Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal (GI) tract.¹ With primary oncogenic drivers in the mutations of exons 9 or 11 in KIT or exon 18 in PDGFRA, additional mutations in these genetic loci are frequently acquired during treatment with imatinib, sunitinib or regorafenib that leads to subsequent drug resistance.² Previously, The National Comprehensive Cancer Network (NCCN) Task Force reported that GIST patients with KIT mutation at exon 9 or PDGFRA mutation at exon 18 had a low objective response rate (ORR) to imatinib of <50% and <37%, respectively.³ In particular, the progression-free survival (PFS) amongst those receiving imatinib, sunitinib or regorafenib were poor after developing drug resistance, ranging from 5 to 24 months.³

To address the drug resistance among patients with advanced GIST, the approved tyrosine kinase inhibitor (TKI) ripretinib can be used to target a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants.^4,5 In the phase 3 randomized, double-blind, placebo-controlled INVICTUS trial, ripretinib significantly improved the median PFS to 6.3 months versus 1 month in those receiving placebo (HR=0.16; 95% CI: 0.10-0.27; p<0.001).⁴ Compared to placebo, ripretinib also significantly improved the median overall survival (OS) to more than 15 months (HR=0.42; 95% CI: 0.26-0.67; p<0.001).² Notably, ripretinib had a numerically greater ORR of 9.4% versus 0% in the placebo group (p=0.0504).2 In terms of safety, a similar rate of treatment-related serious adverse events was reported between ripretinib and placebo (9% vs. 7%).⁴

In addition to ripretinib, the approved TKI avapritinib can also be used to target the primary and secondary mutations in KIT and PDGFRA including the exon 18 PDGFRA D842V mutation which encodes the pan-drug resistance to imatinib, sunitinib and regorafenib.^3,6 In the multicenter, open-label phase 1 NAVIGATOR study, avapritinib achieved an ORR of 88% with 98% of patients attaining clinical benefit, defined as complete response or partial response plus stable disease lasting for at least 16 weeks.⁶ Although >40% of patients receiving avapritinib reported adverse reactions including nausea, malaise, anemia, diarrhea, periorbital edema and memory impairment, a similar rate of treatment-related adverse events was reported in patients who received ≥1 avapritinib dose.6 With the approval of ripretinib and avapritinib, the NCCN guidelines now recommend avapritinib and ripretinib as the first- and fourthline therapy, respectively, for patients who had unresectable GISTs and significant morbidity.

With now 5 FDA approved agents for GISTs, Dr. Richard Riedel, Associate Professor of the Duke Cancer Institute, United States, emphasized that all patients who are considering systemic therapy, regardless of being in the advanced or the neoadjuvant setting, should receive mutational testing to ensure that those with pan-resistant mutations are not exposed to unnecessary therapies that have no benefits. “Importantly, mutational testing really needs to be performed when considering systemic therapy for any individuals [with GIST] to identify the resistant mutations,” reiterated Dr. Riedel.