Management of Recurrent and Metastatic Disease
The majority of GIST recurrences occur in the first 5 years following surgical resection. In a pooled analysis of 10 series including 1625 patients undergoing surgical resection in the absence of adjuvant imatinib treatment, the 5-, 10-, 15-, and 20-year RFS rates were 70.5%, 62.9%, 59.9%, and 57.3%.18 A true local recurrence at the site of a previous macroscopically complete resection is unusual. Unfortunately, even with a macroscopically complete resection, up to 50% of patients with primary GIST will recur at a median of 24 months.17 Up to two-thirds of these patients with a recurrence will have liver metastases and approximately half will have peritoneal disease.65 The three most predictive factors of recurrence are mitotic count, tumor size, and location of tumor origin.72
In patients with advanced (unresectable primary or metastatic) GIST, imatinib is the first line therapy. Multiple clinical trials were sparked by the initial report of successful treatment of metastatic GIST in 2001 to determine the efficacy and optimal dosing of imatinib.10 The Intergroup B2222 trial was a phase II, randomized, open-label, multicenter trial that compared imatinib doses of 400 mg and 600 mg in patients with advanced disease.115 With a median follow-up of 63 months, 2 of 147 patients (1.4%) achieved a complete response and 98 of 147 patients demonstrated a partial response, with no significant difference in response rates between the two imatinib doses. Additionally, there was no difference observed in PFS and OS rates between the two groups. Median time to progression was 24 months and median OS was 57 months for all patients.
The subsequent phase III, randomized, open-label S0033 trial compared outcomes of imatinib 400 mg to 800 mg in patients with advanced GIST.116 A total of 746 patients were enrolled in this multicenter study with a median follow-up 4.5 years. There were no significant differences in response rates between the two treatment arms. Median PFS was 18 months for patients on standard 400 mg dosing and 20 months for the high dosing arm (p = 0.13) and the median OS rates were 55 and 51 months for lower and higher dosing arms, respectively (p = 0.83). After progression on low-dose imatinib, 33% of patients who crossed over to the high-dose regimen achieved either an objective response or stable disease. Subgroup analysis of this crossover group demonstrated a further median PFS of 5 months and an additional median OS of 19 months after dosage increased.
The similarly designed EORTC trial was a phase III randomized trial comparing imatinib 400 mg to 800 mg dosing.117 With a median follow-up of 760 days, the 2-year PFS rates were 56% and 50% (p = NS) and 2-year OS rates were 69% and 74% (p = NS) for low- and high-dose regimens, respectively. There was no significant difference in response rates between the two groups. A meta-analysis combining the results from both the EORTC and S0033 trial (MetaGIST) demonstrated a slight advantage in PFS in patients initially treated with the higher, 800 mg, imatinib dose (p=0.17).118 This PFS advantage was only demonstrated in patients with KIT exon 9 mutations treated in the high-dose arm. The presence of a KIT exon 9 mutation turned out to be the only factor predicting benefit from the high-dose regimen on multivariate analysis. However, there was no significant difference in OS. The PFS curves demonstrated that the majority of the improvement appeared within the first 2 years of high-dose treatment. It should be noted that almost 50% of patients in the high-dose treatment arm required dose reduction within 6 months due to medication intolerance or toxicity.
