ctDNA and avapritinib in GI cancer management

Avapritinib for mutated GIST

The platelet-derived growth factor receptor–alpha (PDGFRA) gene encodes PDGFRA, a member of the type III tyrosine kinase receptor family, which includes the stem cell factor receptor, KIT (present in 95% of GISTs). PDGFRA and KIT have domains with specific roles in tyrosine kinase activation. Several PDGF isoforms bind and activate PDGFRA.

Among patients with GISTs, clinical responses to imatinib and other tyrosine kinase inhibitors (TKIs) correlate with tumor genotype. For example, many GISTs that progress within 6 months of TKI initiation lack mutations in KIT or PDGFRA or have a PDGFRA D842 mutation.

The Food and Drug Administration recently approved avapritinib (Ayvakit) for adults with unresectable or metastatic GISTs with a PDGFRA exon 18 mutation. The approval was based on the results of the NAVIGATOR trial, a single-arm, multicenter, open-label study of 43 patients with PDGFRA exon 18 mutations, including 38 patients with a PDGFRA D842V mutation.

The patients received 300 mg avapritinib once daily and 84% responded to avapritinib, though most were partial responses. Among patients with a D842V mutation, the response rate was also high – at 89% – but most responses were partial. At a median follow-up of 10.6 months, median response duration was not reached, but 61% of responses exceeded 6 months. Toxicity included asthenia, gastrointestinal and central nervous system side effects (including intracranial hemorrhage), hair color changes, lacrimation, and dizziness.

Avapritinib is the first drug approved specifically for patients with advanced or unresectable GISTs with a PDGFRA exon 18 mutation.

How these results influence practice

PDGFRA exon 18 mutations occur in 5%-7% of GISTs and are believed to stabilize the kinase activation loop, perhaps accounting for slow, steady growth of these tumors over a long time period and resistance to TKIs. The most frequent mutation results in an exon 18 D842V substitution (75% of all PDGFRA-mutated tumors). Although dramatic progress has been made in the treatment of patients with GIST since 2000, in patients with GISTs harboring PDGFRA exon 18 mutations, responses to treatment are rare and, when they occur, are more abbreviated.

With a high response rate and impressive response duration, avapritinib will be a valuable resource for oncologists treating this uncommon subset of patients with GISTs. The opportunity to convert unresectable tumors to potentially curable ones seems within reach.

The difficult dilemma will be to decide when treatment is needed and drug-related toxicity is justified in patients with slowly progressive tumors and few symptoms. As with so many decisions in oncology, until newer agents with fewer toxicities and higher complete response rates are developed, the proper time for any individual patient to embark on treatment with avapritinib will be found at the intersection of “precision medicine” and “clinical judgment.”

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.