Imatinib

Neoadjuvant imatinib may be used for patients with very large primary GISTs or poorly positioned small GISTs (considered unresectable without the risk of significant morbidity or functional deficit, such as needing a formal gastrectomy, pancreatectomy, or other major organ resection) until surgical therapy is feasible, which can take as long as 6 to 12 months.[1,2] Neoadjuvant imatinib therapy in patients with GISTs is supported by the early results of two phase II studies in the United States [3] and Asia [4], as well as several case series and small retrospective reports.[2,5-10] Neoadjuvant imatinib may be particularly beneficial in rectal GISTs, given the large bulky nature of the disease and the extensive surgery required for complete resection.[11,12]

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Evidence (phase II studies of neoadjuvant imatinib):

RTOG-0132/ACRIN-6665 (NCT00028002) was a phase II single-arm study of 52 patients with primary GISTs (n = 30) or operable metastatic GISTs (n = 22). Patients received preoperative imatinib (600 mg daily) for 8 to 12 weeks followed by postoperative imatinib for at least 2 years.[3][Level of evidence C3]

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RTOG-0132/ACRIN-6665 (NCT00028002) was a phase II single-arm study of 52 patients with primary GISTs (n = 30) or operable metastatic GISTs (n = 22). Patients received preoperative imatinib (600 mg daily) for 8 to 12 weeks followed by postoperative imatinib for at least 2 years.[3][Level of evidence C3]

Among patients with primary GISTs, 83% had stable disease and 7% had a partial response (7%). Among patients with metastatic GISTs, 91% had stable disease, 4.5% had a partial response, and 4.5% had disease progression.

RTOG-0132/ACRIN-6665 (NCT00028002) was a phase II single-arm study of 52 patients with primary GISTs (n = 30) or operable metastatic GISTs (n = 22). Patients received preoperative imatinib (600 mg daily) for 8 to 12 weeks followed by postoperative imatinib for at least 2 years.[3][Level of evidence C3]

At a median follow-up of 36 months, the 2-year PFS rate was 83% in patients with primary GISTs and 77% in patients with metastatic GISTs. The OS rate was 93% in patients with primary GISTs and 91% in patients with metastatic GISTs.

RTOG-0132/ACRIN-6665 (NCT00028002) was a phase II single-arm study of 52 patients with primary GISTs (n = 30) or operable metastatic GISTs (n = 22). Patients received preoperative imatinib (600 mg daily) for 8 to 12 weeks followed by postoperative imatinib for at least 2 years.[3][Level of evidence C3]

Seventy-seven percent of patients with primary GISTs and 58% of patients with metastatic GISTs went on to have R0 resections. Five patients (10%) had unresectable disease.

RTOG-0132/ACRIN-6665 (NCT00028002) was a phase II single-arm study of 52 patients with primary GISTs (n = 30) or operable metastatic GISTs (n = 22). Patients received preoperative imatinib (600 mg daily) for 8 to 12 weeks followed by postoperative imatinib for at least 2 years.[3][Level of evidence C3]

Imatinib was generally well tolerated, although 35% of patients had grade 3 to 5 adverse events. The median preoperative duration of imatinib was 65 days, and the median time of imatinib discontinuation before surgery was 2 days.

A phase II single-arm study conducted in Asia included 53 evaluable patients with gastric GISTs larger than 10 cm. Patients received preoperative imatinib (400 mg daily) for 6 to 9 months, followed by at least 1 year of postoperative imatinib.[4][Level of evidence C3]

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A phase II single-arm study conducted in Asia included 53 evaluable patients with gastric GISTs larger than 10 cm. Patients received preoperative imatinib (400 mg daily) for 6 to 9 months, followed by at least 1 year of postoperative imatinib.[4][Level of evidence C3]

Forty-six patients (87%) received at least 6 months of preoperative imatinib and 50 patients ultimately underwent gastrectomy. The median duration of preoperative imatinib was 26 weeks. The most common grade 3 to 4 adverse events were neutropenia and rash.

A phase II single-arm study conducted in Asia included 53 evaluable patients with gastric GISTs larger than 10 cm. Patients received preoperative imatinib (400 mg daily) for 6 to 9 months, followed by at least 1 year of postoperative imatinib.[4][Level of evidence C3]

The objective response rate was 62%, and the maximal reduction occurred most commonly at 24 weeks (63% of patients). The R0 resection rate was 91% overall, and at least one-half of the stomach was preserved in 79% of patients.

A phase II single-arm study conducted in Asia included 53 evaluable patients with gastric GISTs larger than 10 cm. Patients received preoperative imatinib (400 mg daily) for 6 to 9 months, followed by at least 1 year of postoperative imatinib.[4][Level of evidence C3]

At a median follow-up of 32 months, the 2-year PFS rate was 89%, and the OS rate was 98%.

If a preoperative TKI is planned, a biopsy to confirm the diagnosis and, potentially, molecular profiling should be considered. Mutational analysis may help to exclude nonsensitive variants before starting imatinib cytoreduction therapy. Biopsy and molecular profiling may also determine whether a tumor harbors a KIT exon 9 variant, which may require an increase in initial imatinib dosing.[1,13] Neoadjuvant imatinib is not used for patients with GISTs harboring a PDGFRA D842V variant. Some guidelines, such as those from the European Society of Medical Oncology, recommend considering neoadjuvant avapritinib.[14] However, avapritinib has not been tested or validated in the neoadjuvant setting. In addition, patients with KIT/PDGFRA wild-type GISTs (i.e., SDH-deficient or neurofibromatosis type 1 [NF1]-related GISTs) would not benefit from neoadjuvant therapy and should proceed directly to surgery, if feasible.

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If indicated, neoadjuvant imatinib is initiated at 400 mg per day in most patients. Patients with KIT exon 9–variant GISTs may be offered a higher dose (800 mg per day) based on data from the advanced setting.[15] Follow-up imaging, with either computed tomography (CT) or positron emission tomography (PET)-CT, is performed at close intervals. PET-CT can be particularly helpful in assessing initial early response if baseline molecular profiling was not done before neoadjuvant therapy.[16] The optimal duration of neoadjuvant treatment is unknown and should be individualized based on multidisciplinary discussion. Neoadjuvant TKI therapy precludes the ability to risk stratify after surgical resection. Therefore, patients should continue imatinib after surgery for at least 3 total years.

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Studies cited in this source section

Publication references