Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children

TY - JOUR

T1 - Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children

AU - Drilon, Alexander

AU - Laetsch, Theodore W

AU - Kummar, Shivaani

AU - DuBois, Steven G

AU - Lassen, Ulrik N

AU - Demetri, George D

AU - Nathenson, Michael

AU - Doebele, Robert C

AU - Farago, Anna F

AU - Pappo, Alberto S

AU - Turpin, Brian

AU - Dowlati, Afshin

AU - Brose, Marcia S

AU - Mascarenhas, Leo

AU - Federman, Noah

AU - Berlin, Jordan

AU - El-Deiry, Wafik S

AU - Baik, Christina

AU - Deeken, John

AU - Boni, Valentina

AU - Nagasubramanian, Ramamoorthy

AU - Taylor, Matthew

AU - Rudzinski, Erin R

AU - Meric-Bernstam, Funda

AU - Sohal, Davendra P S

AU - Ma, Patrick C

AU - Raez, Luis E

AU - Hechtman, Jaclyn F

AU - Benayed, Ryma

AU - Ladanyi, Marc

AU - Tuch, Brian B

AU - Ebata, Kevin

AU - Cruickshank, Scott

AU - Ku, Nora C

AU - Cox, Michael C

AU - Hawkins, Douglas S

AU - Hong, David S

AU - Hyman, David M

PY - 2018/2/22

Y1 - 2018/2/22

N2 - BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progressionfree survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type.

AB - BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progressionfree survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type.

KW - Adolescent

KW - Adult

KW - Aged

KW - Antineoplastic Agents/therapeutic use

KW - Child

KW - Child, Preschool

KW - Disease-Free Survival

KW - Female

KW - Humans

KW - Infant

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Neoplasms/chemistry

KW - Oncogene Proteins, Fusion/analysis

KW - Protein Kinases/analysis

KW - Pyrazoles/therapeutic use

KW - Pyrimidines/therapeutic use

KW - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors

KW - Young Adult

U2 - 10.1056/nejmoa1714448

DO - 10.1056/nejmoa1714448

M3 - Journal article

C2 - 29466156

SN - 0028-4793

VL - 378

SP - 731

EP - 739

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

IS - 8

ER -