Based on the results of these clinical trials, the current standard of care for advanced GISTs is imatinib starting at a dose of 400 mg/d. Imatinib at 800 mg/d (usually dosed as 400 mg twice daily) should be considered as a starting dose for patients with advanced GIST and a confirmed KIT exon 9 mutation. Correlation of kinase genotype and dose selection has been confirmed by analysis of data from both the S0033 and EORTC trials.119,120 Of note, these two studies found that patients with KIT exon 11 mutations are more likely to have a partial response and have a longer PFS than those with a KIT exon 9 mutation or WT GIST. The MetaGIST analysis showed a greater toxicity associated with the higher imatinib dose, resulting in either patient noncompliance or dose reduction.118
Once imatinib therapy is initiated for the treatment of advanced GIST, consideration should be given to indefinite therapy. The French BFR14 trial was a phase III, randomized, open-label, multicenter trial evaluating the effect of imatinib interruption in patients with advanced GISTs.121,122 Patients with nonprogressive disease who were randomized to interruption of imatinib therapy after 1 and 3 years had a much higher rate of disease progression than those who continued therapy. Of those patients randomized to the imatinib continuation treatment arm after 1 year of treatment, progression was noted in 31% of patients and 81% in the interruption arm. When imatinib was reintroduced in the interruption arm, 92% responded. Following 3 years of treatment with imatinib, the 2-year PFS was 80% in the continuation group and 16% in the interruption group (p < 0.0001) after a median follow-up of 35 months. Data presented for interruption of imatinib treatment after 5 years have demonstrated that 45% of patients relapsed during the first year of follow-up, whereas no further progression was noted in any patient assigned to the continuation treatment arm (p = 0.032).123 Based on these results, it is clear that imatinib should be continued until disease progression or treatment-related toxicities become intolerable.
While imatinib will halt disease progression in up to 80% of patients, it is not curative, thus potentially providing an opportunity to combine medical therapy with cytoreductive surgery to improve outcomes. Cytoreductive surgery could potentially delay time to imatinib resistance by exposing fewer cells to imatinib and thereby decreasing likelihood of acquiring a resistant mutation. There are no randomized controlled trials investigating the role of cytoreductive surgery in the management of advanced GISTs. The goal of cytoreductive surgery is to perform a macroscopically complete (R0 or R1) resection when safely possible. Unfortunately, only 12% to 23% of patients with advanced GISTs on imatinib are considered surgical candidates.89,91
The data available on the role of cytoreductive surgery in the management of advanced GIST is based on several single-institution, retrospective studies.89-93,124 A study from the Brigham and Women’s Hospital/Dana-Farber Cancer Institute (BWH/DFCI) evaluated outcomes in 69 patients who underwent cytoreductive surgery while receiving kinase inhibitors. In this study, following surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively (p < 0.0001). For patients with stable, limited, and generalized progression, the 1-year PFS was 80%, 33%, and 0%, respectively, and 1-year OS was 95%, 86%, and 0%, respectively. The authors concluded that patients with stable disease or limited disease progression are more likely to benefit from debulking procedures than those with generalized progression, particularly if a R0 or R1 resection is completed or reduction in tumor burden such that no individual nodule greater than 1 cm in diameter remains.
A study from MSKCC found similar results when evaluating the outcomes following imatinib therapy and cytoreduction for advanced GISTs.124 Patients with responsive disease, defined as having had a partial response or stable disease on kinase inhibitor therapy, had a 2-year PFS of 61% and a 2-year OS of 100%. Those patients with focal resistance, or radiologic evidence of growth in 1 tumor, progressed after surgery at a median of 12 months and had a 2-year OS of 36%. Patients who exhibited growth in more than one tumor that progressed at a median of 3 months had a 1-year OS of 36%. The majority of patients underwent liver resection (43%) and 68% of patients required resection of peritoneal metastases without resection of a major organ, which is similar to the BWH/DFCI study.
These results further support the role of cytoreduction surgery in a subset of potentially resectable patients. However, these studies do not establish the superiority of surgery plus kinase inhibitors over kinase inhibitors alone without surgery. Phase III trials to answer this question were designed or initiated in China, Europe, and the United States but were unsuccessful due to poor accrual. In light of the current data, surgery should not be the first-line treatment for advanced GISTs barring an impending emergency. These patients should be treated with imatinib for a minimum of at least 6 months before proceeding to surgery. Patients with generalized progression have not been shown to benefit from cytoreductive surgery and are best treated nonoperatively. Patients with stable disease should be assessed individually as they may benefit from prolonging PFS following cytoreductive surgery.
