Crizotinib is a
tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell
lung cancers (NSLCL) and
lymphomas expressing activating translocations or mutations of oncogenic
tyrosine kinases (in particular ALK and ROS1). We recently observed that high-dose (final concentration in vivo: ~10 µM)
crizotinib can induce immunogenic cell death (ICD) in
cancer cells lacking ALK/ROS1 activation through off-target effects that require the inhibition of several other
tyrosine kinases. When combined with
cisplatin (which alone does not induce ICD),
crizotinib sensitizes NSCLC models to subsequent
immunotherapy with PD-1 blockade, allowing to cure more than 90% of established orthotopic
cancers. Of note, simultaneous treatment of mice with
cisplatin,
crizotinib and PD-1
blocking antibodies causes acute hepatotoxicity that can be avoided by a sequential regimen involving initial treatment with
cisplatin plus
crizotinib, followed by PD-1 blockade one week later. It will be important to translate these results obtained in mice into a clinical trial in NSCLC patients.