European Oncology & Haematology, 2016;12(Suppl 2):3–8
Both metastatic colorectal cancer (mCRC) and hepatocellular cancer (HCC) are complex diseases in which, during progression, frequently become refractory to treatment and patients are likely to receive a series of different chemotherapy regimens. The multikinase inhibitors (MKIs) have considerable potential in mCRC and HCC treatment and can extend overall and disease-free survival in advanced disease. Clinical experience of some of the newer MKIs in mCRC and HCC is, however, limited. The phase III CORRECT (n=760) and CONCUR (n=204) trials showed that in patients who failed with previous therapy, overall survival (OS) and progression-free survival (PFS) were significantly increased with the MKI, regorafenib compared with placebo (both given with best supportive care). Similar findings were reported in the CONSIGN trial (n=2,872) that assessed regorafenib efficacy in real-world mCRC patients. In CORRECT and CONCUR the objective response rate was low (1–4%) but stable disease was achieved in much greater proportions (40–47%). This indicates that the suitability of some therapeutic goals may change after disease progression. Studies have also indicated the potential of biomarkers such as carcinoembryonic antigen, carbohydrate antigen 19-9 and the consensus molecular subtype in identifying patients who are more suitable for MKI treatment. Results of the RESOURCE study (n=573) show that regorafenib significantly improves OS, PFS and time to progression in HCC compared with placebo. These positive benefits are in contrast to the negative results of many previous trials of other treatments in HCC. Greater use of MKIs, alternating them with other therapies, expanded guidelines for managing disease progression and the identification of biomarkers are likely to improve the otherwise bleak prospects and outcomes in mCRC and HCC. This article reports presentations given at a satellite symposium convened at the European Society for Medical Oncology 18th World Congress on Gastrointestinal Cancer, Barcelona 2nd July 2016.
Metastatic colorectal cancer, hepatocellular carcinoma, inhibiting angiogenesis, signalling pathways, regorafenib, sorafenib
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 Biomedicals. This article reports the proceedings of a sponsored satellite symposium held at the European Society for Medical Oncology 18th World Congress on Gastrointestinal Cancer and, as such, has not been subject to this journal’s usual peer-review process. The report was reviewed for scientific accuracy by the symposium speakers and Editorial Board before publication.
Authorship: 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.
Published Online: 24 November 2016
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.
October 27, 2016
Axel Grothey, MD, Division of Medical Oncology,
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.
The inhibition of angiogenesis and other signalling pathways has great potential in the treatment of various cancers including metastatic colorectal cancer (mCRC) and hepatocellular carcinoma (HCC). This approach is exploited by multikinase inhibitors (MKIs), which, when used in sequence with other chemotherapy agents, have shown to have efficacy with mostly manageable safety profiles although side effects with some of these treatments can be an issue. In the management of mCRC, patients are given widely differing chemotherapy combinations and sequences. The strategy for deriving optimal efficacy from these various agents, however, is not always clear.1 It is therefore worthwhile to explore the data supporting the use of one of these drugs, regorafenib, in this indication and in cancers of gastrointestinal (GI) origin. It is also worthwhile to consider the optimal sequencing of agents, particularly in third-line treatment and the future of combination strategies especially as there is a lack of clinical trial evidence on treatment sequencing.
HCC has proven difficult to treat, particularly in more advanced disease. Recent positive findings with regorafenib in HCC therefore are notable and indicate the potential to stabilise tumours and extend survival (the survival benefit was 2.8 months over placebo) in patients whose prognosis would otherwise be bleak.2 Since many physicians throughout the world have limited experience using the newer MKIs in either mCRC or HCC, there is an educational need to discuss their benefits
and their place in treatment strategies. This article therefore reports the presentations and discussions that took place at a satellite symposium on optimizing clinical outcomes in GI cancers through the inhibition of angiogenesis and other signalling pathways that was convened at the World Congress of Gastrointestinal Cancer at Barcelona in July 2016.
