On January 9, 2020, the FDA approved Blueprint Medicines Corporation’s AYVAKIT™ (avapritinib) for adult patients “with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.” Key findings from the FDA’s Multi-Discipline Review and the Administrative and Correspondence Documents:
Safety and efficacy for AYVAKIT are based on a phase 1, open-label, single-arm study, BLU-285-1101 (NAVIGATOR/NCT02508532, n=38). The overall response rate (ORR) was the major efficacy outcome reported among patients with PDGFRA D842V mutations (ORR=89% [95% CI: 75, 97]). The six- and 12-month duration of response (DOR) were additional efficacy outcome measures (DOR=88% [95% CI: 75, 100] and 68% [95% CI: 45, 91], respectively). To understand the course and treatment of patients with GIST, the FDA reviewed published data and the applicant’s natural history study, BLU-285-1002 (n=22). While BLU-285-1101 was the only data source to assess the efficacy of avapritinib, it was supported by data from BLU-285-1002 .
The Primary Safety Population included 204 patients from BLU-285-1101. Additional safety data on avapritinib is from other ongoing clinical studies: BLU-285-2101 (EXPLORER/NCT02561988) and BLU-285-1303 (VOYAGER/NCT03465722).
Intent of the RWE study
The applicant designed and executed a U.S.-based multi-center, retrospective, observational, natural history study, BLU-285-1002, to to understand the course of patients with PDGFRα D842 mutant GIST and patients’ responses to commercially-available tyrosine kinase inhibitors (TKIs). Specific TKIs include imatinib, regorafenib, and sunitinib.
Protocol for RWE generation
The applicant used data from clinical charts to characterize best response, DOR, and progression-free survival (PFS). The secondary outcome measures were overall survival (OS), sites of recurrence and metastasis, time to recurrence or progressive disease following resection, and spectrum of mutations in PDGFRα gene.
Twenty-two patients were enrolled across three centers; key inclusion criteria:
- “Patient ≥18 years of age at the time of diagnosis
- Patient with GIST that harbors a D842 mutation in the PDGFRα gene
- Patient treated with a commercially available kinase inhibitor for locally advanced, metastatic, or recurrent GIST
- Patient received initial therapy between 01 January 2000 and 01 July 2016.”
Outcome of the RWE submission
Relevant published literature and the natural history study provided evidence that this patient population responds poorly to commercially available TKIs. In the two relevant retrospective studies, none of the 37 patients responded to imatinib or sunitinib (Cassier 2012; Yoo 2016). In response to the relevant published literature, the FDA wrote "although reviewed for context, the literature was not necessary to take an action on this application.” In the natural history study, only one patient experienced a response to commercially available TKIs (ORR=4.5% [95% CI 0, 23]). This patient had a complete response to imatinib, which was taken as a first-line therapy. In addition, one patient had a partial response to investigational TKI crenolanib, which was taken as a fourth-line therapy.
After analyzing the clinical and nonclinical data, including the natural history study, the FDA recommended the applicant seek regular approval of AYVAKIT.
A note on expanded access data
When enrollment was slower than expected for the applicant, the FDA offered solutions to increase enrollment including through the use of real-world data. The “FDA stated that for patients enrolled under expanded access programs, Blueprint could collect images to confirm ORR and DOR.” There is no additional information on this topic for public consumption.
References
Cassier PA, Fumagalli E, Rutkowski P, et al. (2012) Outcome of Patients with Platelet-Derived Growth Factor Receptor ALpha Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era. Clinical Cancer Research; 18 (16): 4458-4464. https://pubmed.ncbi.nlm.nih.gov/22718859/
Yoo C, Ryu MH, Jo J, et al. (2016) Efficacy of Imatinib in Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Tumors. Cancer Research and Treatment; 48(2): 546-552. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843750/