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Ref Type | Journal Article |
PMID | (29466156) |
Authors | Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM |
Title | Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. |
Journal | The New England journal of medicine |
Vol | 378 |
Issue | 8 |
Date | 2018 02 22 |
URL | |
Abstract Text | 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.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, progression-free survival, and safety.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.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. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .). |
Molecular Profile | Treatment Approach |
---|---|
EML4 - NTRK3 | Larotrectinib |
TP53 - NTRK1 | Larotrectinib |
NTRK1 fusion | Trk Receptor Inhibitor (Pan) |
NTRK2 fusion | Trk Receptor Inhibitor (Pan) |
Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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NTRK1 | A608D | missense | unknown | NTRK1 A608D lies within the protein kinase domain of the Ntrk1 protein (UniProt.org). A608D has been demonstrated to promote secondary drug resistance in the context of CTRC-NTRK1 (PMID: 29466156), but has not been biochemically characterized and therefore, its effect on Ntrk1 protein function is unknown (PubMed, Jul 2022). | Y |
NTRK1 | F589L | missense | unknown | NTRK1 F589L lies within the protein kinase domain of the Ntrk1 protein (UniProt.org). F589L has been demonstrated to promote secondary drug resistance in the context of LMNA-NTRK1 (PMID: 29466156) and TMP3-NTRK1 (PMID: 33328556), but has not been biochemically characterized and therefore, its effect on Ntrk1 protein function is unknown (PubMed, Jul 2022). | Y |
NTRK1 | G667S | missense | unknown | NTRK1 G667S lies within the protein kinase domain of the Ntrk1 protein (UniProt.org). G667S has been associated with kinase inhibitor resistance in the context of NTRK1 fusion (PMID: 29466156, PMID: 33328556), but has not been biochemically characterized and therefore, its effect on Ntrk1 protein function is unknown (PubMed, Jul 2022). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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NTRK2 fusion | Advanced Solid Tumor | sensitive | Larotrectinib | FDA approved | Actionable | In three trials that supported FDA approval, Vitrakvi (larotrectinib) treatment resulted in an overall response rate of 75% (41/55) in adult and pediatric patients with advanced solid tumors harboring either an NTRK1, NTRK2, or NTRK3 fusion, including 7 patients achieving a complete response and 34 patients achieving a partial response (PMID: 29466156; NCT02122913, NCT02637687, NCT02576431). | detail... 29466156 |
NTRK1 fusion | pancreatic cancer | predicted - sensitive | Larotrectinib | Case Reports/Case Series | Actionable | In a Phase I trial, Vitrakvi (larotrectinib) treatment resulted in partial response in a patient with pancreatic cancer harboring NTRK1 fusions (PMID: 29466156, Annals of Oncology, Volume 29, Issue suppl_5; NCT02122913, NCT02637687, and NCT02576431). | 29466156 detail... |
NTRK1 fusion | appendix cancer | predicted - sensitive | Larotrectinib | Case Reports/Case Series | Actionable | In a Phase I trial, Vitrakvi (larotrectinib) treatment resulted in stable disease in a patient with appendix cancer harboring NTRK1 fusions (PMID: 29466156, Annals of Oncology, Volume 29, Issue suppl_5; NCT02122913, NCT02637687, and NCT02576431). | 29466156 detail... |
NTRK1 fusion | Advanced Solid Tumor | sensitive | Larotrectinib | FDA approved | Actionable | In three trials that supported FDA approval, Vitrakvi (larotrectinib) treatment resulted in an overall response rate of 75% (41/55) in adult and pediatric patients with advanced solid tumors harboring either an NTRK1, NTRK2, or NTRK3 fusion, including 7 patients achieving a complete response and 34 patients achieving a partial response (PMID: 29466156; NCT02122913, NCT02637687, NCT02576431). | detail... 29466156 detail... |
NTRK1 fusion | colon cancer | sensitive | Larotrectinib | Case Reports/Case Series | Actionable | In a Phase I trial, Vitrakvi (larotrectinib) treatment resulted in partial response in 50% (2/4) and stable disease in 50% (2/4) of patients with colon cancer harboring NTRK1 fusions (PMID: 29466156, Annals of Oncology, Volume 29, Issue suppl_5; NCT02122913, NCT02637687, and NCT02576431). | 29466156 detail... |