FDA Approves Avapritinib for PDGFRA Exon 18+ GIST

The FDA has approved avapritinib (Ayvakit) for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.¹

The approval is based on efficacy results from the phase I NAVIGATOR trial, as well as combined safety data from multiple studies of avapritinib. In the specific PDGFRA exon 18—mutant patient population, avapritinib elicited an 84% overall response rate (ORR; 95% CI, 69%-93%). The ORR comprised a 7% complete response (CR) rate and a 77% partial response (PR) rate. Specifically in patients with PDGFRA D842V mutations, the ORR was 89% (95% CI, 75%-97%), which included an 8% CR rate and an 82% PR rate. The median duration of response (DOR) was not reached in either patient population (range, 1.9+ months to 20.3+ months).

Regarding safety, the most common (≥20%) adverse events (AEs) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness.

The agent is expected to become available in the United States within 1 week, Blueprint Medicines, the developer of avapritinib, stated in a press release.

"Today's approval of Ayvakit brings forward a new standard of care for patients with PDGFRA exon 18 mutant GIST, a genomically defined population that previously had very limited treatment options. For the first time, we can offer these patients a highly effective treatment that targets the underlying genetic cause of their disease," study investigator Michael Heinrich, MD, professor of medicine at Oregon Health and Science University, stated in a press release. "Building on our growing understanding of the molecular basis of GIST, this milestone ushers in a new era of precision medicine in this disease. The FDA approval represents a call to action to conduct mutational testing in all patients with GIST before initiating kinase inhibitor therapy, as recommended by clinical guidelines, so appropriate patients may realize the benefits of this promising new medicine."

In August 2019, the FDA granted a priority review designation to a new drug application (NDA) for avapritinib for the treatment of adult patients with PDGFRA exon 18—mutant GIST, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting.² The initial action date for the FDA was February 14, 2020. In October 2019, the FDA informed Blueprint Medicines that it intended to split the proposed indications for its agent avapritinib into 2 separate NDAs for patients with GIST: one for patients with PDGFRA exon 18—mutant disease regardless of prior therapy, and one for fourth-line GIST.³

At the time that the FDA stated it would split the avapritinib NDA into 2 indications, the agency also requested topline findings from the phase III VOYAGER trial (NCT03465722) of avapritinib versus regorafenib (Stivarga) in the third- or fourth-line setting for patients with GIST; the data are slated to become available in the second quarter of 2020. The agency stated that the results would be informative in its review for the fourth-line indication and in determining avapritinib’s clinical benefit through response rates and safety in this patient population. Blueprint Medicines had stated that there would likely be an extended review period for the NDA for avapritinib in fourth-line GIST, in order to provide the FDA with the topline VOYAGER results.

The company also previously announced that it had completed patient screening in the VOYAGER trial; patient enrollment was expected to be completed by the end of November 2019. Blueprint Medicines added that it planned to prioritize completion of the VOYAGER trial, yet delay initiation of the phase III COMPASS-2L trial, which is evaluating avapritinib in second-line GIST. Should avapritinib receive initial approval, Blueprint Medicines plans to submit a supplemental NDA to the FDA for avapritinib for third-line GIST in the second half of 2020.

In the open-label, dose-escalation/dose-expansion phase I NAVIGATOR (NCT02508532) trial, investigators explored the clinical activity of avapritinib at the recommended phase II dose of 300 mg once daily and the maximum-tolerated dose of 400 mg daily in patients with GIST who had PDGFRA exon 18 mutations (n = 43) or in in the fourth-line setting (n = 121).⁴

Patients must have had metastatic GIST following ≥2 prior lines of TKI therapy and had a mutation in KIT or PDGFRA to be eligible for enrollment. The median ages in the PDGFRA exon 18—mutant and fourth-line cohort were 64 years and 59 years, respectively. Twenty-nine percent and 70% of patients were male in the PDGFRA exon 18—mutant and fourth-line groups, respectively.

In the PDGFRA exon 18—mutant cohort, 67.4% of patients were white, 88.4% of patients harbored a PDGFRA D842V mutation, and the median number of prior therapies was 1. A total of 97.7% of patients had metastatic disease, 46.5% of patients had a target lesion ≤5 cm, and 86.0% of patients had prior surgical resection. Patients had an ECOG performance status of 0 (32.6%), 1 (60.5%), or 2 (7.0%).

In the fourth-line cohort, 71.1% of patient were white, 90.9% of patients had a KIT mutation, the median number of prior therapies was 4, and 98.3% of patients had metastatic disease. A total of 47.1% of patients had a largest target lesion of >5 cm to ≤10 cm, and 88.4% of patients had surgical resection. Moreover, 32.2% of patients had an ECOG performance status of 0, compared with 64.5% who had a status of 1, and 3.3% of whom had a status of 2.