Evolving measures of efficacy in third-line metastatic colon cancer mCRC is a complex disease, and problematic for clinicians when patients become refractory to treatment. Patients with mCRC are most likely to have been pre-treated and have received both chemotherapy and monoclonal antibody treatments. In such patients, the critical issue is what should be given next? Can you still impact survival with third-line treatment? Refractory disease is unlikely to be caused by a single mutation and consequently it could be advantageous for treatment to adopt a ‘poly-pragmatic’ approach i.e., one in which drugs affect multiple different targets such as is the case with the MKIs.3–5
Regorafenib in metastatic colon cancer treatment
The MKI, regorafenib (Stivarga®, Bayer AG, Leverkusen, Germany) has multiple modes of action: it blocks the activity of various protein kinases that are necessary for angiogenesis, oncogenesis and the tumour microenvironment.5 Regorafenib has been investigated for the treatment of mCRC in two international, multicentre pivotal phase III randomised controlled studies: the Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer study (CORRECT, n=760)6 and the Regorafenib Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Asian patients with Previously Treated Metastatic Colorectal Cancer study (CONCUR, n=204);7 the latter included only Asian locations and populations. Importantly, in CORRECT, patients were treated with a single drug and there was an inclusion criterion for previous chemotherapy plus monoclonal antibody treatment whereas in CONCUR this did not apply. In CORRECT, treatment with regorafenib 160 mg resulted in a 23% reduction in the risk of death (primary endpoint) compared with placebo (median 6.4 versus 5.0 months p=0.0052) and in CONCUR this reduction was 45% (median 8.8 versus 6.3 months, p=0.00016).6,7 In addition, there was a 51% reduction in risk of progression or death in CORRECT compared with placebo (median 1.9 versus. 1.7 months, p<0.0001) and a 69% reduction in CONCUR (median 3.2 versus
1.7 months, p<0.0001). These results indicate that regorafenib has pronounced efficacy in mCRC.
1. Lee JJ, Chu E, Sequencing of antiangiogenic agents in the treatment of metastatic colorectal cancer, Clin Colorectal Cancer, 2014;13:135–44.
2. Trojan J, Waidmann O, Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma, J Hepatocell Carcinoma, 2016;3:31–6.
3. Bayer Healthcare Stivarga (regorafinib) Summary of Product Characteristics, 2016. Available at: www.medicines.org.uk/emc/ medicine/28270 (date accessed: 05 August 2016).
4. Pang R, Poon RT, Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma, Cancer Lett, 2006;242:151–67.
5. 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.
6. Grothey A, Van Cutsem E, Sobrero A, et al., Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial, Lancet, 2013;381:303–12 and supplemental appendix material.
7. Li J, Qin S, Xu R, et al., Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Oncol, 2015;16:619–29.
8. Van Cutsem E, Ciardiello F, Seitz JF, et al., CONSIGN: An openlabel phase 3B study of regorafenib in patients with metastatic colorectal cancer (mCRC) who failed standard therapy. Abstract 2139, Presented at: European Cancer Congress, Vienna, Austria, 2015.
9. Eli Lilly and Co., Ramucirumab(Cyramza) Summary of product characteristics, 2016. Available at: www.medicines.org.uk/emc/ medicine/29765 (date accessed: 08 August 2016).
10. Bennouna J, Sastre J, Arnold D, et al., Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial, Lancet Oncol, 2013;14:29–37.
11. Douillard JY, Siena S, Cassidy J, et al., Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study, J Clin Oncol, 2010;28:4697–705.
12. Giantonio BJ, Catalano PJ, Meropol NJ, et al., Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200, J Clin Oncol, 2007;25:1539–44.
13. Mayer RJ, Van Cutsem E, Falcone A, et al., Randomized trial of TAS-102 for refractory metastatic colorectal cancer, N Engl J Med, 2015;372:1909–19.
14. Peeters M, Price TJ, Cervantes A, et al., Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as secondline treatment in patients with metastatic colorectal cancer, J Clin Oncol, 2010;28:4706–13.
15. Saltz LB, Clarke S, Diaz-Rubio E, et al., Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study, J Clin Oncol, 2008;26:2013–9.
16. Tabernero J, Cohn AL, Obermannova R, et al., RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp) Abstract 512, J Clin Oncol 33, 2015;(suppl 3; abstr 512).
17. Van Cutsem E, Kohne CH, Lang I, et al., Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status, J Clin Oncol, 2011;29:2011–9.
18. Van Cutsem E, Tabernero J, Lakomy R, et al., Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen, J Clin Oncol, 2012;30:3499–506.
19. Crabb SJ, Patsios D, Sauerbrei E, et al., Tumor cavitation: impact on objective response evaluation in trials of angiogenesis inhibitors in non-small-cell lung cancer, J Clin Oncol, 2009;27:404–10.