Imatinib Resistance and Progression of Disease on Imatinib
While imatinib benefits the majority of patients with advanced GISTs, there are a subset of patients who will fail to demonstrate a response. Primary resistance is defined as evidence of clinical progression during the first 6 months of imatinib therapy, and occurs in approximately 14% of patients with advanced GISTs.125 Primary resistance is most commonly seen in patients with WT GISTs or with mutations involving the KIT exon 9 or a D842V mutation in PDGFRA exon 18.126 Eventually, most patients develop secondary resistance, which occurs in patients who have been treated with imatinib for longer than 6 months with an initial response who then develop progressive disease. Secondary KIT mutations most commonly occur in KIT exons 13, 14, and 17 and a D842V mutation in PDGFRA exon 18.127-129 Acquisition of secondary KIT mutations has been shown to confer imatinib resistance by either directly altering the adenosine triphosphate (ATP)/drug binding pocket or by interfering with access to this pocket through conformational changes in the activation loop of the kinase.126 Other mechanisms of imatinib resistance involve KIT-dependent and KIT-independent process by KIT gene amplification and complete loss of KIT expression.127 Imatinib resistance is managed by increasing the imatinib dose to 800 mg/d or switching to a second-line agent such as sunitinib malate (Sutent, Pfizer, New York, NY). If a patient demonstrates progression following dose escalation, switching to a second-line therapy is indicated.
Sunitinib is indicated as a second-line therapy for patients with advanced GISTs who progress on or become intolerant to imatinib. Sunitinib is a tyrosine kinase inhibitor that targets KIT, PDGFR, vascular endothelial growth receptor (VEGFR1, VEGFR2, VEGFR3), the ret proto-oncogene receptor (RET), and Fms-like tyrosine kinase-3 receptor (Flt3). A phase III, randomized, placebo-controlled trial evaluated outcomes in patients receiving sunitinib for advanced GISTs after failure and discontinuation of imatinib.130 Significant improvement in time to progression in patients treated with sunitinib was demonstrated when compared to those treated with placebo (27.3 weeks vs. 6.4 weeks, respectively; p < 0.0001) as well as PFS and OS. Sunitinib in this study was administered for 4 weeks followed by 2 weeks off treatment. A phase II, open-label, single arm study has since evaluated the efficacy of continuous, daily dosing of sunitinib at a dose of 37.5 mg/d.131 The study reported a clinical benefit rate of 53%, partial response 13%, and 40% achieved stable disease greater than 24 weeks. The median PFS was 34 weeks and the median OS was 107 weeks. Based on these studies, sunitinib is now considered the standard of care in patients who have progressed on or are intolerant of imatinib and is typically administered in 37.5 mg daily dosing.
A recent phase III, randomized, double-blind, single institution trial was completed to assess the efficacy of imatinib rechallenge in patients who progressed on tyrosine inhbitors.132 After a median follow-up of 5.2 months, median PFS was 1.8 months with imatinib compared with 0.9 months with placebo (p = 0.005). The median PFS improved to 1.7 months in 37/40 patients randomized to the placebo group who crossed over to imatinib treatment. No significant difference, however, in OS was demonstrated between imatinib and placebo groups (8.2 vs. 7.5 months, respectively; p =0.92). The authors conclude that in patients with GISTs that are refractory to treatment with all standard tyrosine kinase inhibitors, the disease may continue to harbor clones that are still sensitive to kinase inhibitors. Continued kinase inhibitor treatment then may slow disease progression.
