Until recently, there were no US Food and Drug Administration (FDA)–approved therapies for the fourth-line treatment of GIST, but now we have ripretinib. Ripretinib, a novel switch control kinase inhibitor, was approved for the treatment of adults with GIST who have already been treated with 3 or more kinase inhibitors, including imatinib. The approval was based on the phase 3 INVICTUS trial, in which patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib were randomized to ripretinib or placebo. Patients in the ripretinib arm experienced a significant improvement in progression-free survival; the median progression-free survival was 6.3 months for ripretinib compared with 1.0 month for placebo.

Patients with GIST who require fourth-line treatment often have secondary mutations in KIT, such as KIT exon 13, 14, 17, or 18 mutations, or in PDGFRA, such as the exon 18 D842V substitution. Thus, mutational testing is needed to help identify the treatment that is the most likely to elicit the best response.

Ripretinib was shown to broadly inhibit KIT and PDGFRA kinase signaling in preclinical studies. In vitro, ripretinib actually seems to inhibit a wider range of relevant mutations than any other drug that is available for advanced GIST. Avapritinib was also recently FDA approved, but its approval was specific to adults with GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Both avapritinib and ripretinib have their own set of side effects. Avapritinib, for instance, is associated with short-term memory loss in some patients, and ripretinib is linked to anemia, fatigue, and hair loss in some patients.

Patients requiring fourth-line treatment generally have multifocal disease that cannot be controlled with localized therapies; an important exception would be patients who progress with clonal outgrowth, which may be treated successfully with radiation, ablation, or surgery. However, advanced GIST requiring fourth-line treatment and beyond is, by and large, a disease that should be treated with systemic therapy. These are generally patients whose performance status is lower than those going on imatinib, and many of them have experienced the different types of side effects that are possible with imatinib, sunitinib, and regorafenib use. So, these individuals have seen a lot and have endured a lot.

We are fortunate to currently have ripretinib, and we hope that new strategies will continue to emerge for patients who have been through imatinib, sunitinib, and regorafenib. Clinical trial participation is an important consideration for all patients with GIST, owing to the rarity of the disease, and not just for those with advanced GIST. Here in our setting, we have an ongoing trial using the PD1 inhibitor nivolumab, either as a single agent or in combination with ipilimumab, against resistant GIST, and approximately one-third of patients in this trial have experienced greater clinical benefit than expected. In addition, we look forward to continued reporting from the phase 3 INVICTUS and Intrigue trials with ripretinib. The former formed the basis of the FDA approval of the agent as a fourth-line therapy, and the latter is comparing the efficacy of ripretinib with sunitinib in patients with GIST who progressed on or were intolerant to first-line imatinib. This is a rapidly evolving field, and we hope to have many new options for patients who do not respond to standard therapies in the near future.