Studies on the Enhancement of Antitumor Effect by Drug Combination in Molecular-Targeted Therapy of Cancer

概要

The oncogenic fusion genes ALK, ROS1, and RET are identified in 5%, 1%–2%, and 1% of
patients with lung adenocarcinoma, respectively16. Such fusions result in the constitutive
dimerization of the kinase domain leading to aberrant activation of downstream signaling, which
promotes tumorigenesis, cellular proliferation, and cancer survival, invasion, and metastasis17-19.
Alectinib is an ALK inhibitor20, and in the phase III ALEX trial, alectinib showed superior
efficacy compared with crizotinib as the primary treatment for ALK-positive NSCLC and was well
tolerated21. Alectinib also shows significant in vitro and in vivo antitumor activity in a RET-fusion
gene positive NSCLC model22, and a phase I/II study of alectinib in recurrent RET-fusion gene
positive NSCLC is ongoing in Japan23. Although the RET-tyrosine kinase inhibitors vandetanib and
cabozantinib are of great clinical benefit to patients with medullary thyroid cancer with RET
mutations24, 25, no effective therapy targeting RET-fusion gene positive NSCLC has yet been
established26. According to case reports, LOXO292 and BLU-667, next-generation selective RET
inhibitors, are considered promising mono-therapeutic approaches for treating patients with RETfusion–positive NSCLC27-29, but their clinical utility is still under investigation, and the emerging
clinical data should be closely monitored.
Recently, combination therapies, such as erlotinib plus bevacizumab, have been achieving
more attractive outcomes than monotherapy as a first-line therapy in NSCLC patients harboring
activating EGFR mutations14. In vitro, ceritinib in combination with trametinib promotes greater
responses against ALK-positive NSCLC cells than does either single agent by minimizing the reactivation of mitogen-activated protein kinases (MAPK) signaling, which cannot be completely
inhibited by ceritinib alone30. Considering these findings, it is possible that a combination therapy
may be a superior treatment for RET-fusion NSCLC compared with treatment with a single agent. ...

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