NCCN: Continuing Education
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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/46929; and 4) view/print certificate.
Release date: June 16, 2014; Expiration date: June 16, 2015
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to NCCN Guidelines for Gastrointestinal Stromal Tumors
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Gastrointestinal Stromal Tumors
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Soft tissue sarcomas (STS) are a heterogeneous group of rare solid tumors with distinct clinical and pathologic features. In 2014, an estimated 12,020 people will be diagnosed with STS in the United States, and approximately 4740 will die of the disease.1 Gastrointestinal stromal tumors (GIST) are the most common STS of the gastrointestinal tract, resulting most commonly from KIT or platelet-derived growth factor receptor α (PDGFRα)-activating mutations.2 Loss-of-function mutations in the succinate dehydrogenase (SDH) gene subunits or loss of SDH subunit B (SDHB) protein expression by immunohistochemistry have been identified in wild-type GIST lacking KIT and PDGFRα mutations; these findings have led to the use of the term SDH-deficient GIST, which is preferred over the older term, wild-type GIST, for this subset of GIST.3-7 SDH gene mutational analysis for the identification of germline mutations in the SDH gene subunits should be considered for patients with GIST lacking KIT or PDGFRα mutations (see GIST-1 and GIST-B, pages 855 and 857).
The introduction of KIT and PDGFRα inhibitors such as imatinib and sunitinib has significantly improved the outcomes in patients with unresectable or metastatic GIST. Regorafenib, another multikinase inhibitor, was recently approved for the treatment of patients with locally advanced, unresectable, or metastatic GIST previously treated with imatinib and sunitinib.
These NCCN Guidelines Insights discuss the management of patients with GIST experiencing disease progression while on imatinib and/or sunitinib.
GIST: Management of Progressive Disease
Resistance to Imatinib and Sunitinib
Imatinib is the standard first-line therapy for patients with unresectable or metastatic GIST. In phase II and III studies, imatinib has resulted in high overall response rates and exceptionally good progression-free survival (PFS) in patients with unresectable and/or metastatic GIST, inducing objective responses in more than 50%.8-12 The presence and type of KIT or PDGFRα mutation status has been identified as the predictor of response to imatinib. In randomized clinical trials, the presence of a KIT exon 11 mutation was associated with better response rates, PFS, and overall survival (OS) than KIT exon 9 mutations or wild-type GISTs.13-16
The EORTC 62005 study group identified the presence of KIT exon 9 mutation as the strongest adverse prognostic factor for risk of progression and death.14 A meta-analysis of the EORTC 62005 and SWOG S0033/CALGB 150105 phase III trials that randomized 1640 patients with advanced GIST to standard-dose (400 mg/d) or high-dose imatinib (800 mg/d) showed a PFS benefit for patients with KIT exon 9 mutations treated with 800 mg of imatinib.17 In a recent international survey that reported the outcome of patients with GIST with PDGFRα mutations, none of the 31 evaluable patients with D842V mutation experienced a response, whereas 21 (68%) experienced disease progression.18 Median PFS was 2.8 months for patients with D842V substitution and 28.5 months for patients with other PDGFRα mutations. With 46 months of follow-up, median OS was 14.7 months for patients with D842V substitutions and was not reached for those with other PDGFRα mutations.
Although imatinib benefits most patients with advanced GIST, some develop resistance to the drug. Primary resistance is defined as the evidence of clinical progression developing during the first 6 months of imatinib therapy, and is most commonly seen in patients with KIT exon 9 mutations treated with imatinib at 400 mg/d or patients with PDGFRα exon 18 D842V mutations, or those with tumors that lack identifiable activating mutations in KIT or PDGFRα, most of which are SDH-deficient GIST.13,14,16,19 Secondary resistance is seen in patients who have been on imatinib for more than 6 months with an initial response or disease stabilization followed by progression, most commonly because of the outgrowth of tumor clones with secondary mutations in KIT.20-23 Dose escalation to 800 mg/d or switching to sunitinib is a reasonable option for patients experiencing disease progression on imatinib at 400 mg/d.10,24,25
Sunitinib is a multikinase inhibitor active against a variety of tyrosine kinases, including KIT, PDGFR, and vascular endothelial growth factor receptor (VEGFR). In randomized clinical studies, sunitinib has resulted in a significant improvement in median time to progression and a significantly greater estimated OS in patients with imatinib-resistant GIST compared with placebo.24,25 Heinrich et al19 reported that sunitinib induced higher response rates in patients with primary KIT exon 9 mutations than those with KIT exon 11 mutations (58% vs 34%, respectively). PFS and OS were significantly longer for patients with KIT exon 9 mutations or wild-type GIST compared with those with KIT exon 11 mutations. Only 4 patients had PDGFRα mutations; of these, 2 had a primary and 1 a secondary D842V mutation and did not experience response to treatment. In patients with KIT exon 11 mutations, PFS and OS were longer for those with secondary exon 13 or 14 mutations compared with those with exon 17 or 18 mutations. Additional studies are needed to confirm these findings.
