Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors

Abstract

Background Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18‐mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence‐based guidance on management of avapritinib‐associated adverse events (AEs), including cognitive effects and intracranial bleeding. Materials and Methods We performed a post hoc analysis of data from a two‐part, single‐arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30–600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression‐free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). Results Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18‐mutation; 66.8% started avapritinib at 300 mg. The most common treatment‐related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment‐related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all‐cause cognitive effects rate (grade 1–2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3–3.1 weeks) than without (4.9–7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. Conclusion Tolerability‐guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. Implications for Practice Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment‐related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

Gastrointestinal Stromal Tumors—A Mini Review

“…Thus, patients with advanced disease require an initial assessment of tumor mutational status for targeted chemotherapy. Clinical responses to TKI are correlated with tumor genotype [ 60 , 61 , 62 ].…”

“…Neoadjuvant imatinib should be considered in patients with large tumors, in whom immediate resection is not possible (e.g., total gastrectomy) [ 60 , 61 , 62 ]. Currently, imatinib can be used for patients with KIT mutations and most PDGFRA mutations (except PDGFRA D842V) [ 60 , 61 , 62 ]. In addition, there are studies suggesting that the real percentage of patients with KIT/PDGFRA wild-type is lower than was considered.…”

“…In patients with unknown KIT mutational status, an alternative second-line treatment is sunitinib [ 62 ]. The presence of PDGFRA D842V mutation confers significant resistance to imatinib [ 62 , 63 ].…”

“…In patients with unknown KIT mutational status, an alternative second-line treatment is sunitinib [ 62 ]. The presence of PDGFRA D842V mutation confers significant resistance to imatinib [ 62 , 63 ]. Thus, avapritinib is recommended in patients with symptomatic or rapidly progressive disease and PDGFRA D842V mutation [ 62 , 63 ].…”

“…The presence of PDGFRA D842V mutation confers significant resistance to imatinib [ 62 , 63 ]. Thus, avapritinib is recommended in patients with symptomatic or rapidly progressive disease and PDGFRA D842V mutation [ 62 , 63 ]. However, if this mutation is identified but the patient is asymptomatic or has a form of indolent disease, an observation period prior to initiating avapritinib is recommended because of treatment toxicity and potential cognitive impairment.…”