Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC).

person Alice Tsang Shaw Massachusetts General Hospital, Boston, MA info_outline Alice Tsang Shaw, Jean-Francois Martini, Benjamin Besse, Todd Michael Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Antonello Abbattista, Francesca Toffalorio, Holger C. Thurm, Miyako Satouchi, D. Ross Camidge, Steven Chuan-Hao Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Benjamin J. Solomon

Authors person Alice Tsang Shaw Massachusetts General Hospital, Boston, MA info_outline Alice Tsang Shaw, Jean-Francois Martini, Benjamin Besse, Todd Michael Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Antonello Abbattista, Francesca Toffalorio, Holger C. Thurm, Miyako Satouchi, D. Ross Camidge, Steven Chuan-Hao Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Benjamin J. Solomon Organizations Massachusetts General Hospital, Boston, MA, Pfizer Inc, San Diego, CA, Gustave Roussy, Villejuif, France, Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville, TN, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, National University Cancer Institute, Singapore, Singapore, Memorial Sloan Kettering Cancer Center, New York, NY, Chao Family Comprehensive Cancer Center, University of California at Irvine Medical Center, Orange, CA, Pfizer Global Product Development-Oncology, Milan, Italy, Pfizer Global Product Development-Oncology, La Jolla, CA, Hyogo Cancer Center, Akashi, Japan, University of Colorado Cancer Center, Aurora, CO, Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia, Azienda Ospedaliera di Perugia, Perugia, Italy, University of Michigan/Rogel Cancer Center, Ann Arbor, MI, Vall d’Hebron Institute of Oncology, Barcelona, Spain, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Other Government Agency Background: Lorlatinib is a selective, potent, brain-penetrant, 3 rd generation (gen) ALK/ROS1 TKI approved for pts with advanced ALK + NSCLC previously treated with a 2 nd gen ALK TKI. We recently showed that ALK mutation tumor genotyping after failure of a 2 nd gen ALK TKI may identify pts more likely to respond to lorlatinib. 1 To identify other molecular response correlates, we evaluated if early ctDNA dynamics predict clinical outcome on lorlatinib. Methods: In pts enrolled on the ongoing ph 2 study (NCT01970865), plasma samples were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1, or 6 weeks) and end of treatment. Plasma DNA was analyzed using Guardant360. Change in variant allele fraction (dVAF) 2 of ALK alterations (fusions and/or mutations) was calculated as (mean VAF C3D1 ) – (mean VAF BL ); dVAF < 0 indicated decreased ctDNA at C3D1. BOR, PFS and OS were evaluated according to dVAF. Results: Of 121 paired BL/C3D1 samples collected from 158 ALK + pts previously treated with one or more 2 nd gen ALK TKIs, 57 (47%) harbored a detectable ALK alteration at BL. At C3D1, mean VAF of ALK fusions and/or mutations was significantly decreased compared to BL (-1.07, p = 0.0014). Mean tumor volume was reduced by 26% in pts with dVAF < 0 (n = 40), but only by 12% in pts with dVAF ≥0 (n = 13) (p = 0.049). Mean dVAF at C3D1 was significantly decreased compared to BL for pts with CR/PR, while there was no significant difference with SD or PD/IND; mean dVAF -1.84, -0.74, and +0.35 in pts with CR/PR, SD, or PD/IND, respectively (p = 0.0011, 0.1444 and 0.3383). Median PFS was 6.6 months (mo) in pts with dVAF < 0 (n = 44) and 2.6 mo in pts with dVAF ≥0 (n = 13) (HR = 2.6, 95% CI: 1.2, 5.8). Median OS was 18.0 mo in pts with dVAF < 0 (n = 34) and 8.6 mo in pts with dVAF ≥0 (n = 13) (HR 2.0, 95% CI, HR 0.9–4.6). Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in ALK + NSCLC, with decreased ctDNA at 6 wks associated with better response and longer PFS. Further studies are needed to validate these findings and to determine whether early intervention based on dynamic ctDNA monitoring may improve outcome. References: 1. Shaw, et al. J Clin Oncol . 2019. 2. Raja, et al. Clin Cancer Res . 2018. Clinical trial information: NCT01970865