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
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
Ensartinib (X-396) is a novel ALK inhibitor with high activity against a broad range of crizotinib-resistant ALK mutations (such as G1269A, F1174, C1156Y, and T1151) and CNS metastases. This Phase I study (NCT02959619) determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), investigated the safety and PK, and explored the clinical efficiency for the compound as monotherapy in Chinese ALK+ NSCLC patients.Patients with advanced ALK+ NSCLC were treated with oral ensartinib (150, 200, 225, or 250 mg once daily) using a conventional 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles. In the dose-expansion phase, ensartinib was given at the recommended dose to further explore PK and clinical efficacy. Treatment was continued until disease progression, or unacceptable toxicity. The study finds ensartinib was well tolerated in Chinese ALK-positive NSCLC patients with high antitumor activity. RP2D was established at 225 mg QD. Ensartini..... READ ARTICLE
Cancer Research DOI:10.1158/1538-7445.AM2020-579
Authors: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Wenfeng Fang, Yunpeng Yang, Jianjin Huang, Jing Zhao, Yan Huang, Lieming Ding, Li Mao, Giovanni Selvaggi, Li Zhang
To our knowledge, this is the first detailed case of an anaplastic lymphoma kinase (ALK)-positive patient with central nervous system (CNS) disease who experienced clinical benefit with lorlatinib after disease progression during treatment with high-dose brigatinib.
The efficacy of lorlatinib might reflect activity against an interval change in the biology of ALK-positive CNS disease occurring after initial brigatinib benefit that was not able to be suppressed by brigatinib. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2018.11.010
Authors: Mandy R. Sakamoto, Justin M. Honce, Deborah L. Lindquist, D. Ross Camidge
Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. In this phase 2 study, we aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. READ ARTICLE
The Lancet Oncology DOI:10.1016/S1470-2045(18)30649-1
Authors: Benjamin J Solomon, Benjamin Besse, Todd M Bauer, Enriqueta Felip, Ross A Soo, D Ross Camidge, Rita Chiari, Alessandra Bearz, Chia-Chi Lin, Shirish M Gadgeel, Gregory J Riely, Eng Huat Tan, Takashi Seto, Leonard P James, Jill S Clancy, Antonello Abbattista, Jean-François Martini, Joseph Chen, Gerson Peltz, Holger Thurm, Sai-Hong Ignatius Ou, Alice T Shaw
The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advancedALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. READ ARTICLE
Annals of Oncology DOI:10.1093/annonc/mdy405
Authors: S.Gadgeel, S.Peters, T.Mok, A.T.Shaw, D.W.Kim, S.I.Ou, M.Pérol, A.Wrona, S.Novello, R.Rosell, A.Zeaiter, T.Liu, E.Nüesch, B.Balas, D.R.Camidge