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Combination of Small-Molecule Kinase Inhibitors and Irinotecan in Cancer Clinical Trials: Efficacy and Safety Considerations

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Combination of Small-Molecule Kinase Inhibitors and Irinotecan in Cancer Clinical Trials: Efficacy and Safety Considerations 1623 Original Article Combination of small-molecule kinase inhibitors and irinotecan in cancer clinical trials: efficacy and safety considerations Ganessan Kichenadasse, Arduino Mangoni, John Miners Department of Clinical Pharmacology, Flinders University, Adelaide, Australia Contributions: (I) Conception and design: G Kichenadasse; (II) Administrative support: G Kichenadasse, J Miners; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: G Kichenadasse; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Dr. Ganessan Kichenadasse. Department of Clinical Pharmacology, Flinders University, Bedford Park, SA 5042, Australia. Email: [email protected]. Background: The combination of small-molecule kinase inhibitors (KI) and the cytotoxic chemotherapy drug irinotecan, albeit studied extensively in both pre-clinical and clinical studies, has not been adopted in clinical practice. We describe the available evidence regarding the efficacy and safety of the combination of KI/irinotecan and explore the possible reasons for its failure to be translated into clinical practice. Methods: Relevant in vitro and in vivo studies were identified from Medline and abstracts of the American Society of Clinical Oncology (ASCO) annual meetings published from inception until June 2017. The results of studies for the combination of irinotecan and KI in cell lines, animal models and human trials are summarized. Results: The majority of KIs exhibit synergistic activity with irinotecan in tumour cell lines. However, published phase I/II clinical trials in cancer patients failed to show good tolerability due to the overlapping toxicity of the combination, particularly diarrhoea and neutropenia. KIs influence the metabolism of the active metabolite SN-38 [through UDP-glucuronosyl transferase 1A1 (UGT1A1) inhibition and impaired transport] resulting in increased exposure and toxicity related to irinotecan. Conclusions: Despite improved tumour cell death, the clinical use of the combination of KIs and irinotecan is limited by significant toxicity. Caution is recommended especially with dosing and scheduling of the regimen when planning future clinical trials. The need for thorough pre-clinical evaluation of the effects of KIs on UDP- glucuronosyl transferase (UGT) enzymes and transporters before human trials cannot be over-emphasised. Keywords: Axitinib; cabozantinib; erlotinib; gefitinib; lapatinib; pazopanib; regorafenib; sorafenib; sunitinib; vandetanib; irinotecan; SN-38 Submitted Sep 02, 2017. Accepted for publication Sep 28, 2017. doi: 10.21037/tcr.2017.10.07 View this article at: http://dx.doi.org/10.21037/tcr.2017.10.07 Introduction drugs in clinical practice and be listed in the World Health Organization’s model list of essential medicines Irinotecan (CPI-11), a camptothecin analogue and (2-5). Irinotecan is associated with significant, but, topoisomerase I inhibitor, is an important cytotoxic drug unpredictable myelosuppression and diarrhoea as major used in the treatment of advanced colorectal cancer (1). dose-limiting toxicities. The incidence of severe diarrhoea It has significant activity against other cancers including and neutropenia in irinotecan containing regimen has small cell lung cancer, gastric cancers and gliomas, been reported up to 40% in published trials (6). Such risk making it one of the most commonly used anti-cancer for adverse effects is partly attributable to its complex © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(Suppl 10):S1613-S1623 S1614 Kichenadasse et al. Irinotecan and KI in cancer pharmacology (7). Moreover, pharmacogenetic testing for Methods UGT1A1 based dosing has been recommended to reduce We identified the relevant in vitro and in vivo studies from irinotecan related toxicity (8). Medline and abstracts of the American Society of Clinical Irinotecan is a prodrug that is activated by carboxylesterases Oncology annual meetings published from inception until (CES) in the blood circulation and tumour cells to its active June 2017. The following search terms were used for the metabolite, SN-38 (7-ethyl-10-hydroxycamptothecin), which literature search—axitinib, cabozantinib, erlotinib, gefitinib, is 10–1,000 fold more active than the parent compound (9). lapatinib, pazopanib, regorafenib, sorafenib, sunitinib, Glucuronidation of SN-38 to form SN-38 glucuronide vandetanib, irinotecan and SN-38. Data on pharmacodynamic (SN-38G) by UGT1A1 results in its inactivation and and pharmacokinetic (PK) interactions between the KIs and