UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Most gastrointestinal stromal tumors (GISTs) occur in the stomach, although such tumors also occur in the small intestine, rectum, and esophagus [117]. Although significant heterogeneity exists [118], GISTs frequently demonstrate immunohistochemical positivity for two oncogenes (KIT and DOG-1) [119–121]. Some GISTs harbor gain-of-function mutations in PDGFRA (particularly stomach GISTs), KIT (particularly small intestine GISTs), and several other genes [122–124]. In localized GIST, imatinib may be considered for patients harboring KIT mutations either in lieu of surgery or in the neoadjuvant setting. TKIs are the standard of care for patients harboring metastatic disease, and five TKIs are indicated for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. Imatinib is commonly administered as first-line therapy and avapritinib is indicated for GIST with PDGFRA exon 18 mutation. Sunitinib is indicated for patients with imatinib-resistant tumors or imatinib intolerance. Regorafenib is administered as third-line therapy following disease progression on imatinib and sunitinib [125]. Ripretinib is indicated for the four-line setting. Saif et al. demonstrated that two patients with Gilbert’s syndrome experienced gradual inclines in bilirubin concentrations that prompted numerous imatinib dose adjustments [116]. Thus, UGT1A1*28 could be a useful tool to determine the cause of hyperbilirubinemia a priori so that dose adjustments could be better informed. Such a strategy is important in GIST management since TKIs are the primary therapies for this disease.
Avapritinib for the treatment of KIT mutation–negative systemic mastocytosis
Published in Baylor University Medical Center Proceedings, 2023
Farhan Azad, Jiahua Zhang, Eunice Wang
Avapritinib is a highly selective and potent D816V inhibitor approved by the Food and Drug Administration for SM based on multiple clinical trial data.12 The PATHFINDER trial showed an overall response rate of 75% in 32 response-evaluable SM patients, with a complete remission rate of 19%. Furthermore, the trial showed reductions of ≥50% from baseline in serum tryptase and bone marrow MC. Responses were seen at all starting doses, with the most rapid response at 200 mg daily or higher. The results corroborated outcomes from the EXPLORER trial,13 which showed an overall response rate of 75% in 53 response-evaluable SM patients and a complete remission rate of 36%. Avapritinib was well tolerated with a recommended dose of 200 mg daily. EXPLORER revealed a consistent reduction in total symptom score, with improvements in gastrointestinal symptoms, skin symptoms, and fatigue.14 Part 1 of the PIONEER trial was set to determine the recommended dose of avapritinib. It showed that 25 to 100 mg daily can rapidly reduce serum tryptase levels in SM.15 In our patient, the starting dose was 200 mg daily, which led to a rapid decline of tryptase level, with symptomatic improvement within months at a reduced dose of 100 mg. Treatment with avapritinib shows promising results in this difficult-to-treat condition.
New insights into the clinical management of advanced gastrointestinal stromal tumors
Published in Expert Opinion on Pharmacotherapy, 2021
Avapritinib is a highly selective inhibitor of KIT and PDGFRA receptors with an extremely powerful action on secondary resistance mutations (exons 17 and 18 of KIT) and on primary resistance mutation (D842V mutation in PDGFRA). Safety and efficacy results from patients treated in the fourth-line setting or with a PDGFRA exon 18 mutation and included in the pivotal NAVIGATOR study (NCT02508532) were recently reported [27]. Patients were reported to use avapritinib at the recommended Phase 2 dose of 300 mg or the maximum tolerated dose of 400 mg. Among the 111 patients treated in the fourth-line setting or above, the objective response rate was 22% (95% CI 14.4–30.4). The median PFS was 3.7 months (3.4–5.6). The most frequent treatment-related adverse events were nausea (59.3%), fatigue (47.1%), anemia (36.3%), and cognitive effects (41.2%). These cognitive effects included memory impairment, cognitive disorder, confusion state, and encephalopathy. The mechanisms involved in these neurological symptoms have not yet been elucidated. Unfortunately, a Phase III study comparing this molecule to regorafenib in the third line of treatment (https://clinicaltrials.gov/ct2/show/NCT03465722) did not meet the primary endpoint of an improvement in progression-free survival.
Emerging drugs for the treatment of gastrointestinal stromal tumors
Published in Expert Opinion on Emerging Drugs, 2021
Daniel F. Pilco-Janeta, Alfonso García-Valverde, David Gomez-Peregrina, César Serrano
The phase I NAVIGATOR trial included two groups in the expansion part that included non-D842V mutant GIST patients treated at any line after imatinib progression (Group 1), and the same GIST population treated with avapritinib as a true second-line (Group 3). The results have been communicated, but not formally reported. Nonetheless, the preliminary encouraging data shown in metastatic GIST, together with avapritinib activity profile against activation-loop mutants, led to the phase III trial VOYAGER (NCT03465722), which compared avapritinib with regorafenib in the third or fourth line. This was an international, multicenter, open-label, phase III study that randomized metastatic GIST patients to either avapritinib (n = 240) or placebo (n = 236). Although the results of this trial have not been communicated yet, a press release from Blueprint Medicines on 28 April 2020 reported that the trial did not meet the primary endpoint, mPFS: avapritinib showed a mPFS of 4.2 months compared to 5.6 months for regorafenib, a difference that was not statistically significant. Thus, although avapritinib appears to be an active agent in GIST patients after progression to imatinib and sunitinib, the findings from this trial were insufficient to support the approval of avapritinib in this setting.
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