20. Kawasaki K, Hamamoto Y, Adachi M, et al., Early tumor cavitation with regorafenib in metastatic colorectal cancer: A case report, Oncol Lett, 2016;11:231–3.
21. Ricotta R, Cavitation of lung metastases induced by regorafenib in patients with colorectal carcinoma: Data from the phase III CORRECT study. Abstract 2015. Presented at: European Cancer Congress Vienna, Austria, 2015.
22. Ricotta R, Sartore-Bianchi A, Verrioli A, et al., Regorafenib for metastatic colorectal cancer, Lancet, 2013;381:1537.
23. Grothey A, Falcone A, Humblet Y, et al.,2015, Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months. Abstract 710, 51st Society for Clinical Oncology Chicago, USA http:// meetinglibrary.asco.org/content/140570–158.
24. Komori A, Taniguchi H, Kito Y, et al., 169P - Serum CA19-9 response is an early predictive marker for the efficacy of regorafenib in refractory metastatic colorectal cancer. Presented at: European Society for medical Oncology Asia meeting Singapore, 2015.
25. Budinska E, Popovici V, Tejpar S, et al., Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer, J Pathol, 2013;231:63–76.
26. De Sousa EMF, Wang X, Jansen M, et al., Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions, Nat Med, 2013;19:614–8.
27. Guinney J, Dienstmann R, Wang X, et al., The consensus molecular subtypes of colorectal cancer, Nat Med, 2015;21:1350–6.
28. Marisa L, de Reynies A, Duval A, et al., Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value, PLoS Med, 2013;10:e1001453.
29. Roepman P, Schlicker A, Tabernero J, et al., Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition, Int J Cancer, 2014;134:552–62.
30. Sadanandam A, Lyssiotis CA, Homicsko K, et al., A colorectal cancer classification system that associates cellular phenotype and responses to therapy, Nat Med, 2013;19:619–25.
31. Schlicker A, Beran G, Chresta CM, et al., Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines, BMC Med Genomics, 2012;5:66.
32. Dienstmann R, Guinney J, Delorenzi M, et al., Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes, J Clin Oncol, 2014;32:5s suppl abstract 3511.
33. Teufel M, Schwenke S, Seidel H, et al., Molecular subtypes and outcomes in regorafenib-treated patients with metastatic colorectal cancer (mCRC) enrolled in the CORRECT trial, J Clin Oncol, 2015;33:15S abstract 3558:.
34. Bokemeyer C, Bondarenko I, Hartmann JT, et al., Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study, Ann Oncol, 2011;22:1535–46.
35. Heinemann V, von Weikersthal LF, Decker T, et al., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial, Lancet Oncol, 2014;15:1065–75.
36. Hurwitz H, Fehrenbacher L, Novotny W, et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer, N Engl J Med, 2004;350:2335–42.
37. Loupakis F, Cremolini C, Masi G, et al., Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer, N Engl J Med, 2014;371:1609–18.
38. Hanna N, Woods C, Zheng Z, et al., Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 metastatic colon cancer patients, J Clin Oncol, 2014;32 Suppl 3 abstract 559.
39. Schmoll HJ, Van Cutsem E, Stein A, et al., ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making, Ann Oncol, 2012;23:2479–516.
40. National Comprehensive Cancer Network, Clinical practice Guidelines Colon Cancer V2, 2016. Available at: www.nccn.org/ professionals/physician_gls/pdf/colon.pdf (date accessed: 15 November 2016).
41. National Comprehensive Cancer Network Clinical Practice Guidelines - Rectal Cancer V1, 2016. Available at: www.nccn. org/professionals/physician_gls/pdf/rectal.pdf (date accessed: 15 November 2016).
42. Van Cutsem E, Cervantes A, Nordlinger B, et al., Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2014;25 Suppl 3:iii1–9.
43. Kidd MT, Wilcox RE, Rogers J, et al., Efficacy of chemotherapy after treatment with regorafenib in metastatic colorectal cancer (mCRC), J Clin Oncol, 2015;33 supple 3 abstract 678.
44. Arita S, Shirakawa T, Matsushita Y, et al., Efficacy and Safety of TAS-102 in Clinical Practice of Salvage Chemotherapy for Metastatic Colorectal Cancer, Anticancer Res, 2016;36:1959–66.
45. Sugimoto N, Yoshimsmi S, Yamamoto S, et al., Effect of regorafenib and TAS-102 in metastatic colorectal cancer (mCRC) patients on survival in salvage line with different toxicity profile (ASCO abstract), J Clin Oncol, 2016;34 (suppl 4S abstract 763).
