Optimising Clinical Outcomes in Gastrointestinal Cancers through Inhibiting Angiogenesis and Other Signalling Pathways

European Oncology & Haematology, 2016;12(Suppl 2):3–8

Abstract:

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.
Keywords: Metastatic colorectal cancer, hepatocellular carcinoma, inhibiting angiogenesis, signalling pathways, regorafenib, sorafenib
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 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
Received: October 27, 2016
Correspondence: Axel Grothey, MD, Division of Medical Oncology,
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.

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.

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Keywords: Metastatic colorectal cancer, hepatocellular carcinoma, inhibiting angiogenesis, signalling pathways, regorafenib, sorafenib