Original Article
Combination of small-molecule kinase inhibitors and irinotecan in cancer clinical trials: efficacy and safety considerations
Abstract
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.
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.
