485P - Growth modulation index (GMI) as a comparative measure of clinical activity of larotrectinib versus prior systemic treatments in adult and pediatric TRK fusion cancer patients

Abstract

BackgroundRandomized controlled trials are not feasible for rare cancer populations particularly when the investigational drug targets a molecular alteration shared by several tumor types with different natural histories. Innovative approaches that incorporate patients as their own control can be utilized in this setting. Growth Modulation Index (GMI) is the ratio of time to progression (TTP) with nth line of therapy (TTPn) to the most recent prior line of therapy (TTPn-1), and a GMI ≥1.33 has been proposed as a marker of meaningful clinical activity. We report here the GMI for patients (pts) diagnosed with TRK fusion cancer and treated with larotrectinib, a selective TRK inhibitor. MethodsTRK fusion cancer pts enrolled in 3 clinical trials (NCT02122913, NCT02637687, NCT02576431) who have been on treatment for at least 6 months (or discontinued early) and had at least one prior line of systemic therapy in metastatic setting were eligible. GMI was calculated as a ratio of progression-free survival (PFS) with larotrectinib (PFSLaro) to TTP of the prior line of therapy (TTPn-1). PFS was determined by independent review committee (IRC) assessments using RECIST 1.1 criteria. ResultsAs of a July 30, 2018 data cut, 53 pts (42 adults, 11 pediatric) were eligible. Sixteen pts (30.2%) had 2 prior therapies and 24 (45.3%) had ≥3 prior lines of therapy. Thirteen different tumor types were represented with the largest being soft tissue sarcoma (n=12), lung cancer (n=7), thyroid cancer (n=6), and colon cancer (n=6). The median GMI (IRC) was 2.87 (range: 0.01–48.75, Table). Thirty-five (66.0%) pts had a GMI ≥1.33. Five of 18 pts with a GMI <1.33 are still on treatment and non-progressive at the time of analysis.Table485PTableGMI (PFSLarotrectinib/TTPprior_line)IRC-assessed pts N=53Mean (SD)6.00 (9.97)Median (min, max)2.87 (0.01, 48.75)GMI category, n (%) <1 ≥1 1 to 1.33 ≥1.33 ≥215 (28.3) 38 (71.7) 3 (5.7) 35 (66.0) 32 (60.4) ConclusionsTRK fusion cancer patients treated with larotrectinib had a clinically meaningful improvement in PFS compared to TTP on prior treatment as evidenced by a GMI >1.33 in two-thirds of evaluable patients. Clinical trial identificationNCT02122913, NCT02637687, NCT02576431. Editorial acknowledgementEditorial assistance was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer. Legal entity responsible for the studyBayer. FundingBayer. DisclosureA. Italiano: Advisory / Consultancy: Bayer, Epizyme, ImmuneDesign, Lilly, Merck, MSD, Novartis, Roche; Research grant / Funding (institution): AstraZeneca, Bayer, Merck, MSD, Pharmamar, Roche. S. Nanda: Full / Part-time employment: Bayer. K. Keating: Full / Part-time employment: Bayer. B.H. Childs: Full / Part-time employment: Bayer. M. Fellous: Full / Part-time employment: Bayer. A. Drilon: Advisory / Consultancy: Loxo Oncology/Bayer, Ignyta, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Honoraria (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: MORE Health. D.M. Hyman: Advisory / Consultancy: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer Pharmaceuticals, Genentech / F. Hoffmann-La Roche; Research grant / Funding (self): Loxo Oncology, Bayer Pharmaceuticals, PUMA Biotechnology, AstraZeneca.