Regorafenib is now approved as third-line treatment in patients with advanced GIST who progress on imatinib and sunitinib. Regorafenib is a tyrosine kinase inhibitor that inhibits VEGF1, VEGF2, and VEGF3; PDGFRB; KIT; RET; fibroblast growth factor receptor (FGFR); and BRAF.133 The recent phase III, randomized, double-blind, placebo-controlled GRID trial evaluated efficacy and safety of regorafenib in patients with advanced GIST who had evidence of progression after failure of at least imatinib and sunitinib.134 The median PFS of patients randomized to regorafenib was 4.8 months and 0.9 months for the placebo group (p < 0.0001). The rate of durable stable disease lasting for greater than 12 weeks was 52.6% and 9.1% in the regorafenib treatment group and placebo group, respectively. The results of this study led to the approval by the U.S. Food and Drug Administration for regorafenib as the third-line drug of choice.
Sorafenib is another tyrosine kinase inhibitor that is selective for KIT, PDGFRB, VEGF (isoforms 1–3), and Flt3, among others, and has shown clinical benefit in retrospective studies and phase II trials in patients who failed other tyrosine kinase inhibitors.135-137 The largest retrospective review by Montemurro et al137 was a multicenter review that included 124 patients treated with sorafenib (400 mg/d) as a third- or fourth-line treatment for advanced GIST. A partial response was observed in 10% of patients, with stable disease noted in 57%. Median PFS was 6.4 months and median OS was 13.5 months. Preliminary results for a multicenter phase II trial showed similar beneficial outcomes.138 Of the 38 patients enrolled, 13% demonstrated a partial response and 55% of patients experienced stable disease over a median follow-up of 31 months. Median PFS was 5.2 months and median OS was 11.6 months, with a 1-year OS of 50%. While these studies suggest that sorafenib is a reasonable third- or fourth-line treatment, additional data from clinical trials are needed to optimize its use.
Nilotinib is a second generation tyrosine kinase inhibitor that was originally designed for the treatment of chronic myelogenous leukemia due to its activity against bcr-abl.139 Nilotinib has been found to have additional activity against PDGFRA and KIT and has been shown to improve outcomes in patients with imatinib- and sunitinib-resistant advanced GISTs.140-142 The use of nilotinib alone or in combination with imatinib was initially shown to be tolerable with clinical activity in imatinib-resistant GISTs in a phase I trial.141 Of the 52 enrolled patients, 38 patients exhibited a stable disease and 2 patients a partial response. A phase III, randomized, open-label trial did not show an improvement in PFS on central review with a median of 109 days in the nilotinib arm and 111 days in the best supportive care control arm.142 It is important to note that 93% of patients in the control arm were receiving imatinib or sunitinib as part of best supportive care. Post hoc subset analyses of patients who were receiving nilotinib after progression on imatinib and sunitinib demonstrated a significantly longer OS of a median of 405 days vs. 280 days (p = 0.02). A multicenter, phase III, randomized trial is currently ongoing to investigate the efficacy and safety of nilotinib versus imatinib as a first-line treatment in patients with advanced GIST.143
Multiple additional tyrosine kinase inhibitors are currently under investigation including dasatinib,144 vatalanib,145 mastinib,146 dovitinib,147 pazopanib,148 and crenolanib.149 Crenolanib is of particular interest as it is a kinase inhibitor of PDGFRA and has been found to be 135-fold more potent than imatinib against the PDGFRA D842V mutation in vitro.149 A multicenter phase II trial investigating the use of crenolanib for treatment of PDGFRA D842V-mutant GIST is ongoing. Additionally, other nontyrosine kinase inhibitor agents are being investigated, including panobinostat,150,151 heat shock protein-90 inhibitors,152,153 and mTOR inhibitors such as everolimus.154 Investigators are also exploring the role the immune response plays in the antitumor effects of imatinib in GIST. Using a mouse model of spontaneous GIST, investigators have found that imatinib therapy results in activation of CD8+ T cells and induces regulatory T-cell apoptosis within the GIST tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido).155 Addition of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade potentiated the effects of imatinib in this model. This immunotherapeutic approach with the combination of imatinib and CTLA-4 blockade is a promising approach in improving outcomes in patients with metastatic GIST and is currently being assessed in a phase I trial.