Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation

Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial pr..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.08.009

Authors: Nicholas J.Thomas, Nathaniel J. Myall, Fangdi Sun, Tejas Patil, Rao Mushtaq, Chandler Yu, Sumi Sinha, Erqi L. Pollom, Seema Nagpal. Ross Camidge, Chad G. Rusthoven, Steve E. Braunstein, Heather A. Wakelee and Caroline E. McCoach

Real-World Outcomes, group3Kirk SmithAugust 26, 2021Non–small cell lung cancer (NSCLC), Central nervous system (CNS), ALK, EGFR, CNS radiation

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922)...

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/jm500261q

Authors: Ted W. Johnson, Paul F. Richardson, Simon Bailey, Alexei Brooun, Benjamin J. Burke, Michael R. Collins, J. Jean Cui, Judith G. Deal, Ya-Li Deng, Dac Dinh, Lars D. Engstrom, Mingying He, Jacqui Hoffman, Robert L. Hoffman, Qinhua Huang, Robert S. Kania, John C. Kath, Hieu Lam, Justine L. Lam, Phuong T. Le, Laura Lingardo, Wei Liu, Michele McTigue, Cynthia L. Palmer, Neal W. Sach, Tod Smeal, Graham L. Smith, Albert E. Stewart, Sergei Timofeevski, Huichun Zhu, Jinjiang Zhu, Helen Y. Zou, and Martin P. Edwards

Pre-ClinicalKirk SmithMay 13, 2014Amides, Peptides and proteins, Central nervous system (CNS), Inhibitors, Macrocycles, Crizotinib