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Promising Therapeutics of Gastrointestinal Cancers in Clinical Trials

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Promising Therapeutics of Gastrointestinal Cancers in Clinical Trials 533 Review Article Promising therapeutics of gastrointestinal cancers in clinical trials Lingling Du1, Zheng Che2, Andrea Wang-Gillam1 1Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; 2University of Toledo, OH, USA Contributions: (I) Conception and design: A Wang-Gillam; (II) Administrative support: A Wang-Gillam; (III) Provision of study material or patients: All authors; (IV) Collection and assembly of data: A Wang-Gillam, L Du; (V) Data analysis and interpretation: A Wang-Gillam, L Du; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Andrea Wang-Gillam, MD, PhD. Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. Email: [email protected]. Abstract: Many novel therapeutics are being developed for patients with cancers along the gastrointestinal (GI) tract. These emerging agents are frequently classified by their biological targets such as tumor growth pathways, tumor metabolism, microenvironment, etc. Some agents targeting cancer growth pathways are based on existing clinically validated therapeutic targets, such as regorafenib for hepatocellular carcinoma (HCC), while other agents focus on newly identified targets, such as FGFR fusions in cholangiocarcinoma. Drugs modifying the immunosuppressive tumor microenvironment have emerged as an attractive area of clinical investigation. Moreover, drugs targeting the stem-cell like qualities of cancer and the tight junction protein claudin 18.2 have generated quite a lot of excitement in the field. In this paper, we will systemically review the recent promising agents and therapeutic strategies in GI cancers. Keywords: Promising therapeutics; gastrointestinal cancers; clinical trials; growth factor signaling pathway; tumor metabolism; tumor microenvironment Submitted Nov 20, 2016. Accepted for publication Dec 12, 2016. doi: 10.21037/jgo.2017.01.08 View this article at: http://dx.doi.org/10.21037/jgo.2017.01.08 Introduction discussion here as it is discussed in great detail in another review in this issue. Over the past few decades, the treatment paradigm of gastrointestinal (GI) cancers has changed substantially. Monoclonal antibodies targeting angiogenesis and the Growth signaling pathway inhibitors epidermal growth factor receptor (EGFR) signaling pathway Inhibition of growth signaling pathways has traditionally have become standard treatments for advanced colorectal been a research hot spot for GI cancers, and it has achieved cancers (CRCs) (1,2). Small molecule multikinase inhibitors significant success with the development and clinical have also demonstrated survival benefit in patients with use of small molecule kinase inhibitors and monoclonal refractory CRCs and hepatocellular carcinomas (HCCs) (3,4). antibodies (1,2,4). Strategies of inhibiting the growth factor Most recently, immunotherapy has shown promising clinical pathways include targeting cell surface receptors or their efficacy in multiple types of GI cancers (5,6). Although downstream cellular cascades. Vascular endothelial growth chemotherapy remains the mainstay of treatments for the factor receptor (VEGFR), MET, c-kit, platelet-derived majority of GI cancers, novel agents either as single agents growth factor receptor (PDGFR), and fibroblast growth or in combination are being evaluated in clinical trials factor receptor (FGFR) are commonly targeted cell surface at an accelerated pace. Here we review the major drugs receptors. Activation of these receptors stimulates various that have demonstrated promising therapeutic activity in downstream signaling pathways that promote tumor cell clinical trials. Immunotherapy is not a significant part of the proliferation and sustain cell survival. One of the pathways © Journal of Gastrointestinal Oncology. All rights reserved. jgo.amegroups.com J Gastrointest Oncol 2017;8(3):524-533 Journal of Gastrointestinal Oncology Vol 8, No 3 June 2017 525 Figure 1 Commonly targeted growth factor signaling pathways. commonly involved is the Raf-MEK-ERK mitogen- who demonstrated partial response (PR) were continued on activated protein kinase (MAPK) cascade, in which activated the treatment, whilst those with stable disease (SD) were Raf kinases phosphorylate the downstream MEK kinases, randomized to continue receiving cabozantinib or placebo. and the latter activate the extracellular signal-regulated Among the 41 patients enrolled, half had received prior kinases (ERK), which lead to cell growth (Figure 1) (7). sorafenib. Cabozantinib was frequently associated with Therapeutics targeting the above cell surface receptors fatigue, diarrhea, hand-foot syndrome, nausea/vomiting, and