Comprehensive molecular studies investigating the mechanisms of resistance to sunitinib are limited because of the small number of patients who are surgical candidates after failure of 2 tyrosine kinase inhibitor (TKI) therapies. Nevertheless, available evidence (both clinical and preclinical) indicates that although sunitinib is very sensitive to ATP-binding pocket mutations that confer resistance to imatinib, it has little activity against other imatinib-resistant mutations in the KIT activation loop.26-28
Management of Resistance to Imatinib and Sunitinib
Regorafenib, a multikinase inhibitor with activity against KIT, PDGFR, and VEGFR, was recently approved by the FDA for the treatment of patients with locally advanced, unresectable, or metastatic GIST previously treated with imatinib and sunitinib. A phase III study randomized 199 patients with metastatic and/or unresectable GIST experiencing disease progression on prior therapy with imatinib and sunitinib to either regorafenib (n=133) or placebo (n=66).29 The median PFS (4.8 vs 0.9 months; P<.0001) and disease control rate (53% vs 9%) were significantly higher for regorafenib compared with placebo. The PFS rates at 3 and 6 months were 60% and 38%, respectively, for regorafenib compared with 11% and 0%, respectively, for placebo. The hazard ratio for OS was 0.77, with 85% of patients in the placebo arm crossing over to regorafenib because of disease progression. The most common treatment-related adverse events (≥ grade 3) were hypertension (23%), hand-foot skin reaction (20%), and diarrhea (5%).
Sorafenib,30-33 nilotinib,34-38 dasatinib,39,40 and pazopanib41 have also shown activity in patients with GIST resistant to imatinib and sunitinib. Much of the data on these TKIs are from phase II studies and retrospective analyses involving small numbers of patients.
In a prospective multicenter phase II study of 38 patients with unresectable KIT+ GIST that had progressed on imatinib and sunitinib, sorafenib resulted in a disease control rate of 68% (55% of patients had stable disease and 13% had a partial response).30 Median PFS and OS were 5.2 and 11.6 months, respectively; 1- and 2-year survival rates were 50% and 29%, respectively. In a retrospective analysis of 124 patients with metastatic GIST resistant to imatinib and sunitinib, sorafenib also demonstrated activity, resulting in a median PFS and OS of 6.4 and 13.5 months, respectively.32 Notably, patients included in this study had not been treated with regorafenib, and the efficacy of sorafenib following regorafenib therapy in patients with metastatic GIST resistant to imatinib and sunitinib has not been studied.
In a retrospective analysis of 52 patients with advanced GIST resistant to imatinib and sunitinib, nilotinib resulted in response and disease control rates of 10% and 37%, respectively.35 Median PFS and OS were 12 and 34 weeks, respectively. In a randomized phase III study of nilotinib as third-line therapy and best supportive care (with or without a TKI) in patients who were resistant or intolerant to imatinib and sunitinib (248 patients), the PFS associated with nilotinib was not found to be superior to best supportive care (109 vs 111 days; P=.56). In a post hoc subset analysis, patients experiencing progression on both imatinib and sunitinib who had not received any other therapy had an improved OS (>4 months) with nilotinib compared with best supportive care (405 vs 280 days; P=.02). The clinical benefit associated with nilotinib may be specific to subsets of patients with KIT exon 17 mutations, previously treated with imatinib and sunitinib.38
Dasatinib has demonstrated activity against the PDGFRα D842V mutation that confers the highest resistance to imatinib, and it could be an effective treatment option for this group of patients with imatinib-resistant GIST.39 In the phase II study of 50 patients with advanced GIST resistant to imatinib, dasatinib was associated with a median PFS and OS of 2 and 19 months, respectively, with response assessment based on Choi criteria.40 Median PFS for patients with wild-type GIST was 8.4 months.
Pazopanib has also shown marginal activity in heavily pretreated patients with advanced GIST. In a multicenter phase II study of patients with advanced GIST following failure of at least imatinib and sunitinib (n=25), pazopanib was well tolerated, resulting in stable disease in 48% of patients, with a 24-week nonprogression (complete response + partial response + stable disease) rate of 17%.41 The median PFS and OS were 1.9 and 10.7 months, respectively.
Dose escalation of imatinib up to 800 mg/d (given as 400 mg twice daily) as tolerated or switching to sunitinib (category 1) are included as options for patients experiencing progressive disease (limited disease or widespread systemic disease in patients with good performance status) on standard-dose imatinib (see GIST-7, page 856).10,24,25 All clinical and radiologic data, including lesion density on CT and patient compliance to treatment with standard-dose imatinib, should be assessed before dose escalation of imatinib or switching to sunitinib.
For patients with limited progressive disease on standard-dose imatinib, second-line therapy with sunitinib should be initiated only if most of the disease is no longer controlled by imatinib; consideration of other therapeutic interventions for progressing lesions is warranted. Surgical resection should be considered in carefully selected patients with limited progressive disease that is potentially easily resectable.42-44 However, incomplete resections are frequent, with high complication rates. The guidelines have included, only for patients with limited progressive disease, continuation of imatinib at the same initial dose and treatment of progressing lesions with resection or radiofrequency ablation or chemoembolization or palliative RT (for rare patients with bone metastases) as an option.45
Regorafenib (category 1) is recommended for patients experiencing disease progression on imatinib and sunitinib.29 Based on the limited data,30-40 the NCCN Guidelines have also included sorafenib, dasatinib, and nilotinib as additional options for patients who are no longer receiving clinical benefit from imatinib, sunitinib, or regorafenib (see SARC-E, page 858), although all data regarding the potential benefit of these agents are from the preregorafenib era.
In patients with progressive disease no longer receiving benefit from current TKI therapy, reintroduction of previously tolerated and effective TKI therapy for palliation of symptoms can be considered (see GIST-7, page 856).46,47 The results of a recent randomized study showed that imatinib rechallenge significantly improved PFS and disease control rate in patients with advanced GIST after failure of at least imatinib and sunitinib.47 However, the duration of survival benefit was brief because of continued progression of TKI-resistant clones.
Any patient who experiences disease progression despite prior therapy or who has a recurrence, regardless of presentation, should be considered a candidate for enrollment in a clinical trial, if an appropriate trial is available.
Continuation of TKI Therapy
The optimal duration of TKI therapy in patients with responding or stable disease is not known. The results of a prospective, multicenter, randomized phase III study (BFR14) showed a significant increase in the rate of disease progression when imatinib was interrupted in patients with advanced disease who were stable or responding to imatinib.48,49 A recent report from this study confirmed that patients with rapid disease progression after interruption of imatinib had a poorer prognosis.50 More importantly, the quality of response on reintroduction of imatinib did not reach the tumor status observed at randomization.
The panel strongly recommends that TKI therapy at the prescribed daily dose should be continued as long as patients are experiencing clinical benefit (response or stable disease). The panel also feels that continuation of TKI therapy lifelong for palliation of symptoms should be an essential component of best supportive care (see GIST-7, page 856). However, short interruptions of 1 to 2 weeks, when medically necessary, have not been shown to impact negatively on disease control or other outcomes.
GIST is the most common STS of the gastrointestinal tract, resulting most commonly from KIT- or PDGFRα-activating mutations. TKI therapy with imatinib, sunitinib, and regorafenib has emerged as an effective treatment option for patients with unresectable or metastatic GIST. Dose escalation of imatinib up to 800 mg/d as tolerated or switching to sunitinib are included as options for patients with progressive disease on standard-dose imatinib. Regorafenib is recommended for patients experiencing disease progression while on imatinib and sunitinib. TKI therapy at the prescribed daily dose should be continued as long as patients are receiving clinical benefit (response or stable disease).
DoyleLANelsonDHeinrichMC. Loss of succinate dehydrogenase subunit B (SDHB) expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumours: a comprehensive genotype-phenotype correlation study. Histopathology2012;61:801–809.
BlankeCDRankinCDemetriGD. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol2008;26:626–632.
Debiec-RychterMDumezHJudsonI. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer2004;40:689–695.
HeinrichMCOwzarKCorlessCL. Correlation of kinase genotype and clinical outcome in the North American Intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol2008;26:5360–5367.
KindlerHLCampbellNPWroblewskiK. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): final results of a University of Chicago phase II consortium trial [abstract]. J Clin Oncol2011;29(15 Suppl):Abstract 10009.
BlayJYLe CesneARay-CoquardI. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol2007;25:1107–1113.