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

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

Abstract:

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: grothe.axel@mayo.edu
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.

References:
1. Candelaria M, de la Garza J, Duenas-Gonzalez A, A clinical and biological overview of gastrointestinal stromal tumors, Med Oncol, 2005;22:1–10.
2. Giuliani J, Bonetti A, The Occurrence of Gastrointestinal Stromal Tumors and Second Malignancies, J Gastrointest Cancer, 2015;46:408–12.
3. Mastrangelo G, Coindre JM, Ducimetiere F, et al., Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions, Cancer, 2012;118:5339–48.
4. Soreide K, Sandvik OM, Soreide JA, et al., Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies, Cancer Epidemiol, 2016;40:39–46.
5. Alturkmani HJ, Pessetto ZY, Godwin AK, Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor, Expert Opin Investig Drugs, 2015;24:1045–58.
6. Burgess M, Tawbi H, Immunotherapeutic approaches to sarcoma, Curr Treat Options Oncol, 2015;16:26.
7. Gettys SC, Anderson JE, Davis JE, New and emerging therapies for advanced or metastatic soft tissue sarcoma, J Oncol Pharm Pract, 2014;20:288–97.
8. Segaliny AI, Tellez-Gabriel M, Heymann MF, et al., Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers, J Bone Oncol, 2015;4:1–12.
9. Corless CL, Barnett CM, Heinrich MC, Gastrointestinal stromal tumours: origin and molecular oncology, Nat Rev Cancer, 2011;11:865–78.
10. Lasota J, Miettinen M, KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs), Semin Diagn Pathol, 2006;23:91–102.
11. Gastrointestinal Stromal Tumor Meta-Analysis G, Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients, J Clin Oncol, 2010;28:1247–53.
12. Blay JY, Le Cesne A, Cassier PA, et al., Gastrointestinal stromal tumors (GIST): a rare entity, a tumor model for personalized therapy, and yet ten different molecular subtypes, Discov Med, 2012;13:357–67.
13. Blay JY, Shen L, Kang YK, et al., Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial, Lancet Oncol, 2015;16:55–60.
14. Demetri GD, Reichardt P, Kang YK, et al., Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial, Lancet, 2013;381:295–302.
15. Demetri GD, van Oosterom AT, Garrett CR, et al., Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial, Lancet, 2006;368:1329–38.
16. Fabian MA, Biggs WH, 3rd, Treiber DK, et al., A small moleculekinase interaction map for clinical kinase inhibitors, Nat Biotechnol, 2005;23:329–36.
17. Murphy EA, Shields DJ, Stoletov K, et al., Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRbeta/B-RAF, Proc Natl Acad Sci U S A, 2010;107:4299–304.
18. Wilhelm SM, Dumas J, Adnane L, et al., Regorafenib (BAY 73- 4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity, Int J Cancer, 2011;129:245–55.
19. Liegl B, Kepten I, Le C, et al., Heterogeneity of kinase inhibitor resistance mechanisms in GIST, J Pathol, 2008;216:64–74.
20. Ben-Ami E, Barysauskas CM, von Mehren M, et al., Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy, Ann Oncol, 2016;27:1794–9.
21. Demetri GD, Jeffers M, Reichardt P, et al., Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes, J Clin Oncol, 2013;31:15 (Suppl) ASCO abstracts 10503.
22. Richardson AL, Iglehart JD, BEAMing up personalized medicine: mutation detection in blood, Clin Cancer Res, 2012;18:3209–11.
23. Ryu MH, Ryoo BY, Kim HJ, et al., Randomized phase III trial of imatinib (IM) rechallenge versus placebo (PL) in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): RIGHT study, J Clin Oncol, 2013;31:LBA10502.
24. Cinicaltrails.gov, A Randomised Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST) (ALT GIST), 2016. Available at: https://clinicaltrials.gov/ ct2/show/NCT02365441?term=02365441&rank=1 (accessed 22 November 2016).
25. van der Graaf WT, Blay JY, Chawla SP, et al., Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial, Lancet, 2012;379:1879–86.
26. Mir O, Brodowicz T, Italiano A, et al., Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial, Lancet Oncol, 2016;17:1732–42.
27. Penel N, Mir O, Italiano A, et al., Regorafenib (RE) in liposarcomas (LIPO), leiomyosarcomas (LMS), synovial sarcomas (SYN), and other types of soft-tissue sarcomas (OTS): Results of an international, double-blind, randomized, placebo (PL) controlled phase II trial ASCO abstract 11003, J Clin Oncol, 2016;34.
28. International Agency for Research on Cancer, Globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/ (accessed 24 May 2016).
29. Burtness B, Ilson D, Iqbal S, New directions in perioperative management of locally advanced esophagogastric cancer, Am Soc Clin Oncol Educ Book, 2014;e172–8.
30. Mohammad NH, ter Veer E, Ngai L, et al., Optimal first-line chemotherapeutic treatment in patients with locally advanced or metastatic esophagogastric carcinoma: triplet versus doublet chemotherapy: a systematic literature review and meta-analysis, Cancer Metastasis Rev, 2015;34:429–41.
31. Ajani JA, D’Amico TA, Almhanna K, et al., Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology, J Natl Compr Canc Netw, 2016;14:1286–312.
32. Waddell T, Verheij M, Allum W, et al., Gastric cancer: ESMOESSO- ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2013;24 Suppl 6:vi57–63.
33. Bayer HealthCare Pharmaceuticals, Inc Whippany, NJ, Stivarga (regorafenib) Summary of product characteristics, 2015. Available at: www.accessdata.fda.gov/drugsatfda_docs/ label/2015/203085s004lbl.pdf (accessed 17 November 2016).
34. European Medicines Agency, EPAR - Stivarga (regorafenib), 2016. Available at: www.ema.europa.eu/ema/index.jsp?curl=pages/ medicines/human/medicines/002573/human_med_001684. jsp&mid=WC0b01ac058001d124 (accessed 17 November 2016). 35. Pavlakis N, Sjoquist KM, Martin AJ, et al., Regorafenib for the Treatment of Advanced Gastric Cancer (INTEGRATE): A Multinational Placebo-Controlled Phase II Trial, J Clin Oncol, 2016;34:2728–35.
36. Pavlakis N, Sjoquist KM, Tsobanis E, et al., INTEGRATE: A randomized, phase II, double-blind, placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC): A study by the Australasian Gastrointestinal Trials Group (AGITG)—Final overall and subgroup results. ASCO abstract 4003, J Clin Oncol, 2015;33:suppl; abstr 4003.
37. Clinicaltrials.gov, A Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (INTEGRATEII), 2016. Available at: https://clinicaltrials.gov/ct2/show/ NCT02773524?term=NCT02773524&rank=1 (accessed 21 November 2016).
38. Takigawa H, Kitadai Y, Shinagawa K, et al., Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma, Cancer Sci, 2016;107:601–8.
39. Kang Y-K, Ryu MH, Ryoo B-Y, et al., Randomized phase III trial of imatinib (IM) rechallenge versis placebo (PL) in patients (pts) with metastatic aand/or unresectable gastrointestimal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): RIGHT study, J Clin Oncol, 2013;31(suppl) LBA10502.
Keywords: Gastrointestinal stromal cancer, sarcoma, oesophagogastric cancer, regorafenib, multikinase inhibitor