1196P Pre-existing and acquired mechanisms of resistance to lorlatinib in previously treated patients (pts) with ALK+ advanced non-small cell lung cancer (NSCLC)

Lorlatinib, a potent, brain-penetrant, 3rd-generation (gen) ALK/ROS1 tyrosine kinase inhibitor (TKI) active against most known resistance mutations, showed robust clinical activity in ALK+ or ROS1+ NSCLC in a Ph 1/2 study that enrolled mostly heavily pretreated pts with CNS metastases. We evaluated potential resistance mechanisms, pre-existing or acquired, and efficacy in these settings.Limitations apply to ctDNA analyses, but in this heavily pretreated group of pts with ALK+ NSCLC, presence of TP53 mutations at BL was potentially associated with decreased lorlatinib efficacy, while presence of bypass mechanism aberrations with reduced activity. Upon progression, ALK compound mutations and bypass mechanism aberrations emerged in ∼28% of pts. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1801

Authors: B.J. Solomon, J-F. Martini, A. Bearz, E.H. Tan, R. Soo, B. Besse, T.M. Bauer, D. Shepard, F. Toffalorio, A. Abbattista, E. Felip, A.T. Shaw, S. Viteri, D.R. Camidge, T. Seto, S-H.I. Ou

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib, CNS, AE

1199P Dose modification for the management of CNS adverse events in the phase III CROWN study of lorlatinib in non-small cell lung cancer (NSCLC)

In the ongoing phase III CROWN study (NCT03052608), lorlatinib, a 3rd-generation inhibitor of anaplastic lymphoma kinase (ALK), improved progression-free survival (PFS) and intracranial response rates vs crizotinib in patients with previously untreated ALK-positive NSCLC. Here we present data on lorlatinib dose modification for the management of CNS adverse events (AEs). CNS AEs spontaneously resolved in 53% of cases, and lorlatinib dose modification was effective in managing CNS AEs without compromising efficacy. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1804

Authors: B.J. Solomon, T.S.K. Mok, H. Hayashi, A. Bearz, K.D. Penkov, Y-L. Wu, O. Arrieta, A.M. Calella, G. Peltz, A. Polli, H. Thurm, T.M. Bauer

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib, CNS, AE

1197P First-line lorlatinib versus crizotinib in ALK-positive non-small cell lung cancer: Asian subgroup analysis of CROWN

Lorlatinib, a 3rd-generation ALK inhibitor, significantly prolonged progression-free survival (PFS) vs crizotinib in the CROWN trial in patients with untreated ALK-positive non-small cell lung cancer (NSCLC). We report data from the Asian subgroup of CROWN. In the Asian subgroup, a consistent and clinically meaningful improvement in PFS was observed for lorlatinib vs crizotinib. The efficacy and safety of lorlatinib vs crizotinib in the Asian subgroup of CROWN was consistent with the overall population. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1802

Authors: Q. Zhou, H.R. Kim, R. Soo, G-C. Chang, C-H. Chiu, H. Hayashi, S-W. Kim
S. Teraoka, Y. Goto, J. Zhou, V.H.F. Lee, B. Han, J.C.M. Ho, D-W. Kim
C-C. Lin, S. Lu, A. Polli, A.M. Calella, T.S.K. Mok, Y-L. Wu