FDA-Approved Advanced GIST Therapy Can Elicit Durable Responses With Tolerable Safety


In patients with gastrointestinal stromal tumors who have received 3 or more prior therapies, there remain unmet needs to overcome resistance to the standard-of-care, imatinib, a tyrosine kinase inhibitor, and prolong the 6.3-month+ progression-free survival achieved with the FDA-approved TKI ripretinib.

In patients with gastrointestinal stromal tumors (GIST) who have received 3 or more prior therapies, there remain unmet needs to overcome resistance to the standard-of-care, imatinib (Gleevec), a tyrosine kinase inhibitor (TKI), and prolong the 6.3-month+ progression-free survival (PFS) achieved with the FDA-approved TKI ripretinib (Qinlock).1

Avapritinib (Ayvakit) is a newer TKI that demonstrated clinical activity against resistance mutations in GIST in preclinical studies. Later, in the phase 1 NAVIGATOR study (NCT02508532), the agent achieved an 84% (95% CI, 69%-93%) overall response rate (ORR) in the subset of patients with unresectable or metastatic platelet-derived growth factor receptor alpha (PDGFRA) exon 18–mutant GIST. The result is 1 of multiple outcomes that led to the FDA approval of avapritinib for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. It is the first precision therapy approved in this patient population.1,2

Months following the announcement of the FDA approval, the full results from the NAVIGATOR study were published.1

The first-in-human, 2-part, single-arm, multicenter NAVIGATOR study was designed to assess the safety and activity of avapritinib in patients with unresectable GIST. Part 1 of the study was the dose-finding phase and part 2 was the dose-expansion study. Results published included part 2 data from patients with KIT- or PDGFRA-mutant GIST who were treated with avapritinib 300 mg or 400 mg once daily in the fourth-line setting or a later setting.

A total of 191 patients made up the part 2 cohort and the patients were categorized into 3 groups based on their mutational status. The 117 patients in group 1 were those without D842V mutations who were treated with ≥2 previous lines of TKI therapy. Group 2 had 36 patients who were positive for D842V mutations, and group 3 included 38 patients who did not have Patients without D842V mutations and were treated with 1 previous line of TKI therapy. When factoring in the 46 patients from the dose-finding portion of the study, 237 patients were treated with avapritinib. Of the patients treated, 154 received the 300-mg dose, 50 received the 400-mg dose, and the remaining 33 patients received other dose levels of avapritinib.

The overall efficacy population included patients of all genotypes. There were 121 patients evaluated for efficacy. At baseline, screening data from the patients showed a median age of 59 (range, 33-80) in the predominantly male (58%) and White (71%) population. Ninety-one percent of the patients were positive for KIT mutations, while 7% had PDGFRA D842V mutations, and 2% had PDGFRA exon 18 non-D842V mutations. An ECOG performance status of 1 was shown in 64% of patients following by a score of 0 for 32% of patients. The majority of patients in the stud (98%) had metastatic disease.

Target lesion sizes were measured at baseline and classified as either 5 cm or larger, >5 cm to 10 cm, or >10 cm. Most patients (47%) had lesions >5 cm to 10 cm. Thirty-three percent of patients had lesions of 5 cm or larger, and 18% had lesions >10 cm in diameter.

The median prior lines of therapy received by patients according to baseline data were 4 prior lines (range, 3-11), and the most common prior therapy was sunitinib (Sutent; 98%). Regorafenib (Stivarga) had been previously received by 85% of patients, and 85% had previously undergone surgical resection.

Overall, baseline demographics were well balanced between the 300-mg cohort and the 400-mg cohort.

The ORR observed with avapritinib by central radiology assessment per modified RECIST v1.1 criteria as well as safety were the coprimary end points of the study. The secondary end points were duration of response (DOR), PFS, clinical benefit rate (CBR), and response rate according to Choi criteria. Overall survival (OS) was also evaluated as an exploratory end point.

One-hundred-three patients of 121 were evaluable for response. Avapritinib achieved an ORR of 17% (95% CI, 10%-25%). The best response was a partial response which was observed in 17% of the response-evaluable population. Fifty percent of patients in the population achieved stable disease while 34% had progressive disease (PD). The clinical benefit rate was 38% (95% CI, 29%-48%).

In the 113 patients with KIT/non-D842V PDGFRA-mutant advanced GIST who were assessed per Choi criteria, the ORR was 31% (95% CI, 23%-40%).

In terms of the secondary study outcomes, the median DOR was 10.2 months (95% CI, 7.2-10.2). The median PFS achievement was modest at 3.7 months (95% CI, 2.8-4.6). The median OS was 11.6 months (95% CI, 8.5-14.4) and OS was notably longer among patients who received the 400-mg dose of avapritinib at 12.4 months (95% CI, 6.9-16.4) compared with 10.9 months (95% CI, 8.1-14.4) in the 300-mg cohort.

The subgroup of patients who did not have PDGFRA D842V mutations achieved a median PFS of 3.7 months (95% CI, 2.8-4.6). Kaplan-Meier PFS rates were estimated as 31% (95% CI, 22%-40%) at 6 months and 10% (95% CI, 3%-17%) at 12 months. The median OS was 11.6 months (95% CI, 8.5-14.4).

Safety was assessed in 204 patients from parts 1 and 2 of NAVIGATOR. Among those treated with a 300-mg starting dose, 65% required at least 1 dose interruption, and 68% of the 400-mg group required at least 1 dose interruption. Overall, 99% of patients experienced an adverse event (AE), 72% had a grade 3 or higher AE, and treatment-related AEs occurred in 51% of patients.

The most common AEs of any grade observed in the study were nausea (64%), fatigue (55%), anemia (50%), cognitive effects (41%), and periorbital edema (41%). Most AEs were either grade 1 or 2, but of the grade ≥3 AEs observed, the most common were anemia (16%) and fatigue (6%).

Cognitive effects were also seen in the study patients of which 69% were grade 1, 21% were grade 2, and 10% were grade 3. These effects were caused by memory impairment and other issues. Two patients from the safety population notably experienced intracranial bleeding.

Treatment was discontinued for 68% of the population, which was primarily due to disease progression (45%, but some patients did discontinue avapritinib due to treatment-related AEs. Encephalopathy and fatigue were the most commonly seen treatment-related AES, having occurred in 1% of patients each. The occurrence of cognitive effects led to treatment discontinuation in 2% of the population.

The results of the NAVIGATOR study show that avapritinib has the ability to achieve moderate clinical activity in patients with GIST who harbor KIT or PDGFRA mutations with or without D842V being treated in the fourth- or later-line setting.


George S, Jones RL, Bauer S, et al. Avapritinib in patients with advanced gastrointestinal stromal tumors following at least three prior lines of therapy. Oncologist. 2021;25:1-11. doi: 10.1002/onco.13674

Blueprint Medicines announces FDA approval of Ayvakit™ (avapritinib) for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant gastrointestinal stromal tumor. News release. Blueprint Medicines, Inc. January 9, 2020. Accessed February 19, 2021. https://bit.ly/37sN9zY

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