and the downstream Raf-MEK-ERK pathway have shown thrombocytopenia. Sixty percent of patients needed dose some promising results in GI cancers in early phase clinical reductions during the lead-in stage. The overall response studies. rate (ORR) was 5%, but 78% of patients had SD. The Cabozantinib is a dual inhibitor of the cell surface growth median progression-free survival (PFS) was 4.4 months, receptors VEGFR2 and MET. In a phase II study, patients and the median overall survival (OS) was 15.1 months. with advanced HCCs were treated with cabozantinib at These results were encouraging given that historically, 100 mg daily for 12 weeks as the lead-in stage (8). Patients the ORR and the median OS for untreated HCC patients © Journal of Gastrointestinal Oncology. All rights reserved. jgo.amegroups.com J Gastrointest Oncol 2017;8(3):524-533 526 Du et al. Promising new drugs of GI cancers in trials who received sorafenib were only 2% and 10.7 months, family consists of four receptors that are activated by respectively (4). A phase III study evaluating cabozantinib binding fibroblast growth factors using heparin or heparin at a dose of 60 mg daily versus placebo in patients with sulfate proteoglycan as a co-factor (11). Activated FGFR advanced HCC who have received prior sorafenib is triggers complex downstream pathways including the ongoing (NCT01908426). phosphoinositide 3-kinase (PI3K)-AKT cascades and the Another multikinase inhibitor, regorafenib, targets Raf-MEK-ERK signaling pathway. FGFR2 fusions have multiple cell surface growth signaling receptors including been identified in approximately 13% of intrahepatic VEGFR1-3, KIT, PDGFR, and FGFR. It has been cholangiocarcinomas (12,13). Preliminary efficacy of approved for the treatment of advanced CRC. Recent FGFR inhibitors has been demonstrated in patients with data indicated that it is also effective in treating advanced FGFR2 fusion and preclinical models (14,15). A phase HCC. The phase III RESORCE study tested the efficacy II study examined the activity of a pan-FGFR inhibitor, of regorafenib in patients with HCC who had progressed BGJ398, in patients with previously treated advanced on sorafenib. The results were presented at the European cholangiocarcinoma harboring FGFR2 alterations (16). Society for Medical Oncology (ESMO) World Congress Forty-seven patients received the study drug. FGFR2 of Gastrointestinal Cancer 2016 (9). A total of 573 patients translocations were found in 38 patients, with FGFR2- were randomized 2:1 to receive regorafenib at 160 mg BICC1 fusions being the most common (n=9). Nine patients for 3 weeks every 4-week cycle versus placebo. Severe had other FGFR alterations, including mutations in FGFR adverse events were experienced in 79.7% of patients and amplifications in FGFR2 and FGFR3. This was a treated with regorafenib versus 58.5% of those received heavily pretreated patient population, with 62% of patients placebo. Common adverse events of regorafenib included receiving ≥2 prior lines of therapies, and 11% with ≥4 prior hypertension, hand-foot syndrome, fatigue, and diarrhea. regimens. Adverse events were overall manageable, with Regorafenib significantly improved the ORR (10.6% vs. hyperphosphatemia, fatigue, constipation, and diarrhea 4.1%; P=0005), PFS (3.1 vs. 1.5 months; HR 0.46; 95% CI: being the most common. Among a total of 36 evaluable 0.37–0.56; P<0.001), and OS (10.6 vs. 7.8 months; HR 0.62; patients, eight patients (22%) had PR and 19 (53%) had 95% CI: 0.50–0.78; P<0.001) compared to placebo. These SD. Median duration of drug exposure was 188 days. These results are very encouraging and make regorafenib an results were encouraging when compared to the median attractive agent for HCC patients progressed on sorafenib. PFS of approximately 3 months in patients who received Similar to regorafenib, nintedanib is also a multikinase second-line therapies for advanced cholangiocarcinoma inhibitor targeting VEGFR1–3, FGFR, and PDGFR, but (17,18). Several clinical studies are ongoing to test the role with a better toxicity profile. In a phase I study, 30 patients of other FGFR inhibitors in cholangiocarcinomas or other with previously treated advanced CRC were treated with solid tumors harboring FGFR alterations (NCT02834780, nintedanib (10). This was a heavily pretreated population NCT01752920). with prior lines of treatment ranging from 1–5. Nintedanib Moving from the cell surface receptors to downstream was well tolerated with the most common adverse events signaling cascades, the Raf-MEK-ERK signaling pathway being mild nausea, vomiting, and diarrhea. Only 10% of is frequently involved in carcinogenesis. The BRAF gene patients had ≥ grade 3 toxicities. Twenty-four patients (80%) encodes an intracellular Raf protein,
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