ALK Disease: Best First or Later, and Do we Care about Variants?

Petros Christopoulos, M.D. Department of Medical Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany

The therapeutic landscape in advanced ALK+ NSCLC is rapidly evolving due to the increasing availability of potent and selective tyrosine-kinase inhibitors (TKI), of which three generations are already in use. Compared with crizotinib, the second-generation compounds ceritinib, alectinib and brigatinib show improved efficacy with overall and intracranial response rates about 80%. Ongoing head-to-head randomized phase 3 trials of upfront alectinib or brigatinib versus crizotinib have demonstrated impressive hazard ratios of approximately 0.5 and below 0.3 for systemic and brain progression, respectively, resulting in median progression-free survival over 2 years, along with generally better tolerability.1,2 On the other hand, benefit from these compounds after failure of crizotinib has been much lower and, considered in conjunction with the generally modest activity of first-line crizotinib, suggests an inferior overall outcome. Therefore, even though overall survival data from head-to-head TKI trials are still pending, upfront treatment with a more potent ALK inhibitor emerges currently as the preferred strategy, further encouraged by the fact that approximately half of patients failing second-generation TKI have been amenable to next-line targeted therapies in previous studies. Dissection of molecular mechanisms underlying TKI resistance will be key for further therapeutic advances, with recent data suggesting an important role for specific molecular properties of the tumor, especially the type of ALK fusion variant and presence of TP53 mutations. These novel insights can help refine prognostication, select patients for more aggressive monitoring and guide preclinical studies, but their utility for individualization of treatment is still unclear and an area of intense investigation.

References
1. Peters S., Camidge D.R., Shaw A.T., Gadgeel S., Ahn J.S., Kim D.W., Ou S.I., Perol M., Dziadziuszko R., Rosell R., Zeaiter A., Mitry E., Golding S., Balas B., Noe J., Morcos P.N., Mok T., and Investigators A.T., Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med, 2017. 377(9): p. 829-838.
2. Camidge D.R., Kim H.R., Ahn M.J., Yang J.C., Han J.Y., Lee J.S., Hochmair M.J., Li J.Y., Chang G.C., Lee K.H., Gridelli C., Delmonte A., Garcia Campelo R., Kim D.W., Bearz A., Griesinger F., Morabito A., Felip E., Califano R., Ghosh S., Spira A., Gettinger S.N., Tiseo M., Gupta N., Haney J., Kerstein D., and Popat S., Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med, 2018.