Effects of ALK inhibitors (PF-02341066 and PF-06463922) with radiotherapy in EML4 – ALK fusion positive (H2228 and 185IG) and negative (A549) experimental lung cancer cell lines

Purpose/Objective(s): The management of non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) is challenging. Indeed, the efficacy of the tyrosine kinase inhibitor (TKI) of novel generation may discuss the place of combined treatment with radiotherapy. We aimed to investigate the effects of combined radiotherapy and PF-02341066 or PF-06463922 in A549 and 185IG or H2228 cell lines, the former is a wild type ALK NSCLC model and the two latter are ALK-positive NSCLC models... Conclusion: In the current study, PF-02341066 induced notably cell cycle arrest at G2/M phase and PF-06463922 induced G1 arrest, in H2228 cells. Also, results suggest that the administration of PF-02341066 and PF-06463922 after irradiation could increase the induction of DNA damages due to IR in a panel of 3 NSCLC cell lines, compared to IR first followed by TKI treatment. These results could influence the clinical combination strategy for EML4 – ALK..... READ ARTICLE

International Journal of Radiation Oncology*Biology*Physics DOI:10.1016/j.ijrobp.2020.07.1599

Authors: D.N. Antoni, H. Burckel, G. Noel

Case StudyKirk SmithNovember 1, 2020ALK inhibitors, PF-02341066, PF-06463922, radiotherapy, EML4 – ALK fusion, positive H2228 and 185IG, negative A549, experimental lung cancer cell lines

Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066

The MTD of PF is 250 mg BID. The major AEs were fatigue or GI-related, and all AEs were manageable and reversible. There was no evidence of non-linear PK at PF doses >100 QD. Treatment with PF-02341066 resulted in promising clinical activity against tumors carrying activating ALK gene rearrangements. Further study of PF in pts with ALK-dependent tumors is warranted. READ ARTICLE

Journal of Clinical Oncology

Authors: E. L. Kwak, D. R. Camidge, J. Clark, G. I. Shapiro, R. G. Maki, M. J. RatainB. Solomon, Y. Bang, S. Ou, R. Salgia

Clinical TrialsKirk SmithMay 1, 2009PF-02341066, crizotinib, ALK inhibitor