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Avapritinib in advanced gastrointestinal stromal tumor: case series and review of the literature from a tertiary care center in India.

ABSTRACT: The therapeutic landscape in advanced gastrointestinal stromal tumor has evolved. Avapritinib and ripretinib have now been approved by the US FDA for platelet-derived growth factor alpha D842V-mutant and refractory gastrointestinal stromal tumor patients, respectively. Here we report five patients who have been on avapritinib under an expanded access program. Response assessment was available for four patients - a partial response in two patients and stable disease in one, while one patient had progressive disease. Though preliminary results of the VOYAGER trial have shown less activity of avapritinib and no significant difference in progression-free survival when compared with regorafenib, avapritinib may show some clinical benefit in a subset of patients refractory to approved therapies. We share our experience of five cases, with clinical benefit in three. We believe avapritinib should be further evaluated in clinical trials.

SUBMITTER: Verma S

PROVIDER: S-EPMC8015663 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Avapritinib in advanced gastrointestinal stromal tumor: case series and review of the literature from a tertiary care center in India.

Verma Saurav S Reddy Rohit R Chandrashekhara Sheragaru Hanumanthappa SH Shamim Shamim Ahmed SA Tripathy Sarthak S Rastogi Sameer S

Future science OA 20210119 4

The therapeutic landscape in advanced gastrointestinal stromal tumor has evolved. Avapritinib and ripretinib have now been approved by the US FDA for platelet-derived growth factor alpha D842V-mutant and refractory gastrointestinal stromal tumor patients, respectively. Here we report five patients who have been on avapritinib under an expanded access program. Response assessment was available for four patients - a partial response in two patients and stable disease in one, while one patient had ...[more]

PMID: 33815822

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Project description:BackgroundMost gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.Materials and methodsEligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy.ResultsAs of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6).ConclusionAvapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations.Implications for practiceIn the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.

Project description:BackgroundAvapritinib, 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 methodsWe 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).ResultsOf 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.ConclusionTolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs.Implications for practiceEarly 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.

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Avapritinib in advanced gastrointestinal stromal tumor: case series and review of the literature from a tertiary care center in India.

Publications

Avapritinib in advanced gastrointestinal stromal tumor: case series and review of the literature from a tertiary care center in India.

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