Central nervous system involvement in ALK-rearranged NSCLC: promising strategies to overcome crizotinib resistance.
BACKGROUND
ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition..


METHODS
The CNS activity of Crizotinib and novel generation ALK inhibitors will be summarized in this review, evaluating the strengths and weaknesses of the therapeutic strategies developed to date in this specific subgroup of NSCLCs with a look towards the future. Expert commentary: In the next few years, the results of ongoing comparative head-to-head trials will provide the definitive conclusions on the optimal treatment sequence in ALK-rearranged NSCLCs. Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.
a Medical Oncology Unit A.O. Papardo and Department of Human Pathology , University of Messina , Messina , Italy.
Alessandro
A
Russo
a Medical Oncology Unit A.O. Papardo and Department of Human Pathology , University of Messina , Messina , Italy.
Tindara
T
Franchina
a Medical Oncology Unit A.O. Papardo and Department of Human Pathology , University of Messina , Messina , Italy.
Giuseppina Rosaria Rita
GR
Ricciardi
a Medical Oncology Unit A.O. Papardo and Department of Human Pathology , University of Messina , Messina , Italy.
Giuseppa
G
Ferraro
a Medical Oncology Unit A.O. Papardo and Department of Human Pathology , University of Messina , Messina , Italy.
Antonino
A
Scimone
b Department of Surgical, Oncological and Oral Sciences , University of Palermo , Palermo , Italy.
Giuseppe
G
Bronte
b Department of Surgical, Oncological and Oral Sciences , University of Palermo , Palermo , Italy.
Antonio
A
Russo
c Department of Medical Oncology , Antwerp University Hospital , Antwerp , Belgium.
Christian
C
Rolfo
a Medical Oncology Unit A.O. Papardo and Department of Human Pathology , University of Messina , Messina , Italy.
Vincenzo
V
Adamo
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
ALK translocations; Brain metastases; NSCLC; central nervous system metastases; leptomeningeal metastases