ALK inhibitor

[1] They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells.

[5] At the time of the discovery of ALK translocations as a molecular driver in NSCLC, crizotinib was being investigated by Pfizer as a potential c-MET inhibitor.

Crizotinib's efficacy was proven in phase III trial, PROFILE 1007,[6] when it was compared to then-standard second-line pemetrexed or docetaxel chemotherapy.

[10] Despite the excitement of crizotinib's therapeutic success, there was a need to conceive new drugs with better brain penetrance, higher specificity and targeting a broader set of resistance mutations.

[2][11] It provided good brain penetrance and a significant progression-free survival benefit against chemotherapy in the first line as demonstrated in the ASCEND-4 trial.

Additional ALK inhibitors currently (or soon to be) undergoing clinical trials include: Discontinued While the response to ALK inhibitors is often very encouraging in patients with ALK+ NSCLC and lasts for a relatively long time, most of them eventually develop resistance, either through mutations in the ATP binding pocket or activation of alternative oncogenic pathways.

The MEK pathway (short for MAPK/ERK-Kinase) has been extensively shown to be critical for the survival of tumour cells subjected to ALK inhibition.

In all cases, the responses were enhanced by the combination with respect to monotherapy, but seemed more pronounced in afatinib and lapatinib (dual EGFR/HER2 inhibitors) than in erlotinib (which only inhibits EGFR).