State-of-the-art Integration of Multikinase Inhibitors in the Treatment of Gastrointestinal Cancers

European Oncology & Haematology, 2017;(Suppl 1):2–7


Gastrointestinal stromal tumours (GISTs) are caused mainly by KIT mutations in the tyrosine kinase and platelet-derived growth factor receptor genes. Several tyrosine kinase inhibitors (TKIs) are effective against GISTs, including imatinib, pazopanib, nilotinib and sunitinib, but their clinical performance is largely dependent on the types of mutations present. Analysis of these mutations can therefore inform treatment choices. The multikinase inhibitor (MKI) regorafenib has shown efficacy in GISTs in several clinical trials, including the GIST Regorafenib In Progressive Disease (GRID) study (n=199), in which patients with unresectable or metastatic GIST showed significantly longer progression-free survival (PFS) compared with best supportive care (4.8 months versus 0.9 months, p<0.0001). This treatment is now approved for use in GISTs. Other potential indications for regorafenib include soft tissue sarcoma (STS), visceral sarcoma (VS) and bone sarcoma (BS). Another cancer type with limited treatment options is esophagogastric cancer. In the phase II INTEGRATE study (n=152) regorafenib showed significantly longer PFS than placebo (2.6 months versus 0.9 months, p<0.0001) in patients with varying types of oesophagogastric cancer. Stable disease was achieved in 40% versus 14%, respectively, and the treatment was well tolerated. Further evaluation of regorafenib in this indication is in progress in a phase III trial. Increased use of MKIs such as regorafenib and more widespread genetic testing to identify suitable patients therefore have the potential to improve the outlook for patients with GISTs and, in the future, to possibly improve the currently bleak prognosis for patients with other problematic sarcomas, including STS, VS, BS and oesophagogastric cancers.
Keywords: Gastrointestinal stromal cancer, sarcoma, oesophagogastric cancer, regorafenib, multikinase inhibitor
Disclosure: James Gilbart is an employee of Touch Medical Media. The Mayo Clinic Foundation received grants and honoraria for activities conducted by Axel Grothey from Bayer, Genentech, Taiho, Eli-Lilly, Amgen, BMS, Eisai and Boston Biomedical. This article reports the proceedings of a sponsored satellite symposium held at European Society for Medical Oncology Congress 2016 and, as such, has not been subject to this journal’s usual peer-review process. The report was reviewed for scientific accuracy by the Editorial Board before publication.
Acknowledgments: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Compliance with Ethics: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions, and informed consent was received from the patient involved in this case study.
Received: January 12, 2017
Correspondence: Axel Grothey, Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester,MN 55905, US. E:
Support: The publication of this article was supported by Bayer. The views and opinions expressed are those of the author and do not necessarily reflect those of Bayer.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Targeting kinase pathways to treat progressive gastrointestinal stromal tumours and sarcomas
Gastrointestinal stromal tumours

Medications that target multiple kinase pathways have proven to be a successful and are a frequently used approach in treating progressive gastrointestinal stromal tumours (GISTs), which are the most common type of sarcomas.1–4 Tyrosine kinase inhibitors (TKIs), which have shown efficacy and are approved for use in GISTs include regorafenib, imatinib, sunitinib and pazopanib. Some of these, and other TKIs also have potential for the treatment of other cancers, including soft tissue sarcomas (STS) and bone sarcomas (BS).5–8

GISTs are caused mainly by KIT mutations in the tyrosine kinase gene at exon 11 (67.5%), exon 9 (11%), exon 13 (0.9%) and exon 17 (0.5%) and less frequently by platelet-derived growth factor receptor (PDGFRA) mutations at exon 18 (6.3%), exon 12 (0.9%) and exon 14 (0.3%).9 The efficacy of the TKI imatinib is dependent on the type of mutation present, for example, patients’ KIT mutations at exon 9 or 11 and PDGFRA exon 12 are imatinib sensitive.9,10 Findings from the GIST meta-analysis group have suggested that patients with KIT exon 9 mutations may have progressionfree survival (PFS) on a higher dose of imatinib (800 mg compared with 400 mg), but the analysis was insufficiently powered to make a definitive conclusion.11 Findings also show that the PDGFRA-D842V mutation is particularly resistant to imitanib treatment, whereas some other PDGFRA mutations are not resistant to this treatment.11,12 Patients with unresectable or metastatic GIST are very difficult to treat but imatinib is effective as first-line therapy in many such cases. A recent comparative study of patients with advanced GIST (ENESTg1) showed that in those with KIT exon 9 mutations, nilotinib (a newer treatment in this class) was not as effective as high-dose imatinib as first-line therapy in terms of PFS and overall survival (OS) over 2 years.13 More recently, in phase III clinical trials, the TKIs sunitinib and regorafenib have demonstrated efficacy in advanced GIST after failure of imatinib or other treatments.14,15 At present, the median PFS in GIST is approximately 3 years and new treatments are needed to improve this.

The kinase inhibitory profiles of imatinib, sunitinib and regorafenib are different and, as a result, it is not surprising that their clinical performance in GIST also differs.16–18 Heterogenicity of primary and secondary mutations in the kinase enzyme set (kinome), principally in exons 13, 14, 17 and 18, result in variable resistance profiles to TKIs and in problems treating GIST with either imatinib or sunitinib.19 Despite encouraging results, it should be stressed that there is no evidence that regorafenib has better clinical efficacy in GIST than imatinib or sunitib and no headto- head studies have been conducted. These medications are beneficial in different situations and there can be advantages in switching between them as discussed below.

The multikinase-inhibiting mechanism of action of regorafenib can provide extended efficacy and control of GIST even in the presence of some secondary mutations. This was demonstrated in the long-term follow-up of a phase II study (n=33) in patients with metastatic GIST who were treated with regorafenib (160 mg OD).20 The median follow-up was 41 months, and only four patients (12%) had no disease progression. Overall PFS was 13.2 months and OS was 25.0 months. However, the longest median PFS (13.4 months) was seen in patients with a primary KIT exon 11 mutation, whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumours showed a much shorter median PFS (1.6 months, p<0.0001).

Further evidence of regorafenib efficacy in GIST was provided by the multicentre phase III GIST Regorafenib In Progressive Disease (GRID) trial. 14 Patients with metastatic or unresectable GIST, who had failed on at least imatinib and sunitinib were randomised to receive either regorafenib (n=133) or placebo (n=66), with both groups receiving best supportive care (BSC). When disease progression occurred, patients were unblinded; those receiving placebo were crossed over to regorafenib or continued on active treatment until the next progression. The patient populations in the treatment and placebo groups were balanced in terms of gender, race, proportions who received two or more prior lines of GIST therapies and Eastern Cooperative Oncology Group (ECOG) status (0 or 1). The median PFS for regorafenib was 4.8 months versus 0.9 months for placebo (hazard ratio [HR]: 0.27 p<0.0001, see Figure 1). Due to progression, 56/66 (85%) placebo-treated patients switched to regorafenib, which resulted in there being no significant difference in OS (HR: 0.77, p=0.199). This lack of difference was a result of the study design and was expected.

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Keywords: Gastrointestinal stromal cancer, sarcoma, oesophagogastric cancer, regorafenib, multikinase inhibitor