Most advanced gastrointestinal stromal tumors (GISTs) are due to a recurrence of localized disease, with only a small minority presenting with metastatic disease.1 Compared with chemotherapy, tyrosine kinase inhibitors (TKIs) have significantly improved the natural history of the disease, with median overall survival (OS) increasing from less than 1 year to about 5 years and approximately 1 in 5 patients achieving long-term survival.2 In addition, newer drugs in development and in clinical trials appear promising and have the potential to improve outcomes even further. This article reviews current evidence on options for treating metastatic or recurrent GISTs and GISTs that have progressed following initial therapy. The evaluation and diagnosis of GIST along with management of localized disease are reviewed in a separate article.
A 64-year-old African American man underwent surgical resection of a 10-cm gastric mass, which pathology reported was positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. There were 10 mitoses per 50 HPF, and there was no intraoperative or intraperitoneal tumor rupture. The patient was treated with adjuvant imatinib, which was discontinued after 3 years due to grade 2 myalgias, periorbital edema, and macrocytic anemia. Surveillance included office visits every 3 to 6 months and a contrast CT abdomen and pelvis every 6 months. For the past 5 years, he has not had any clinical or radiographic evidence of disease recurrence. New imaging reveals multiple liver metastases and peritoneal implants. He feels fatigued and has lost about 10 lb since his last visit. He is 5 years out from his initial diagnosis and 2 years out from last receiving imatinib. His original tumor harbored a KIT exon 11 deletion.
What treatment should you recommend now?
Imatinib for Advanced GISTs
Before the first report of the efficacy of imatinib for metastatic GISTs in 2002, patients with advanced unresectable or metastatic GISTs were routinely treated with doxorubicin-based chemotherapy regimens, which were largely ineffective, with response rates (RRs) of around 5% and a median overall survival (OS) of less than 1 year.3,4 In 2002 a landmark phase 2 study revealed imatinib’s significant efficacy profile in advanced or metastatic GISTs, resulting in its approval by the US Food and Drug Administration (FDA).5 In this study, 147 patients with CD117-positive GISTs were randomly assigned to receive daily imatinib 400 mg or 600 mg for up to 36 months. The RRs were similar between the 2 groups (68.5% vs 67.6%), with a median time to response of 12 weeks and median duration of response of 118 days. Results of this study were much more favorable when compared to doxorubicin, rendering imatinib the new standard of care for advanced GISTs. A long-term follow-up of this study after a median of 63 months confirmed near identical RRs, progression-free survival (PFS), and median survival of 57 months among the 2 groups.6
Imatinib Daily Dosing
Although 400 mg of daily imatinib proved to be efficacious, it was unclear if a dose-response relationship existed for imatinib. An EORTC phase 2 study demonstrated a benefit of using a higher dose of imatinib at 400 mg twice daily, producing a RR of 71% (4% complete , 67% partial) and 1-year PFS of 73%, which appeared favorable compared with once-daily dosing and set the framework for larger phase 3 studies.7 Two phase 3 studies compared imatinib 400 mg once daily versus twice daily (until disease progression or unacceptable toxicity) among patients with CD117-positive advanced or metastatic GISTs. These studies were eventually combined into a meta-analysis (metaGIST) to compare RR, PFS and OS between the treatment groups. Both studies allowed cross-over to the 800 mg dose for patients who progressed on 400 mg daily.
The first study, conducted jointly by the EORTC, Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group (EU-AUS),8 randomly assigned 946 patients to 400 mg once daily or twice daily. There were no differences in response rates between the groups, but the twice-daily group had a predicted 18% reduction in the hazard for progression compared with the once-daily group (estimated HR, 0.82; P = 0.026), which came at the expense of greater toxicities warranting dose reductions (60%) and treatment interruptions (64%). Cross-over to high-dose imatinib was feasible and safe, producing a partial response in 2%, stable disease in 27%, and a median PFS of 81 days. The second study was an intergroup study conducted jointly by SWOG, CALGB, NCI-C, and ECOG (S0033, US-CDN), with a nearly identical study design as the EU-AUS trial.9 The trial enrolled 746 patients. After a median follow up of 4.5 years, the median PFS and OS were not statistically different (18 vs 20 months and 55 vs 51 months, respectively). There were also no differences in response rates. One third of patients initially placed on the once-daily arm who crossed over after progression achieved a treatment response or stable disease.
The combined EU-AUS and US-CDN analysis (metaGIST) included 1640 patients with a median age of 60 years and 58% of whom were men; 818 and 822 patients were assigned to the 400 mg and 800 mg total daily doses, respectively.10 The median follow-up was 37.5 months. There were no differences in OS (49 vs 48.7 months), median PFS (18.9 vs 23.2 months), or overall response rates (51.4% vs 53.9%). Patients who had crossed over (n = 347) to the 800 mg total daily dose arm had a 7.7-month average PFS while on the higher daily dose. An analysis was performed on 377 patients in the EU-AUS trial assessing the impact of mutational status on clinical outcomes among imatinib-treated patients. KIT exon 9 activating mutations were found to be a significant independent prognostic factor for death when compared with KIT exon 11 mutations. However, the adverse prognostic value of KIT exon 9 mutations was partially overcome with higher doses of imatinib, as those who received 800 mg total had a significantly better PFS, with a 61% relative risk reduction, than those who received 400 mg. Altogether, it was concluded that imatinib 400 mg once daily should be the standard-of-care first-line treatment for advanced or metastatic GISTs, unless a KIT exon 9 mutation is present, in which case imatinib 800 mg should be considered, if 400 mg is well tolerated. In addition, patients treated with frontline imatinib at 400 mg once daily, if tolerated well, should be considered for imatinib 800 mg upon progression of disease.
Despite there being problems with secondary resistance, significant progress has occurred in the treatment of metastatic disease over a short period of time. Prior to 2000, median OS for patients with metastatic GISTs was 9 months. With the introduction of imatinib and other TKIs, the median OS has increased to 5 years, with an estimated 10-year OS rate of approximately 20%.2