CSF Concentration of Crizotinib in Two ALK-Positive Non–Small-Cell Lung Cancer Patients with CNS Metastases Deriving Clinical Benefit from Treatment

Metro, Giulio; Lunardi, Gianluigi; Floridi, Piero; Pascali, Jennifer P.; Marcomigni, Luca; Chiari, Rita; Ludovini, Vienna; Crinò, Lucio; Gori, Stefania

doi:10.1097/jto.0000000000000468

Cited by 102 publications

(75 citation statements)

References 5 publications

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“…Most small molecule TKIs, including crizotinib [Costa et al 2011;Metro et al 2015], imatinib [Motl et al 2006], gefitinib [Jackman et al 2006] and erlotinib [Clarke et al 2010] have been shown to exhibit low CSF to plasma ratios. Consequently, the CNS is a sanctuary site where ALK+ NSCLC can disseminate [Gainor et al 2013].…”

Section: Secondary or Acquired Resistancementioning

confidence: 99%

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

2015

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Abstract:The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinibresistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/ AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic.

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Section: Secondary or Acquired Resistancementioning

confidence: 99%

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

2015

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“…The central nervous system (CNS) has been reported to be a frequent site of acquired resistance to crizotinib in patients with ALK-positive NSCLC (26)(27)(28). In the present study, cerebral progression occurred in more patients in the crizotinib group (n=10; 50%) in comparison with those in the chemotherapy group (n=4; 8.5%).…”

Section: Discussionmentioning

confidence: 50%

“…This phenomenon can be largely attributed to the following two reasons: Firstly, crizotinib is a substrate of P-glycoprotein, a membranous transporter overexpressed in the hematoencephalic barrier and responsible for the efflux of the drug. Low cerebrospinal fluid-to-serum ratios have been reported for crizotinib in the range between 0.06 and 0.26% (31,32). Furthermore, crizotinib extended the patient survival, which to a certain extent may be contributed to the higher incidence of CNS metastases as compared with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

A real‑world study of treatment patterns and survival outcome in advanced anaplastic lymphoma kinase‑positive non‑small‑cell lung cancer

Jin

Chen

et al. 2018

Oncol Lett

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Abstract.Crizotinib is an anti-cancer drug with a substantial beneficial effect in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, the real-world data currently available on this drug are limited. Thus, the present study aimed to retrospectively examine the treatment patterns and survival outcome of 83 advanced NSCLC patients with ALK rearrangement in a single center in China. Of the 83 patients enrolled, 33 (39.8%) patients received crizotinib and the remaining 50 (60.2%) patients received chemotherapy as the initial therapy. The first-line use of crizotinib prolonged the PFS1 (progression-free survival to the first detection of subsequent disease progression) compared with chemotherapy (median, 18.5 vs. 4.9 months; P<0.001), however, it did not prolong the overall survival (OS; P= 0.802). At the last follow up, 71 (85.5%) patients had received crizotinib and 12 (14.5%) patients were crizotinib-naive. Patients who had received crizotinib exhibited a significantly longer OS as compared with those who were crizotinib-naive [hazard ratio (HR) for mortality, 0.279; 95% confidence interval, 0.107-0.727; P<0.05). Among the 71 patients who had received crizotinib, this was administered as a first-line therapy in 33 (46.5%) cases, as a second-line therapy in 22 (31.0%) cases and after the second-line therapy in 16 (22.5%) cases. No significant difference in the OS among the three groups was observed (P=0.577). The Cox multivariate analysis identified the following independent negative prognostic factors for OS: Smoking history (HR=4.565), liver invasion at diagnosis (HR=4.294) and bone invasion at diagnosis (HR=2.587). In addition, the use of crizotinib (HR= 0.319) was identified as a positive prognostic factor for OS. In conclusion, the present real-world study revealed that the use of crizotinib improved the long-term survival of patients with ALK-positive advanced NSCLC. There was no difference in survival outcome between patients with initial use of crizotinib and those with subsequent use of crizotinib after first-line therapy.

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“…In fact, high tumor activity of these compounds with prolonged control of extra-cranial disease could make emerge CNS as relevant site of progression. This is particularly true for crizotinib, which may inefficiently cross the blood brain barrier thus reaching limited concentration in the cerebrospinal fluid (CSF) (16,101,102). CNS involvement resulted the first site of progression in 46% of ALK-positive patients treated with crizotinib, with 85% of these lacking systemic progression (103).…”

Section: Efficacy Of Alk Inhibitors On Brain Metastasesmentioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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CSF Concentration of Crizotinib in Two ALK-Positive Non–Small-Cell Lung Cancer Patients with CNS Metastases Deriving Clinical Benefit from Treatment

Cited by 102 publications

References 5 publications

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

A real‑world study of treatment patterns and survival outcome in advanced anaplastic lymphoma kinase‑positive non‑small‑cell lung cancer

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

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