facilitates elimination. Other enzymes, notably UGT1A7, irinotecan were extracted from studies published in full or UGT1A9 and cytochrome P450 3A4/5 (CYP3A4/5) abstract only in English language and summarized in cell lines, may also contribute to SN-38 metabolism in liver, animal models and human clinical trials. gastrointestinal tract and kidney (10). Enterohepatic cycling of SN-38G is known to be associated with delayed diarrhoea, a common toxicity in irinotecan treated patients (11). Results Moreover, various transporters (SLCO1B1, ABCB1, ABCC1 Pharmacodynamic interactions and 2, and ABCG2) are also involved in the clearance of irinotecan and SN-38 (12). Polymorphic variants of UGTs Pre-clinical studies—cell lines and xenografts and transporters lead to high inter-individual variability in Most of the KIs showed synergistic activities when used in pharmacokinetics (13,14) . combination with irinotecan or SN-38 in cell line studies In current clinical practice, irinotecan is administered or xenografts in animal models. Tumour cell apoptosis, either alone or in combination with other cytotoxic drugs cell proliferation, reduction in tumour size and survival such as 5-fluorouracil or capecitabine. In addition, it has of the animals were the common outcomes assessed in been safely and effectively combined with various targeted these studies. One common theme from these studies agents such as monoclonal antibodies (15)—bevacizumab, confirmed a schedule-dependent interaction between KIs cetuximab or panitumumab, but, not with the small-molecule and irinotecan. For example, concurrent administration of kinase inhibitors (KIs). Many KIs have been approved since gefitinib and irinotecan resulted in an antagonistic effect 2001 to treat various malignancies, either as monotherapy in two different lung cancer cell lines (PC-9 and PC-9/ZD or in combination with chemotherapy drugs (16). cells) (17) while sequential administration of gefitinib after Despite synergistic activities for the combination of a KI irinotecan resulted in potent inhibition of various cell lines (18). with irinotecan, none of the KIs are currently used with Studies addressing the mechanism responsible for synergism irinotecan in clinical practice. Possible reasons include identified that KIs caused inhibition of efflux ATP-binding overlapping toxicity, drug-drug interactions and lack of cassette (ABC) transporters (ABCB1 and/or ABCG2) efficacy in human trials. within tumour cells thereby increasing the intra-tumoral In this review, we summarize the available evidence concentration of irinotecan and SN-38. Another potential on the in vitro and in vivo studies addressing the effects mechanism is inhibition of intra-tumoral UGT1A enzymes of the combination of irinotecan with the approved KIs. by the KIs (19). We focused on the anti-vascular endothelial growth factor (VEGF) pathway inhibitors (axitinib, pazopanib, In vitro cell line studies evaluating the combination of regorafenib, sorafenib, sunitinib), and epidermal growth irinotecan/SN-38 and KIs factor (EGF) pathway inhibitors (erlotinib, gefitinib, Gefitinib exhibited synergistic activities with irinotecan (20-22). lapatinib). These two groups of KIs have been commonly In gastric cancer cell lines (19), decreased expression of evaluated in combination with irinotecan in the treatment of UGT1A1 and ABCG2 was detected when the combination various cancers. We further summarize the effects of these was tested. Lapatinib restored sensitivity to SN-38 in small KIs on the in vivo metabolism of irinotecan/SN-38. Finally, cell cancer cell lines through ABCB1 inhibition (23), and we address the potential pitfalls to avoid while planning potentiated the activity of irinotecan in colorectal cancer future studies that address the feasibility of combining a KI cell lines (24). Similarly to gefitinib, lapatinib decreased with irinotecan. expression of UGT1A1 and ABCG2 in gastric cancer cell © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(Suppl 10):S1613-S1623 Translational Cancer Research, Vol 6, Suppl 10 December 2017 S1615 lines (19). Moreover, erlotinib (25), gefitinib (26), and regorafenib would similarly inhibit the glucuronidation lapatinib (27) inhibited ABCG2 mediated resistance to of other UGT1A1 substrates (38). Not un-expectantly, irinotecan in cell lines by reducing the efflux of SN-38. sorafenib has been reported to inhibit human liver Among the VEGF pathway inhibitors, most KIs had microsomal SN-38 glucuronidation (Ki—2.7 μM) (39). synergistic activity with irinotecan; axitinib demonstrated The Ki for sorafenib inhibition of SN-38 glucuronidation activity in pancreatic cancers (28), sunitinib in esophagogastric is almost certainly over-estimated, probably by an order and paediatric brain tumours (29,30), and sorafenib in
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