The China National Medical Products Administration has accepted a new drug application for avapritinib for 2 indications in gastrointestinal stromal tumors.
Frank Jiang, MD, PhD
"In just 3 months after avapritinib was approved by the US FDA, CStone has submitted NDAs for this drug candidate in Taiwan and mainland China, which we hope will soon make this first-in-class precision therapy candidate accessible to patients with advanced GIST in Greater China," Frank Jiang, MD, PhD, chairman and CEO of CStone, which collaborated on commercialization and development of avapritinib with Blueprint Medicines, stated in a press release.
The KIT and PDGFRA inhibitor avapritinib was evaluated in the open-label, dose-escalation/dose-expansion phase 1 NAVIGATOR (NCT02508532) trial, which 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).2
Patients had to have 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 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 end points were overall response rate (ORR), duration of response (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, 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 progression-free survival (PFS) was not estimated (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.
Regarding safety, most adverse events (AEs) were mostly 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.
CStone is also conducting a phase 1/2 bridging study in China in patients with advanced GIST. Early findings from the study have so far shown concordance with safety and pharmacokinetic data from the NAVIGATOR study.
"Avapritinib has demonstrated outstanding antitumor activity and a well-tolerated safety profile in advanced PDGFRA exon 18 mutant GIST and fourth-line GIST. Due to the very limited benefits from approved treatment options in these 2 groups of GIST patients, there is an urgent unmet clinical need for new therapies," Lin Shen, MD, professor and director of the Department of Gastrointestinal Oncology, vice president of Peking University Cancer Hospital and Institute, and the principal investigator for the bridging study, stated in the press release. "As a physician, I hope avapritinib will soon be available in our clinical practice for the treatment of advanced GIST."
The US FDA previously approved avapritinib for the treatment of adult patients with unresectable or metastatic GIST harboring PDGFRA exon 18 mutations, including PDGFRA D842V mutations. The agency is currently reviewing an application for avapritinib for use as a fourth-line treatment for patients with GIST.
The China National Medical Products Administration (NMPA) has accepted a new drug application (NDA) for avapritinib (Ayvakit) for 2 indications: the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations, and the fourth-line treatment of adult patients with unresectable or metastatic GIST.