46. Napolitano S, Martini G, Rinaldi B, et al., Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab, Clin Cancer Res, 2015;21:2975–83.
47. Weekes C, Lockhart AC, Lenz H-J, et al., A phase Ib study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors. Presented at: American Association for Cancer Research, New Orleans, USA, 2016, abstract number: CT148.
48. Sanz-Garcia E, Grasselli J, Argiles G, et al., Current and advancing treatments for metastatic colorectal cancer, Expert Opin Biol Ther, 2016;16:93–110.
49. O’Neil B, O’Reilly S, Kasban S, et al., A multi-center, randomized, double-blind phase II trial of FOLFIRI + regorafenib or placebo for patients with metastatic colorectal cancer who failed one prior line of oxaliplatin-containing therapy (ESMO abstract), Annals of Oncology, 2016;27:(Suppl 6) abstract 464PD.
50. Moehler M (PI), REMETY - Planned Phase IIb dose-finding study Regorafenib + TAS-102 - Bayer Clinical Trial #17949, 2016.
51. Ott PA, Hodi FS, Buchbinder EI, Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data, Front Oncol, 2015;5:202.
52. Bruix J, Reig M, Sherman M, Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma, Gastroenterology, 2016;150:835–53.
53. Park JW, Chen M, Colombo M, et al., Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study, Liver Int, 2015;35:2155–66.
54. Llovet JM, Ricci S, Mazzaferro V, et al., Sorafenib in advanced hepatocellular carcinoma, N Engl J Med, 2008;359:378–90.
55. Cheng AL, Kang YK, Chen Z, et al., Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial, Lancet Oncol, 2009;10:25–34.
56. Clinicaltrials.gov PD Dr. med. Matthias Dollinger, Sorafenib Plus Doxorubicin Versus Sorafenib Alone for the Treatment of Advanced Hepatocellular Carcinoma: a Randomized Phase II Trial (SoraDox), 2016. Available at: https://clinicaltrials.gov/ ct2/show/NCT01272557?term=NCT01272557&rank=1 (date accessed: 16 August 2016).
57. Abou-Alfa GK, Qin S, Ryoo B-Y, et al., Phase III randomized study of second line ADI-peg 20 (A) plus best supportive care versus placebo (P) plus best supportive care in patients (pts) with advanced hepatocellular carcinoma (HCC), J Clin Oncol, 2016;34:(suppl; abstr 4017).
58. Cainap C, Qin S, Huang WT, et al., Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial, J Clin Oncol, 2015;33:172–9.
59. Cheng AL, Kang YK, Lin DY, et al., Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial, J Clin Oncol, 2013;31:4067–75.
60. Johnson PJ, Qin S, Park JW, et al., Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study, J Clin Oncol, 2013;31:3517–24.
61. Llovet JM, Decaens T, Raoul JL, et al., Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study, J Clin Oncol, 2013;31:3509–16.
62. Zhu AX, Kang YK, Rosmorduc O, et al., Biomarker Analyses of Clinical Outcomes in Patients With Advanced Hepatocellular Carcinoma Treated With Sorafenib With or Without Erlotinib in the SEARCH Trial, Clin Cancer Res, 2016;22:4870–9. 63.
63. Zhu AX, Kudo M, Assenat E, et al., Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial, JAMA, 2014;312:57–67. 64.
64. Zhu AX, Park JO, Ryoo BY, et al., Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial, Lancet Oncol, 2015;16:859–70.
65. Bruix J, Tak WY, Gasbarrini A, et al., Regorafenib as second– line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study, Eur J Cancer, 2013;49:3412–9.
66. Bruix J, Merle P, Granito A, et al., Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial. Abstract LBA-03, Annals of Oncology, 2016;27 Suppl 2 ii140–ii1.
67. Bruix J, Sherman M, American Association for the Study of Liver D, Management of hepatocellular carcinoma: an update, Hepatology, 2011;53:1020–2.
68. European Association For The Study Of The L, European Organisation For R, Treatment Of C, EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma, J Hepatol, 2012;56:908–43.
69. Forner A, Llovet JM, Bruix J, Hepatocellular carcinoma, Lancet, 2012;379:1245–55.
Metastatic colorectal cancer, hepatocellular carcinoma, inhibiting angiogenesis, signalling pathways, regorafenib, sorafenib