Clinical Activity of Alectinib in Advanced RET -Rearranged Non–Small Cell Lung Cancer

Abstract

Alectinib demonstrated preliminary antitumor activity in patients with advanced RET-rearranged NSCLC, most of whom had received prior RET inhibitors. Larger prospective studies with longer follow-up are needed to assess the efficacy of alectinib in RET-rearranged NSCLC and other RET-driven malignancies. In parallel, development of more selective, potent RET TKIs is warranted.

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

“…It exhibits ten-fold greater potency in kinase assays than the first generation of ALK inhibitor crizotinib [23, 39]. Alectinib is derived from a carbonitrile in physical structure and shows potent inhibitory effects against tumors addicted to ALK activity, such as NSCLC which expresses the EML4-ALK fusion protein [30, 32, 38, 39, 54]. Unlike other ALK inhibitors, the crystal structural analysis of alectinib exhibits only one hinge hydrogen bond with kinase, indicating that this compound may achieve higher selectivity for ALK [39].…”

RET‐rearranged non‐small‐cell lung cancer and therapeutic implications

“…She was subsequently commenced on alectinib, another TKI with documented anti-RET activity. 12 She did not experience any side effects; however, a repeat CT scan 6 weeks later showed re-emergence of the right-sided pleural effusion and progressive mediastinal disease. She was also experiencing haemoptysis and severe back pain.…”

“…Our patient reported almost immediate resolution of her symptoms and achieved several more months of markedly improved quality of life. Similarly impressive responses to other TKIs such as alectinib, cabozantinib, sorafenib and sunitinib in pre‐treated RET ‐rearranged tumours have been reported …”

“…Treatment was changed to carboplatin and pemetrexed chemotherapy which was poorly tolerated and ceased after two cycles due to disease progression. She was subsequently commenced on alectinib, another TKI with documented anti‐RET activity . She did not experience any side effects; however, a repeat CT scan 6 weeks later showed re‐emergence of the right‐sided pleural effusion and progressive mediastinal disease.…”

Standardizing Biomarker Testing for Canadian Patients with Advanced Lung Cancer

“…There is no current standard test for identification of RET fusions in patient samples, but fish or targeted capture/ngs are potential methods. At this point, there are no approved therapies for RET in nsclc, although multiple studies with RET inhibitors are underway [68][69][70][71] .…”