The key endpoints were ORR, DOR, and safety.

As of the data cutoff date of November 16, 2018, most patients were able to remain on treatment with dose modifications when needed. The relative dose intensity was 86% at 300 mg daily and 73% at 400 mg daily.

In the PDGFRA exon 18—mutant cohort, previous results showed that the ORR was 86.0% (95% CI, 72.1-94.7); this included 3 complete responses (CRs), 34 partial responses (PRs), and 1 patient with stable disease (SD). The clinical benefit rate (CBR) was 95.3%, while the median DOR (95% CI, 11.5–NE) and median PFS was not evaluable (NE; 95% CI, 13.4–NE). As of the data cutoff date, which was at a median follow-up of 10.9 months, 78% of patients in this cohort were still in response.

In the fourth-line cohort, data showed that the ORR was 22% (95% CI, 14.4-30.4), with 1 CR and 23 PRs; 52 patients had SD and 35 patients had progressive disease. The CBR was 41%, the median DOR was 10.2 months (95% CI, 7.2—NE) and the median PFS was 3.7 months (95% CI, 3.4-5.6) at a median follow-up of 10.8 months.

The safety profile of avapritinib in patients with unresectable or metastatic GIST was evaluated in 204 patients who received avapritinib at 300 mg or 400 mg once daily in the NAVIGATOR trial.

Regarding safety, most adverse events (AEs) were grade 1/2, with a higher incidence of commonly reported AEs in the 400-mg cohort versus the 300-mg group. Grade ≥3 treatment-related AEs included anemia (33%), fatigue (13%), cognitive effects (8%), increase in blood bilirubin (8%), and diarrhea (6%). No treatment-related grade 5 AEs were reported. Moreover, 8.3% of patients discontinued avapritinib for a treatment-related toxicity overall, but 2.0% of patients discontinued therapy due to cognitive effects.

Enrollment for a second-line cohort in NAVIGATOR is complete, and an analysis is pending.

In the ongoing, international, open-label, randomized phase III VOYAGER trial, patients with locally advanced unresectable or metastatic GIST, who previously received imatinib (Gleevec) and 1 or 2 other TKIs, receive oral avapritinib at 300 mg daily or oral regorafenib at 160 mg daily on a 3-weeks-on/1-week-off schedule. The primary endpoint is progression-free survival (PFS); secondary endpoints include objective response rate (ORR), overall survival, and European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30).

The FDA previously granted a breakthrough therapy designation to avapritinib for the treatment of patients with unresectable or metastatic GIST harboring PDGFRα D842V mutations. Moreover, the European Medicines Agency validated a marketing authorization application for avapritinib in adult patients with PDGFRA D842V mutant GIST, regardless of prior therapy, and in the fourth-line setting of GIST.

"The full approval of Ayvakit based on robust data from our phase I NAVIGATOR clinical trial is an incredibly exciting milestone for our company and, more importantly, for GIST patients with a PDGFRA exon 18 mutation, who have been waiting for a new treatment option," Jeff Albers, chief executive officer at Blueprint Medicines, stated in the press release. "Ayvakit is the first of what we hope will be many approved medicines enabled by our research platform. Now, as we begin to deliver Ayvakit to patients and their healthcare providers, we aim to fortify our leadership in the field of precision medicine and build a foundation for our broader portfolio by pairing our strong research and development capabilities with an equally talented commercial organization focused on addressing patient needs, accelerating diagnostic testing and enabling access."

References

1. Blueprint Medicines announces FDA approval of Ayvakit (avapritinib) for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant gastrointestinal stromal tumor [news release]. Blueprint Medicines Corporation. Published January 9, 2020. https://bit.ly/2sTz3GX. Accessed January 9, 2020.
2. Blueprint Medicines Announces FDA Acceptance of New Drug Application for Avapritinib for the Treatment of PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST. Blueprint Medicines Corporation. Published August 7, 2019. https://bit.ly/2Kn4Ply. Accessed August 7, 2019.
3. Blueprint Medicines Announces FDA Intent to Split Avapritinib New Drug Application into Separate Submissions for PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST. Blueprint Medicines Corporation. Published October 28, 2019. https://bit.ly/2NqcFLA. Accessed October 28, 2019.
4. Heinrich M, Jones RL, von Mehren M, et al. Clinical activity of avapritinib in ≥4th line (4L+) and PDGFRA exon 18 gastrointestinal stromal tumors (GIST). J Clin Oncol. 2019;37 (suppl; abstr 11022).