Abstract 542P
Background
Larotrectinib is a CNS-active, highly selective TRK inhibitor that demonstrated durable responses in three phase I/II single-arm studies of patients (pts) with TRK fusion cancer. While single-arm studies are often used for rare cancer populations, they do not provide comparative data. GMI uses pts as their own control and can be used in this setting. GMI is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the most recent prior line of therapy; GMI ≥1.33 is considered a threshold of meaningful clinical activity. We report GMI for pts with TRK fusion cancer treated with larotrectinib.
Methods
Pts with TRK fusion cancer enrolled in three clinical trials on treatment for ≥4 mo with ≥1 prior line of systemic therapy in the advanced setting were eligible for retrospective GMI analysis. TTP on the prior line of therapy was investigator-assessed. PFS on larotrectinib was determined by independent review committee per RECIST v1.1. Pts who had not progressed were censored as of date of last visit.
Results
As of 15 July 2019, 122 pts were eligible for analysis, including 81 (66%) with metastatic disease. Median GMI was 3.35 (range 0.0–337.0; Table); 76 (62%) pts had not progressed, including 20 with GMI <1.33. Eighty-four (69%), 78 (64%) and 47 (39%) pts had GMI ≥1.33, ≥2 and ≥5, respectively. In the 81 pts with metastatic disease, 57 (70%), 55 (68%) and 34 (42%) pts had GMI ≥1.33, ≥2 and ≥5, respectively. In the complete analysis set (N=122), median TTP on prior line of therapy was 2.7 mo (95% CI 2.0–3.1). Median PFS on larotrectinib was 33.4 mo (95% CI 13.8–NE; HR 0.20 [95% CI 0.14–0.29]). In metastatic pts, median TTP on prior line of treatment was 2.3 mo (95% CI 1.9–3.0) and median PFS on larotrectinib was 23.4 mo (95% CI 10.9–NE; HR 0.24 [95% CI 0.16–0.36]).
Conclusions
More than two-thirds of pts with TRK fusion cancer treated with larotrectinib had GMI ≥1.33, demonstrating a clinically meaningful improvement in PFS vs. TTP on their prior treatment. Table: 542P
| GMI (PFSLarotrectinib/TTPPrior line) | Metastatic (n=81) | Metastatic + locally advanced (N=122) |
| Mean (SD) | 15.02 (45.78) | 10.83 (37.53) |
| Median (range) | 3.45 (0.01–337.00) | 3.35 (0.00–337.00) |
| GMI category, n (%) | ||
| <1 | 21 (25.9) | 32 (26.2) |
| 1 to <1.33 | 3 (3.7) | 6 (4.9) |
| ≥1.33 | 57 (70.4) | 84 (68.9) |
| ≥2 | 55 (67.9) | 78 (63.9) |
| ≥5 | 34 (42.0) | 47 (38.5) |
Clinical trial identification
NCT02122913, first posted April 25, 2014; NCT02637687, first posted 22 December 2015; NCT02576431: first posted 15 October 2015.
Editorial acknowledgement
Editorial assistance was provided by Farzana Miah and Annabel Ola (Scion, London, UK), funded by Bayer HealthCare Pharmaceuticals, Inc.
Legal entity responsible for the study
Bayer HealthCare Pharmaceuticals, Inc and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lily and Company.
Funding
Bayer HealthCare Pharmaceuticals, Inc. and Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lily and Company.
Disclosure
A. Italiano: Honoraria (self), Advisory/Consultancy: Bayer, Daiichi, Epizyme, Ipsen, Roche, Springwork; Research grant/Funding (self): AstraZeneca, Bayer, Merck, MSD, Pharmamar, Roche. D.S. Hong: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy: Merck; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Roche ; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Pfizer; Honoraria (institution): Bristol-Myers Squibb; Honoraria (institution): Takeda; Honoraria (self): Boehringer Ingelheim; Research grant/Funding (self): GSK. A. Briggs: Advisory/Consultancy: Bayer. J. Garcia-Foncillas: Honoraria (self), Advisory/Consultancy: Abbott, Amgen, Astellas, AstraZeneca, Biocartis, Boehringer Ingelheim, BMS, Bayer, Celgene, Eisai, Foundation Medicine, GlaxosmithKline, Hospira, Janssen, Lilly, Loxo Oncology, Merck Serono, MSD, Novartis, Pharmamar, Pfizer, Roche, Sanofi, Regeneron, Serv. U.N. Lassen: Advisory/Consultancy: Bayer. G. Vassal: Advisory/Consultancy: Bayer. S. Kummar: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer. C.M. van Tilburg: Advisory/Consultancy: Bayer; Advisory/Consultancy: Novartis. K. Keating: Full/Part-time employment: Bayer. J.A. Reeves: Full/Part-time employment: Bayer. M. Fellous: Full/Part-time employment: Bayer. H. Nogai: Full/Part-time employment: Bayer. T.W. Laetsch: Advisory/Consultancy: Novartis, Bayer, Loxo, Lilly, Cellectis; Research grant/Funding (self): Pfizer, Novartis, Bayer, Loxo, AbbVie, Amgen, Atara, Biotherapeutics, BMS, Lilly, Epizyme, GSK, Janssen, Jubilant Pharmaceuticals, Novella Clinical, Servier. A. Drilon: Honoraria (self), Advisory/Consultancy: Ignyta/Genentech/Roche, Loxo Oncology/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, and MORE Health; Research grant/Funding (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; Research grant/Funding (self): Foundation Medicine; Licensing/Royalties: Wolters Kluwer; Travel/Accommodation/Expenses, Food and beverages: Merck and Puma Biotechnology; Honoraria (self), CME honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice.