544892 research-article2014
TAM0010.1177/1758834014544892Therapeutic Advances in Medical OncologyD Ferraro and J Zalcberg
Therapeutic Advances in Medical Oncology
Review
Regorafenib in gastrointestinal stromal tumors: clinical evidence and place in therapy
Ther Adv Med Oncol 2014, Vol. 6(5) 222–228 DOI: 10.1177/ 1758834014544892 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Danielle Ferraro and John Zalcberg
Abstract: Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with highrisk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.
Keywords: gastrointestinal stromal tumors, regorafenib, targeted therapies Gastrointestinal stromal tumors Gastrointestinal stromal tumors (GISTs) are nonepithelial malignancies that arise most often in the gastrointestinal tract, particularly in the stomach (60%) and small intestine (30%), but much less frequently in the appendix, colon or rectum, or esophagus [Miettinen and Lasota, 2006]. GISTs account for less than 1% of all reported gastrointestinal cancers, with approximately 10–15 cases per million worldwide, although this may well be an underestimate of the incidence due to the presence of small, low-risk tumors within the spectrum of GISTs that may not be recorded in cancer registries. Further to this, autopsy series would suggest that the occurrence of low-grade GISTs may not be as rare an event as previously believed, with evidence of very small gastric GISTs in 2.9–35% of cases [Muenst
et al. 2011; Agaimy et al. 2007; Kawanowa et al. 2006]. GIST cells arise from pluripotent precursor mesenchymal cells that normally differentiate into the interstitial cells of Cajal, which are found in the myenteric plexus and play a key role in the regulation of gut motility. The finding that these precursor cells expressed the receptor tyrosine kinase KIT in a similar manner to malignant GIST cells confirmed the origin of these cells [Hirota et al. 1998; Kindblom et al. 1998]. In physiological situations, the binding of the ligand (stem cell factor) to KIT results in homodimerization and phosphorylation of the tyrosine kinase portion of intracellular KIT. This results in activation predominantly of the MEK–MAPK and PI3K–AKT pathways, causing cell proliferation. The presence
Correspondence to: Danielle Ferraro, MBBS, FRACP Oncology Clinical Research Fellow, NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; and PhD Candidate, Department of Pathology, Medical Building 181, University of Melbourne, Parkville, Victoria 3010, Australia danielle.ferraro@ unimelb.edu.au John Zalcberg, OAM, MB BS, PhD, FRACP, FRACMA FAICD School of Public Health and Preventative Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia
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D Ferraro and J Zalcberg of mutations in the KIT proto-oncogene is commonly detected in GISTs, with 75–90% of tumors harboring these abnormalities. The acquisition of these mutations appear to be an early event in the pathogenesis of these tumors, with even small tumors and those with otherwise benign morphology showing abnormal variants of the KIT gene. These oncogenic mutations in the KIT gene lead to constitutive activation of these pathways, resulting in uncontrolled growth and proliferation. These deletions, point mutations or duplications occur most frequently in exon 9 and 11 (with mutations in exon 13 and 17 also reported) [Kinoshita et al. 2003]. Platelet derived growth factor receptor (PDGFR) A mutations (occurring in exons 12, 14 and 18) are also found in approximately 5–10% of GISTs, although they are mutually exclusive with KIT mutations. PDGFR mutations also cause constitutive phosphorylation and activate pathways similar to those critical in the growth of GISTs with a KIT mutation. Historically, treatment of GISTs with chemotherapy resulted in minimal response, with objective response rates in the order of 0–5% [Edmonson et al. 2002], and rarely altered the natural history of the disease. Prior to the use of targeted therapies, survival following detection of metastatic disease was usually less than 2 years. This represented an enormous area of unmet need for patients with this cancer, with no effective conventional therapy available. The era of personalized medicine and targeted therapy has led to very significant changes in the management algorithm for the treatment of GISTs, with the discovery of driver mutations and the development of agents able to target these abnormal pathways. Imatinib, initially used in the treatment of chronic myelogenous leukemia for its dramatic effects on the bcr-abl tyrosine kinase, is now the standard of care for the adjuvant treatment of high-risk resected disease, as well as in the first-line treatment of metastatic disease. Imatinib is able to bind in a reversible manner to the adenosine triphosphate (ATP) binding pocket of ABL, KIT, PDGFRA and PDGFRB, which prevents pathway activation and inhibits growth of tumor cells [Hantschel et al. 2008]. In preclinical studies, imatinib was noted to have profound effects on the uncontrolled activity of these activated tyrosine kinases. Further research has shown significant benefit from the use of imatinib in both the adjuvant and metastatic setting of GISTs in patients with KIT or PDGFRA
mutation, with dramatic improvements in tumor control and survival. Of those with PDGFRA mutations, a proportion exhibit sensitivity to imatinib and derive benefit from treatment [Corless et al. 2005]. The use of imatinib has decreased relapse rates for high-risk tumors following surgical resection when administered for 1 year compared with placebo [with a median follow up of 19.7 months, 30 (8%) patients in the imatinib arm and 70 (20%) in the placebo arm had recurrence of their tumor or died] [DeMatteo et al. 2009]. Imatinib also improved recurrencefree survival at 1 year compared with placebo [98% versus 83%; hazard ratio (HR) 0.35, onesided p < 0.0001]. The Joensuu study has also shown an improvement with longer (3 years) versus shorter (1 year) length of adjuvant treatment, with improved recurrence-free survival periods and survival time in patients at high risk of recurrence [Joensuu et al. 2012]. This rational drug design has become the model for subsequent advances in targeted cancer treatment. However, not all patients receive such profound or significantly long-lasting benefits from imatinib. Those with mutations in the exon 9 gene of KIT appear to have less benefit than those with exon 11 mutations [Heinrich et al. 2003, 2008; DebiecRychter et al. 2004], although outcomes appear to improve somewhat for those with exon 9 mutations treated with higher doses of imatinib [Gastrointestinal Stromal Tumor Meta-Analysis Group, 2010]. There are also a group of patients (less than 15% of GISTs) who demonstrate primary resistance to imatinib and have disease progression despite treatment. In addition, for those with metastatic disease, the majority will experience tumor progression during the course of imatinib treatment despite initial responses or disease stabilization. This is usually due to the emergence of resistant clones through the development of new KIT mutations, for example those that interfere with binding of imatinib to the kinase domains [Debiec-Rychter et al. 2005; Heinrich et al. 2006]. On this basis, interest has increased in the use of tyrosine kinases with broader spectra of activity than imatinib. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor effects, has shown benefit in the imatinib-resistant population in a randomized, placebo-controlled trial, which allowed crossover to sunitinib on progression [Demetri et al. 2006]. Sunitinib proved superior to placebo with respect to median progression-free survival (PFS) [median 24.1 weeks, 95% confidence
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Therapeutic Advances in Medical Oncology 6(5) interval (CI) 11.1–28.3 in the sunitinib arm; 6.0 weeks, 4.4–9.9 in the placebo arm; HR 0.33, 95% CI 0.24–0.47, p < 0.0001]. Similarly, overall survival was improved (HR 0.49 during the initial treatment period). However, for the population whose condition failed to respond to both imatinib and sunitinib, no established third-line treatment options existed until recently, obviously an area of unmet clinical need. Regorafenib, a multitargeted tyrosine kinase inhibitor, has now shown benefit in this setting of resistant metastatic GISTs and has promising clinical utility. Regorafenib Regorafenib, chemical name 4-[4-({[4-chloro-3(trifluoromethyl)phenyl]carbamoyl}amino)3-fluorophenoxy]-n-methylpyridine-2-carboxamide, is an orally available, multitargeted tyrosine kinase inhibitor. It has inhibitory actions against several tyrosine kinases that are important for oncogenesis, tumor angiogenesis and the maintenance of the tumor microenvironment, including KIT, PDGFRA, bFGFR, VEGFR1-3, TIE2, RET, BRAF and BRAF V600E [Wilhelm et al. 2011]. Regorafenib is structurally similar to sorafenib. Regorafenib is currently approved for use in a number of countries for metastatic colorectal cancer after failure of irinotecan- and oxaliplatinbased chemotherapy, and a vascular endothelial growth factor (VEGF) targeted agent [as well as epidermal growth factor receptor (EGFR) targeted agent if Kras wild type]. This approval was based on findings from the pivotal phase III CORRECT trial, which included patients whose condition had progressed on all standard therapies, and demonstrated a modest (although statistically significant) improvement in both PFS and overall survival [Grothey et al. 2013]. Phase I and II studies In preclinical studies, regorafenib demonstrated significant tumor inhibition in a variety of cancer xenograft models, including in GISTs, colorectal, renal cell, lung, melanoma, pancreatic and ovarian tumor cell lines, at clinically achievable doses [Wilhelm et al. 2011]. A phase I dose escalation study [Mross et al. 2012] established an optimal dose of regorafenib of 160 mg orally daily, administered for 21 out of 28 days, supported by pharmacodynamic and pharmacokinetic evidence. In
the phase I study which recruited patients with a variety of solid tumors, 66% of patients experienced disease control, with 3 of 47 patients having a partial response. Adverse events noted in the study were consistent with the mechanism of action of regorafenib and similar to those seen in trials of other multikinase inhibitors. The spectrum of kinases targeted by regorafenib and these early clinical results led to the commencement of phase II studies conducted in patients with GIST and colorectal cancer. In 2010, George and colleagues undertook a phase II study of regorafenib in patients whose condition had previously failed to respond to both imatinib and sunitinib treatment for GISTs [George et al. 2012]. In this trial of 33 patients, an impressive 75% experienced clinical benefit from the use of regorafenib (tumor response of complete or partial response, or stable disease for at least 16 weeks), with an overall PFS for the entire cohort of 10 months (95% CI 8.3–14.9 months). Both patients with wild-type GIST (no documented KIT or PDGRFA mutations) and KIT exon 9 and 11 mutations experienced clinical benefit at comparable rates (no PDGFRA mutations were detected among those in the trial). Those with KIT exon 11 mutations appeared to have a longer PFS compared with those with exon 9 mutations, although numbers were small. Most patients required at least one dose reduction due to toxicity (82%), with the most common adverse events being hand–foot–skin reaction, hypertension, fatigue and diarrhea. A number of these patients were subsequently able to re-escalate their dose of regorafenib. On the basis of the promising results obtained from the phase II study in GISTs, the phase III GRID trial was undertaken. Phase III trial in GIST GRID, a multicenter, randomized, placebo-controlled phase III trial of 199 patients with metastatic or unresectable disease that had failed to respond to at least two previous lines of therapy for GIST (including imatinib and sunitinib) was conducted in 2011 [Demetri et al. 2013]. This trial found a statistically significant improvement in PFS with the use of regorafenib compared with the placebo arm (median PFS 4.8 versus 0.9 months, HR 0.27). Disease control rate was 52.6% for the regorafenib arm and 9.1% for the placebo arm (p < 0.0001). Overall survival was not different between groups, but was likely
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D Ferraro and J Zalcberg influenced by the ability of patients to crossover to open-label regorafenib if on placebo during the double-blinded portion of the trial (85% of patients on placebo initially crossed over). There was no significant difference in benefit achieved between those with exon 9 or exon 11 KIT mutations in this study. Subgroup analysis showed benefit across age groups, geographic location, and line of therapy (third versus fourth line), with only those who had an imatinib duration of less than 6 months failing to show a PFS benefit. Adverse events were frequent during treatment with regorafenib but generally manageable and within the spectrum of expected events from this class of agents. During the double-blind phase of the same trial, the most common grade 3 or higher adverse events recorded in the regorafenib arm were hypertension (23%), hand–foot syndrome (20%) and diarrhea (5%). Grade 5 adverse events occurred in both arms at a rate of 5%. Dose modifications were required more frequently in the regorafenib arm compared with the placebo arm, but the rate of permanent treatment discontinuation due to adverse events in the regorafenib arm (6%) was similar to that in the placebo group (8%). This trial established that GISTs may remain responsive to treatment targeted at oncogenic drivers, even though resistance to similar agents was present previously. The broader spectrum of kinase inhibition achieved through the use of regorafenib allows targeting of recognized mechanisms of resistance (and also possibly as-yet unknown escape pathways) and can induce response even after failure of other agents. This finding has opened the door to extending the range of effective agents in GISTs and presents an exciting option for further research. Use in clinical practice The development and use of imatinib has revolutionized the management of GISTs and has given patients with previously poor prognosis effective treatment options. However, there remains substantial work to be done. There are a number of patients who have been lacking an effective treatment, including those with primary imatinib-resistant disease and those who, despite progressing through two lines of therapy, remain appropriate candidates for further treatment. Based on the positive results from the GRID trial, in February 2013 the United States Food and Drug Administration
(FDA) licensed regorafenib for use in the third-line setting for unresectable GIST, after the failure (or intolerance) of imatinib and sunitinib. A number of other international regulators have also approved this agent for this indication. Regorafenib may now be considered the standard of care for appropriate patients in this situation. The recognition and timely management of toxicities relating to the use of regorafenib is improving as clinician experience with the use of this agent grows. As most toxicities are predictable and tend to appear soon after beginning regorafenib, patient education and close patient monitoring in the early stages of treatment are particularly important [Grothey et al. 2014]. This will both minimize the severity and duration of the events and ideally prolong time on treatment for many patients through the judicious use of symptomatic treatments, dose adjustments and treatment breaks. Given the promise of significant activity from the use of a drug with manageable toxicity, regorafenib is likely to play an important role in the future direction of GIST treatment. An important challenge now is how to best utilize the agents available, such as regorafenib, to maximize outcomes for patients. A number of strategies could be considered for further investigation. By identifying survival mechanisms that bypass the effects of targeted treatment and selectively pursupossibility ing these with synergistic agents, the exists to provide a longer and more profound response to treatment, with the ultimate aim of effecting cure even in the metastatic setting. This may involve the use of multidrug treatment regimens. Currently, studies are underway on the combination of regorafenib with chemotherapy regimens such as Folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) or Folinic acid, 5-fluorouracil, irinotecan (FOLFIRI), or the EGFR targeted antibody, cetuximab, in colorectal cancer [ClinicalTrials. gov identifier: NCT01298570; NCT01289821; NCT01973868]. Although there is not a suitable active chemotherapy backbone for the use of such a combination in GISTs, the theoretical benefit of combination therapy remains intriguing. A recent preclinical study established that regorafenib in combination with inhibitors of the PI3K/AKT pathway (a possible survival pathway for tumor cells in the setting of tyrosine kinase blockade) work synergistically to kill cancer cells
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Therapeutic Advances in Medical Oncology 6(5) [Sajithlal et al. 2013]. However, the use of multiple targeted agents administered simultaneously has historically been difficult to implement, due to overlapping side-effect profiles and significant toxicity, particularly toxicity to normal cells which may rely on similar mechanisms to maintain homeostasis. Early phase trials of combinations of tyrosine kinase inhibitors have often found unexpected adverse events, or side effects with a synergistically increased severity limiting clinical applicability. Although promising in xenograft models, combination therapy targeting EGFR and VEGF, or dual EGFR blockade, resulted in increased numbers of patient discontinuing treatment due to side effects. Simultaneous use of two VEGF inhibitors or combinations of mammalian target of rapamycin inhibitors with EGFR and VEGF targeted agents have also been disappointing [Park et al. 2013]. Better understanding of the on- and off-target mechanisms of action of targeted agents is likely to provide the key to minimizing this problem in the future. More novel methods to allow use of two similar drugs, such as sequential or alternating therapy, may prove to be efficacious while minimizing side effects prevalent with concurrent administration. Given that the activity of regorafenib has been established in later lines of GIST treatment, questions now arise about using this agent in earlier lines of treatment, including first-line management of those with metastatic disease. Imatinib, the current standard of care, although well tolerated, rarely results in cure for those with metastatic disease. An agent with an ability to target a wider range of pathways activated in cancer may both improve response rates and decrease resistance to treatment. With no current trials underway in this setting, either to establish activity or to compare with current standard of care (imatinib in the first-line setting or sunitinib in the secondline setting), regorafenib cannot be recommended as a substitute for currently approved therapies in these patients. With an understanding that direct targeting prolongs survival in the metastatic setting, there is also reason to consider the use of regorafenib in the adjuvant treatment of GISTs. Imatinib has decreased relapse rates for high-risk GISTs post resection, although there remains scope to improve outcomes in this population. In colorectal cancer, a study is underway to evaluate the activity of ‘adjuvant’ regorafenib given after the resection of liver metastases [ClinicalTrials.gov
identifier: NCT01939223]. Some caution is required given that targeted agents which have shown promise in the metastatic setting have not translated into benefit in the adjuvant setting (for example, bevacizumab in colorectal cancer) [de Gramont et al. 2012]. The reasons for this are not completely elucidated, but may relate to a decreased reliance on angiogenesis in the setting of micrometastatic disease, limiting the utility of antiangiogenic agents. Again, with no evidence for the benefit of adjuvant regorafenib in GISTs, and no evidence to date of benefit in the first-line setting, this cannot be recommended as a treatment option. The elucidation of biomarkers to predict response, or resistance, to targeted agents will allow the identification of subgroups of patients who received marked benefit, and in contrast, groups that may have deleterious effects from treatment. This information will help to optimize the clinical use of agents such as regorafenib. A preplanned retrospective biomarker analysis has used the pretreatment tissue specimens from patients enrolled in the GRID trial and compared the mutations detected with those subsequently found in blood samples at the time of resistance to imatinib and sunitinib at the time of entry to GRID. The group found resistance mutations in 48% of the blood samples, but only 12% of the pretreatment tissue samples. In addition, in almost half of those samples that harbored known secondary mutations, multiple mutations were present [Cancer Discovery 2013]. Regorafenib showed activity across a range of secondary KIT mutations, reinforcing its utility in this setting, but questions remain about how to differentiate those most likely to respond to treatment from those who will not. In addition, two trials are currently underway, attempting to determine biomarkers that may correlate with clinical efficacy of regorafenib when used for metastatic colorectal cancer [ClinicalTrials.gov identifier: NCT01949194; NCT01996969]. Any positive results from these studies would warrant investigation in the GIST population to determine if the findings were similarly useful and could lead to more judicious use of regorafenib in this group. Conclusion The prognosis for patients with GIST, both with early and advanced disease, has changed enormously over the last decades. Increasing understanding of the mechanisms that underlie the evolution and progression of this disease has
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D Ferraro and J Zalcberg allowed the development of agents targeted at the molecular abnormalities widely seen in GIST, such as activating mutations of KIT and PDGFRA. Imatinib has provided considerable benefit for a previously largely untreatable disease, but has not proven to be the complete answer for patients with GIST. For those with disease refractory to imatinib, as well as the vast majority who develop resistance to imatinib, further options are required. There are now an increasing number of targeted agents which hold promise for improving outcomes in patients with GIST. The promising activity of regorafenib in the third-line setting provides an active alternative treatment in later stages of disease after failure of other agents, and raises interesting questions about the optimal utilization of this agent in both the adjuvant and metastatic setting. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement John R. Zalcberg is the principal AGITG investigator of the EORTC 62005 trial of imatinib in metastatic GIST. He has received research support, travel support and honoraria from Bayer and Novartis over the past 3 years. He has provided expert testimony for Bayer.
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TAM0010.1177/1758834014544892Therapeutic Advances in Medical OncologyD Ferraro and J Zalcberg
Therapeutic Advances in Medical Oncology
Review
Regorafenib in gastrointestinal stromal tumors: clinical evidence and place in therapy
Ther Adv Med Oncol 2014, Vol. 6(5) 222–228 DOI: 10.1177/ 1758834014544892 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Danielle Ferraro and John Zalcberg
Abstract: Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with highrisk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.
Keywords: gastrointestinal stromal tumors, regorafenib, targeted therapies Gastrointestinal stromal tumors Gastrointestinal stromal tumors (GISTs) are nonepithelial malignancies that arise most often in the gastrointestinal tract, particularly in the stomach (60%) and small intestine (30%), but much less frequently in the appendix, colon or rectum, or esophagus [Miettinen and Lasota, 2006]. GISTs account for less than 1% of all reported gastrointestinal cancers, with approximately 10–15 cases per million worldwide, although this may well be an underestimate of the incidence due to the presence of small, low-risk tumors within the spectrum of GISTs that may not be recorded in cancer registries. Further to this, autopsy series would suggest that the occurrence of low-grade GISTs may not be as rare an event as previously believed, with evidence of very small gastric GISTs in 2.9–35% of cases [Muenst
et al. 2011; Agaimy et al. 2007; Kawanowa et al. 2006]. GIST cells arise from pluripotent precursor mesenchymal cells that normally differentiate into the interstitial cells of Cajal, which are found in the myenteric plexus and play a key role in the regulation of gut motility. The finding that these precursor cells expressed the receptor tyrosine kinase KIT in a similar manner to malignant GIST cells confirmed the origin of these cells [Hirota et al. 1998; Kindblom et al. 1998]. In physiological situations, the binding of the ligand (stem cell factor) to KIT results in homodimerization and phosphorylation of the tyrosine kinase portion of intracellular KIT. This results in activation predominantly of the MEK–MAPK and PI3K–AKT pathways, causing cell proliferation. The presence
Correspondence to: Danielle Ferraro, MBBS, FRACP Oncology Clinical Research Fellow, NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; and PhD Candidate, Department of Pathology, Medical Building 181, University of Melbourne, Parkville, Victoria 3010, Australia danielle.ferraro@ unimelb.edu.au John Zalcberg, OAM, MB BS, PhD, FRACP, FRACMA FAICD School of Public Health and Preventative Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia
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D Ferraro and J Zalcberg of mutations in the KIT proto-oncogene is commonly detected in GISTs, with 75–90% of tumors harboring these abnormalities. The acquisition of these mutations appear to be an early event in the pathogenesis of these tumors, with even small tumors and those with otherwise benign morphology showing abnormal variants of the KIT gene. These oncogenic mutations in the KIT gene lead to constitutive activation of these pathways, resulting in uncontrolled growth and proliferation. These deletions, point mutations or duplications occur most frequently in exon 9 and 11 (with mutations in exon 13 and 17 also reported) [Kinoshita et al. 2003]. Platelet derived growth factor receptor (PDGFR) A mutations (occurring in exons 12, 14 and 18) are also found in approximately 5–10% of GISTs, although they are mutually exclusive with KIT mutations. PDGFR mutations also cause constitutive phosphorylation and activate pathways similar to those critical in the growth of GISTs with a KIT mutation. Historically, treatment of GISTs with chemotherapy resulted in minimal response, with objective response rates in the order of 0–5% [Edmonson et al. 2002], and rarely altered the natural history of the disease. Prior to the use of targeted therapies, survival following detection of metastatic disease was usually less than 2 years. This represented an enormous area of unmet need for patients with this cancer, with no effective conventional therapy available. The era of personalized medicine and targeted therapy has led to very significant changes in the management algorithm for the treatment of GISTs, with the discovery of driver mutations and the development of agents able to target these abnormal pathways. Imatinib, initially used in the treatment of chronic myelogenous leukemia for its dramatic effects on the bcr-abl tyrosine kinase, is now the standard of care for the adjuvant treatment of high-risk resected disease, as well as in the first-line treatment of metastatic disease. Imatinib is able to bind in a reversible manner to the adenosine triphosphate (ATP) binding pocket of ABL, KIT, PDGFRA and PDGFRB, which prevents pathway activation and inhibits growth of tumor cells [Hantschel et al. 2008]. In preclinical studies, imatinib was noted to have profound effects on the uncontrolled activity of these activated tyrosine kinases. Further research has shown significant benefit from the use of imatinib in both the adjuvant and metastatic setting of GISTs in patients with KIT or PDGFRA
mutation, with dramatic improvements in tumor control and survival. Of those with PDGFRA mutations, a proportion exhibit sensitivity to imatinib and derive benefit from treatment [Corless et al. 2005]. The use of imatinib has decreased relapse rates for high-risk tumors following surgical resection when administered for 1 year compared with placebo [with a median follow up of 19.7 months, 30 (8%) patients in the imatinib arm and 70 (20%) in the placebo arm had recurrence of their tumor or died] [DeMatteo et al. 2009]. Imatinib also improved recurrencefree survival at 1 year compared with placebo [98% versus 83%; hazard ratio (HR) 0.35, onesided p < 0.0001]. The Joensuu study has also shown an improvement with longer (3 years) versus shorter (1 year) length of adjuvant treatment, with improved recurrence-free survival periods and survival time in patients at high risk of recurrence [Joensuu et al. 2012]. This rational drug design has become the model for subsequent advances in targeted cancer treatment. However, not all patients receive such profound or significantly long-lasting benefits from imatinib. Those with mutations in the exon 9 gene of KIT appear to have less benefit than those with exon 11 mutations [Heinrich et al. 2003, 2008; DebiecRychter et al. 2004], although outcomes appear to improve somewhat for those with exon 9 mutations treated with higher doses of imatinib [Gastrointestinal Stromal Tumor Meta-Analysis Group, 2010]. There are also a group of patients (less than 15% of GISTs) who demonstrate primary resistance to imatinib and have disease progression despite treatment. In addition, for those with metastatic disease, the majority will experience tumor progression during the course of imatinib treatment despite initial responses or disease stabilization. This is usually due to the emergence of resistant clones through the development of new KIT mutations, for example those that interfere with binding of imatinib to the kinase domains [Debiec-Rychter et al. 2005; Heinrich et al. 2006]. On this basis, interest has increased in the use of tyrosine kinases with broader spectra of activity than imatinib. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor effects, has shown benefit in the imatinib-resistant population in a randomized, placebo-controlled trial, which allowed crossover to sunitinib on progression [Demetri et al. 2006]. Sunitinib proved superior to placebo with respect to median progression-free survival (PFS) [median 24.1 weeks, 95% confidence
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Therapeutic Advances in Medical Oncology 6(5) interval (CI) 11.1–28.3 in the sunitinib arm; 6.0 weeks, 4.4–9.9 in the placebo arm; HR 0.33, 95% CI 0.24–0.47, p < 0.0001]. Similarly, overall survival was improved (HR 0.49 during the initial treatment period). However, for the population whose condition failed to respond to both imatinib and sunitinib, no established third-line treatment options existed until recently, obviously an area of unmet clinical need. Regorafenib, a multitargeted tyrosine kinase inhibitor, has now shown benefit in this setting of resistant metastatic GISTs and has promising clinical utility. Regorafenib Regorafenib, chemical name 4-[4-({[4-chloro-3(trifluoromethyl)phenyl]carbamoyl}amino)3-fluorophenoxy]-n-methylpyridine-2-carboxamide, is an orally available, multitargeted tyrosine kinase inhibitor. It has inhibitory actions against several tyrosine kinases that are important for oncogenesis, tumor angiogenesis and the maintenance of the tumor microenvironment, including KIT, PDGFRA, bFGFR, VEGFR1-3, TIE2, RET, BRAF and BRAF V600E [Wilhelm et al. 2011]. Regorafenib is structurally similar to sorafenib. Regorafenib is currently approved for use in a number of countries for metastatic colorectal cancer after failure of irinotecan- and oxaliplatinbased chemotherapy, and a vascular endothelial growth factor (VEGF) targeted agent [as well as epidermal growth factor receptor (EGFR) targeted agent if Kras wild type]. This approval was based on findings from the pivotal phase III CORRECT trial, which included patients whose condition had progressed on all standard therapies, and demonstrated a modest (although statistically significant) improvement in both PFS and overall survival [Grothey et al. 2013]. Phase I and II studies In preclinical studies, regorafenib demonstrated significant tumor inhibition in a variety of cancer xenograft models, including in GISTs, colorectal, renal cell, lung, melanoma, pancreatic and ovarian tumor cell lines, at clinically achievable doses [Wilhelm et al. 2011]. A phase I dose escalation study [Mross et al. 2012] established an optimal dose of regorafenib of 160 mg orally daily, administered for 21 out of 28 days, supported by pharmacodynamic and pharmacokinetic evidence. In
the phase I study which recruited patients with a variety of solid tumors, 66% of patients experienced disease control, with 3 of 47 patients having a partial response. Adverse events noted in the study were consistent with the mechanism of action of regorafenib and similar to those seen in trials of other multikinase inhibitors. The spectrum of kinases targeted by regorafenib and these early clinical results led to the commencement of phase II studies conducted in patients with GIST and colorectal cancer. In 2010, George and colleagues undertook a phase II study of regorafenib in patients whose condition had previously failed to respond to both imatinib and sunitinib treatment for GISTs [George et al. 2012]. In this trial of 33 patients, an impressive 75% experienced clinical benefit from the use of regorafenib (tumor response of complete or partial response, or stable disease for at least 16 weeks), with an overall PFS for the entire cohort of 10 months (95% CI 8.3–14.9 months). Both patients with wild-type GIST (no documented KIT or PDGRFA mutations) and KIT exon 9 and 11 mutations experienced clinical benefit at comparable rates (no PDGFRA mutations were detected among those in the trial). Those with KIT exon 11 mutations appeared to have a longer PFS compared with those with exon 9 mutations, although numbers were small. Most patients required at least one dose reduction due to toxicity (82%), with the most common adverse events being hand–foot–skin reaction, hypertension, fatigue and diarrhea. A number of these patients were subsequently able to re-escalate their dose of regorafenib. On the basis of the promising results obtained from the phase II study in GISTs, the phase III GRID trial was undertaken. Phase III trial in GIST GRID, a multicenter, randomized, placebo-controlled phase III trial of 199 patients with metastatic or unresectable disease that had failed to respond to at least two previous lines of therapy for GIST (including imatinib and sunitinib) was conducted in 2011 [Demetri et al. 2013]. This trial found a statistically significant improvement in PFS with the use of regorafenib compared with the placebo arm (median PFS 4.8 versus 0.9 months, HR 0.27). Disease control rate was 52.6% for the regorafenib arm and 9.1% for the placebo arm (p < 0.0001). Overall survival was not different between groups, but was likely
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D Ferraro and J Zalcberg influenced by the ability of patients to crossover to open-label regorafenib if on placebo during the double-blinded portion of the trial (85% of patients on placebo initially crossed over). There was no significant difference in benefit achieved between those with exon 9 or exon 11 KIT mutations in this study. Subgroup analysis showed benefit across age groups, geographic location, and line of therapy (third versus fourth line), with only those who had an imatinib duration of less than 6 months failing to show a PFS benefit. Adverse events were frequent during treatment with regorafenib but generally manageable and within the spectrum of expected events from this class of agents. During the double-blind phase of the same trial, the most common grade 3 or higher adverse events recorded in the regorafenib arm were hypertension (23%), hand–foot syndrome (20%) and diarrhea (5%). Grade 5 adverse events occurred in both arms at a rate of 5%. Dose modifications were required more frequently in the regorafenib arm compared with the placebo arm, but the rate of permanent treatment discontinuation due to adverse events in the regorafenib arm (6%) was similar to that in the placebo group (8%). This trial established that GISTs may remain responsive to treatment targeted at oncogenic drivers, even though resistance to similar agents was present previously. The broader spectrum of kinase inhibition achieved through the use of regorafenib allows targeting of recognized mechanisms of resistance (and also possibly as-yet unknown escape pathways) and can induce response even after failure of other agents. This finding has opened the door to extending the range of effective agents in GISTs and presents an exciting option for further research. Use in clinical practice The development and use of imatinib has revolutionized the management of GISTs and has given patients with previously poor prognosis effective treatment options. However, there remains substantial work to be done. There are a number of patients who have been lacking an effective treatment, including those with primary imatinib-resistant disease and those who, despite progressing through two lines of therapy, remain appropriate candidates for further treatment. Based on the positive results from the GRID trial, in February 2013 the United States Food and Drug Administration
(FDA) licensed regorafenib for use in the third-line setting for unresectable GIST, after the failure (or intolerance) of imatinib and sunitinib. A number of other international regulators have also approved this agent for this indication. Regorafenib may now be considered the standard of care for appropriate patients in this situation. The recognition and timely management of toxicities relating to the use of regorafenib is improving as clinician experience with the use of this agent grows. As most toxicities are predictable and tend to appear soon after beginning regorafenib, patient education and close patient monitoring in the early stages of treatment are particularly important [Grothey et al. 2014]. This will both minimize the severity and duration of the events and ideally prolong time on treatment for many patients through the judicious use of symptomatic treatments, dose adjustments and treatment breaks. Given the promise of significant activity from the use of a drug with manageable toxicity, regorafenib is likely to play an important role in the future direction of GIST treatment. An important challenge now is how to best utilize the agents available, such as regorafenib, to maximize outcomes for patients. A number of strategies could be considered for further investigation. By identifying survival mechanisms that bypass the effects of targeted treatment and selectively pursupossibility ing these with synergistic agents, the exists to provide a longer and more profound response to treatment, with the ultimate aim of effecting cure even in the metastatic setting. This may involve the use of multidrug treatment regimens. Currently, studies are underway on the combination of regorafenib with chemotherapy regimens such as Folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) or Folinic acid, 5-fluorouracil, irinotecan (FOLFIRI), or the EGFR targeted antibody, cetuximab, in colorectal cancer [ClinicalTrials. gov identifier: NCT01298570; NCT01289821; NCT01973868]. Although there is not a suitable active chemotherapy backbone for the use of such a combination in GISTs, the theoretical benefit of combination therapy remains intriguing. A recent preclinical study established that regorafenib in combination with inhibitors of the PI3K/AKT pathway (a possible survival pathway for tumor cells in the setting of tyrosine kinase blockade) work synergistically to kill cancer cells
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Therapeutic Advances in Medical Oncology 6(5) [Sajithlal et al. 2013]. However, the use of multiple targeted agents administered simultaneously has historically been difficult to implement, due to overlapping side-effect profiles and significant toxicity, particularly toxicity to normal cells which may rely on similar mechanisms to maintain homeostasis. Early phase trials of combinations of tyrosine kinase inhibitors have often found unexpected adverse events, or side effects with a synergistically increased severity limiting clinical applicability. Although promising in xenograft models, combination therapy targeting EGFR and VEGF, or dual EGFR blockade, resulted in increased numbers of patient discontinuing treatment due to side effects. Simultaneous use of two VEGF inhibitors or combinations of mammalian target of rapamycin inhibitors with EGFR and VEGF targeted agents have also been disappointing [Park et al. 2013]. Better understanding of the on- and off-target mechanisms of action of targeted agents is likely to provide the key to minimizing this problem in the future. More novel methods to allow use of two similar drugs, such as sequential or alternating therapy, may prove to be efficacious while minimizing side effects prevalent with concurrent administration. Given that the activity of regorafenib has been established in later lines of GIST treatment, questions now arise about using this agent in earlier lines of treatment, including first-line management of those with metastatic disease. Imatinib, the current standard of care, although well tolerated, rarely results in cure for those with metastatic disease. An agent with an ability to target a wider range of pathways activated in cancer may both improve response rates and decrease resistance to treatment. With no current trials underway in this setting, either to establish activity or to compare with current standard of care (imatinib in the first-line setting or sunitinib in the secondline setting), regorafenib cannot be recommended as a substitute for currently approved therapies in these patients. With an understanding that direct targeting prolongs survival in the metastatic setting, there is also reason to consider the use of regorafenib in the adjuvant treatment of GISTs. Imatinib has decreased relapse rates for high-risk GISTs post resection, although there remains scope to improve outcomes in this population. In colorectal cancer, a study is underway to evaluate the activity of ‘adjuvant’ regorafenib given after the resection of liver metastases [ClinicalTrials.gov
identifier: NCT01939223]. Some caution is required given that targeted agents which have shown promise in the metastatic setting have not translated into benefit in the adjuvant setting (for example, bevacizumab in colorectal cancer) [de Gramont et al. 2012]. The reasons for this are not completely elucidated, but may relate to a decreased reliance on angiogenesis in the setting of micrometastatic disease, limiting the utility of antiangiogenic agents. Again, with no evidence for the benefit of adjuvant regorafenib in GISTs, and no evidence to date of benefit in the first-line setting, this cannot be recommended as a treatment option. The elucidation of biomarkers to predict response, or resistance, to targeted agents will allow the identification of subgroups of patients who received marked benefit, and in contrast, groups that may have deleterious effects from treatment. This information will help to optimize the clinical use of agents such as regorafenib. A preplanned retrospective biomarker analysis has used the pretreatment tissue specimens from patients enrolled in the GRID trial and compared the mutations detected with those subsequently found in blood samples at the time of resistance to imatinib and sunitinib at the time of entry to GRID. The group found resistance mutations in 48% of the blood samples, but only 12% of the pretreatment tissue samples. In addition, in almost half of those samples that harbored known secondary mutations, multiple mutations were present [Cancer Discovery 2013]. Regorafenib showed activity across a range of secondary KIT mutations, reinforcing its utility in this setting, but questions remain about how to differentiate those most likely to respond to treatment from those who will not. In addition, two trials are currently underway, attempting to determine biomarkers that may correlate with clinical efficacy of regorafenib when used for metastatic colorectal cancer [ClinicalTrials.gov identifier: NCT01949194; NCT01996969]. Any positive results from these studies would warrant investigation in the GIST population to determine if the findings were similarly useful and could lead to more judicious use of regorafenib in this group. Conclusion The prognosis for patients with GIST, both with early and advanced disease, has changed enormously over the last decades. Increasing understanding of the mechanisms that underlie the evolution and progression of this disease has
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D Ferraro and J Zalcberg allowed the development of agents targeted at the molecular abnormalities widely seen in GIST, such as activating mutations of KIT and PDGFRA. Imatinib has provided considerable benefit for a previously largely untreatable disease, but has not proven to be the complete answer for patients with GIST. For those with disease refractory to imatinib, as well as the vast majority who develop resistance to imatinib, further options are required. There are now an increasing number of targeted agents which hold promise for improving outcomes in patients with GIST. The promising activity of regorafenib in the third-line setting provides an active alternative treatment in later stages of disease after failure of other agents, and raises interesting questions about the optimal utilization of this agent in both the adjuvant and metastatic setting. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement John R. Zalcberg is the principal AGITG investigator of the EORTC 62005 trial of imatinib in metastatic GIST. He has received research support, travel support and honoraria from Bayer and Novartis over the past 3 years. He has provided expert testimony for Bayer.
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