ALK Inhibitors



ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation.



They are tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumor cells. 



ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. 



A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion.



The response to ALK inhibitors is often significant  in patients with ALK+ NSCLC and lasts for a relatively long time.



Over 92 fusion partners have been discovered in ALK+ NSCLC.



Of the several fusion variants depending on the position the two fused genes, there may have implications on the response of the tumour and prognosis of the patient.



First generation ALK inhibitors: 



Crizotinib which a is also a ROS1 and c-MET inhibitor, was approved in Aug 2011.



Crizotinib’s efficacy was proven in phase III trial, PROFILE 1007, when it was compared to then-standard second-line pemetrexed or docetaxel chemotherapy.



It induced tumour stabilization or shrinkage in 90% of patients. 



Second generation ALK inhibitors



Ceritinib provides good brain penetrance and a significant progression-free survival benefit against chemotherapy in the first line as demonstrated in the ASCEND-4 trial.



Allectinib provides excellent brain penetrance and high response rates. 



It demonstrated a clear benefit against both first-line chemotherapy and first-line crizotinib: phase 3 ALEX trial.



Brigatinib, also an inhibitor of mutated EGFR, a second-generation inhibitor similar to alectinib in efficacy, while being active against some resistant mutations such as the common G1202R mutation that provides resistance to alectinib.



Third generation



Lorlatinib was the first third-generation inhibitor designed  to address some  recalcitrant resistance mutations. 



Most tumours eventually develop resistance through various mechanisms, namely compound-mutations or activation of alternative pathways, such as the c-MET pathway.



Entrectinib for the treatment of neuroblastoma and TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive NSCLC.




Repotrectinib (TPX-0005, Turning Point Therapeutics)



Most responses in NSCLC  eventually develop resistance, either through mutations in the ATP binding pocket or activation of alternative oncogenic pathways.



The MAPK/ERK-Kinase pathway is critical for the survival of tumour cells subjected to ALK inhibition. 



Combinations of ALK inhibitors with MEK inhibitors are being tested.



Trials are investigating the combination of anti-VEGF antibody bevacizumab with ALK inhibitors such as alectinib and brigatinib.



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