secondary end points are objective response rate, overall survival, and quality-of-life scores.

The company has also decided to delay the initiation of its planned COMPASS-2L trial, which will investigate the use of avapritinib in second-line GIST, so that the company can focus on the completion of the VOYAGER trial.

Reference:

Blueprint Medicines Announces FDA Intent to Split Avapritinib New Drug Application into Separate Submissions for PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST [news release]. Cambridge, MA: Blueprint Medicines Corporation; October 28, 2019. https://bit.ly/2Nj8bpR. Accessed October 28, 2019.