FDA Green Lights Companion Diagnostic for Avapritinib in Gastrointestinal Stromal Tumors

August 8, 2023

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The FDA has approved the therascreen PDGFRA RGQ PCR kit for use as a companion diagnostic, co-developed by Qiagen and Blueprint Medicines, to assist in the identification of patients with gastrointestinal stromal tumors who may be candidates to receive avapritinib.

Jonathan Arnold

The real-time qualitative polymerase chain reaction (PCR) in vitro diagnostic assay identifies D842V somatic mutation in the PDGFRA gene to determine which patients may be eligible for treatment with the TKI, which received regulatory approval in January 2020.² Avapritinib is indicated for use in adult patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.

The decision was supported by findings from the phase 1 NAVIGATOR trial (NCT02508532), and combined safety data collected from several trials examining the drug. Avapritinib induced an overall response rate of 84% (95% CI, 69%-93%) in this subset of patients with PDGFRA exon 18 mutation–positive disease (n = 43); this included a complete response (CR) rate of 7% and a partial response (PR) rate of 77%. In those with PDGFRA D842V mutations (n = 38), the ORR with the agent was slightly higher, at 89% (95% CI, 75%-97%); this comprised CR and PR rates of 8% and 82%, respectively.

“The therascreen PDGFRA kit is an FDA-approved and validated test, delivering results in a fast turnaround time. This ensures that physicians receive results promptly, enabling them to make informed treatment decisions for their [patients with] GIST in a timely and effective manner,” Jonathan Arnold, vice president and head of Translational Science and Precision Diagnostics at Qiagen, stated in a press release.¹ “This latest approval confirms Qiagen’s leadership in companion diagnostics development. It adds to Qiagen’s extensive list of now 12 FDA-approved companion diagnostics.”

The therascreen kit extracts genomic DNA from a patient’s formalin-fixed paraffin-embedded tumor tissue. The specimens are processed with the QIAamp DSP DNA FFPE Tissue Kit for sample preparation as well as the Rotor-Gene Q MDx instrument to detect for DNA amplification and mutations.

The multicenter, single-arm, open-label, NAVIGATOR trial enrolled patients with a confirmed GIST diagnosis who had an ECOG performance status ranging from 0 to 2.³ Investigators identified those with PDGFRA exon 18 mutations through local or central assessment leveraging a PCR or next generation sequencing–based assay.

On the study, 204 patients were administered 300 mg or 400 mg of the agent once daily until progressive disease or intolerable toxicity. Participants started at the 400-mg dose and were later reduced to the 300-mg dose due to toxicity; the latter dose became the recommended dose. ORR by independent radiological review and RECIST v1.1 criteria served as the primary efficacy end point. An additional efficacy end point of interest was duration of response (DOR).

Efficacy was evaluated in 43 patients, 38 of whom harbored the PDGFRA D842V mutation. The median age in this group was 64 years (range, 29-90) and more than half were male (67%) and White (67%). The majority of patients had an ECOG performance status of 0 or 1 (93%) and metastatic disease (98%). Eighty-six percent of patients previously underwent surgical resection. Patients received a median of 1 prior kinase inhibitor (range, 0 to 5).

The median DOR had not yet been reached in the PDGFRA exon 18 population (n = 36) or the D842V population (n = 34; range, 1.9+ to 20.3+). The percentages of those with a DOR of 6 months or longer were 61% and 59%, respectively.

Fifty-six percent of patients who received avapritinib were exposed to the agent for at least 6 months; 44% had exposure for over 1 year.

Regarding safety, approximately half (52%) of patients had serious adverse effects (AEs); those occurring in 1% or more of patients included anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%), and tumor hemorrhage (1%). Moreover, 3.4% of patients experienced fatal toxicities, which included sepsis (1%) and tumor hemorrhage (1%).

Moreover, 57% of patients experienced AEs that required dose interruptions, and 49% had toxicities that led to dose reductions. Sixteen percent of patients experienced AEs that resulted in permanent treatment discontinuation; these effects comprised fatigue, vomiting, sepsis, anemia, abdominal pain, acute kidney injury, and encephalopathy.

The most common toxicities with avapritinib that were observed in 20% or more of patients included edema (all grade, 72%; grade ≥3, 2%), nausea (64%; 2.5%), fatigue or asthenia (61%; 9%), cognitive impairment (48%; 4.9%),vomiting (38%; 2%), reduced appetite (38%; 2.9%), diarrhea (37%; 4.9%), increased lacrimation (33%; 0%), abdominal pain (31%; 6%), constipation (23%; 1.5%), rash (23%; 21%), dizziness (22%; 0.5%), and hair color changes (21%; 0.5%).