Avapritinib Considered to be a Promising Option for Locally Advanced Metastatic or Unresectable GIST

Suzanne George, MD

Suzanne George, MD

The phase III VOYAGER study may soon introduce a new treatment option for patients with locally advanced metastatic or unresectable gastrointestinal stromal tumors (GIST), a patient population with an unmet need for novel agents that are durable and can target specific drivers. The trial is looking at the efficacy of novel drug avapritinib (BLU-285) versus standard-of-care regorafenib (Stivarga).

"Patients need better strategies because although kinase inhibitors have made such a great impact on GIST, we still don’t have a cure and subsequent lines of therapy are yielding less durable benefit with the currently approved drugs,” Suzanne George, MD, stated during an interview withTargeted Oncology.

Treating patients with GIST who are refractory to regorafenib and other agents is an ongoing challenge. This shows that there is not only a need for new therapies but also a greater focus on genomic testing so new drivers can be uncovered and so that emerging therapies can be more targeted against these disease drivers.

“I think the biggest challenge with treating this population is resistance toward emerging therapies. We need to be strategic and continue to be mindful of the need for new therapies,” said George, senior physician and director of clinical research, Sarcoma Center, Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School. “There’s an emerging role of mutation testing in GIST to try to understand primary mutations and how they may impact treatment. Particularly, the ability to identify the platelet-derived growth factor receptor alpha [PDGFRA] gene, which is a primary driver mutation that is resistant to all currently approved agents, but avapritinib has shown activity in.”

The rationale behind launching the international, multicenter, open-label, randomized phase III VOYAGER study was the phase I NAVIGATOR study, an open-label, first-in-human study that evaluating safety, tolerability, pharmacokinetics, pharmacodynamics. and the antineoplastic activity of avapritinib in GIST and other relapsed or refractory solid tumors. Two-hundred and thirty-seven patients in the NAVIGATOR trial with unresectablePDGFRAD842V—positive GIST or another GIST mutation who progressed on imatinib (Gleevec) and at least 1 other tyrosine kinase inhibitor (TKI) were treated with the maximum tolerated dose of avapritinib for a cycle of 28 days.

The most recent results show that among patients receiving avapritinib who had been treated with at least 4 prior TKIs had a median 10.2 months duration of response (mDOR) (95% CI, 7.2-not evaluable). Among these patients, there was 1 complete response, 23 partial responses, and 52 patients with stable disease. The objective response rate was 22%. In this group, a progression-free survival benefit of 3.7 months (95% CI, 3.4-5.6) was also seen.¹

In the population of patients withPDGFRAexon 18—mutant GIST, there were 3 complete responses, 34 partial responses, and 5 patients with stable disease. The mDOR was not reached.¹

There were 204 adverse events (AEs) seen in the phase I study. The AEs most common were nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (29%). Two patients experienced grade 3 intracranial hemorrhage and 1 patient had a grade 1 intracranial hemorrhage. Less than 15% of patients discontinued treatment as a result of toxicity.¹

Based on these data, investigators concluded that the drug is tolerable with a predictable and manageable safety profile. It also shows important clinical activity, the most notable being its ability to targetPDGFRAD842V, a target for which no approved targeted therapy exists. Investigators consider avapritinib to have a role in the fourth-line setting for patients with GIST who have failed prior lines of therapy and currently have no other options.

The VOYAGER study is ongoing and actively recruiting patients. In anticipation of the VOYAGER study results, George stated, “the drug has clear promise and demonstrated activity in the advanced GIST population after prior lines of therapy. This an interesting study. I look forward to the results and to see how they will impact care.”

Reference:

Heinrich M, Jones RL, von Mehren M, et al. Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).J Clin Oncol. 2019;37 (suppl; abstr 11022).