Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children

A. Drilon, T. W. Laetsch, S. Kummar, S. G. Dubois, U. N. Lassen, G. D. Demetri, M. Nathenson, R. C. Doebele, A. F. Farago, A. S. Pappo, B. Turpin, A. Dowlati, M. S. Brose, L. Mascarenhas, N. Federman, J. Berlin, W. S. El-Deiry, C. Baik, J. Deeken, V. Boni & 18 others R. Nagasubramanian, M. Taylor, E. R. Rudzinski, F. Meric-Bernstam, D. P.S. Sohal, P. C. Ma, L. E. Raez, J. F. Hechtman, R. Benayed, M. Ladanyi, B. B. Tuch, K. Ebata, S. Cruickshank, N. C. Ku, M. C. Cox, D. S. Hawkins, D. S. Hong, D. M. Hyman

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)731-739
Number of pages9
JournalNew England Journal of Medicine
Volume378
Issue number8
DOIs
StatePublished - Feb 22 2018

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Neoplasms
Research Personnel
tropomyosin kinase
Confidence Intervals
Safety
Drug-Related Side Effects and Adverse Reactions
Disease-Free Survival
Survival
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Drilon, A., Laetsch, T. W., Kummar, S., Dubois, S. G., Lassen, U. N., Demetri, G. D., ... Hyman, D. M. (2018). Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. New England Journal of Medicine, 378(8), 731-739. https://doi.org/10.1056/NEJMoa1714448

Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. / Drilon, A.; Laetsch, T. W.; Kummar, S.; Dubois, S. G.; Lassen, U. N.; Demetri, G. D.; Nathenson, M.; Doebele, R. C.; Farago, A. F.; Pappo, A. S.; Turpin, B.; Dowlati, A.; Brose, M. S.; Mascarenhas, L.; Federman, N.; Berlin, J.; El-Deiry, W. S.; Baik, C.; Deeken, J.; Boni, V.; Nagasubramanian, R.; Taylor, M.; Rudzinski, E. R.; Meric-Bernstam, F.; Sohal, D. P.S.; Ma, P. C.; Raez, L. E.; Hechtman, J. F.; Benayed, R.; Ladanyi, M.; Tuch, B. B.; Ebata, K.; Cruickshank, S.; Ku, N. C.; Cox, M. C.; Hawkins, D. S.; Hong, D. S.; Hyman, D. M.

In: New England Journal of Medicine, Vol. 378, No. 8, 22.02.2018, p. 731-739.

Research output: Contribution to journalArticle

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 2018, 'Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children', New England Journal of Medicine, vol. 378, no. 8, pp. 731-739. https://doi.org/10.1056/NEJMoa1714448
Drilon, A. ; Laetsch, T. W. ; Kummar, S. ; Dubois, S. G. ; Lassen, U. N. ; Demetri, G. D. ; Nathenson, M. ; Doebele, R. C. ; Farago, A. F. ; Pappo, A. S. ; Turpin, B. ; Dowlati, A. ; Brose, M. S. ; Mascarenhas, L. ; Federman, N. ; Berlin, J. ; El-Deiry, W. S. ; Baik, C. ; Deeken, J. ; Boni, V. ; Nagasubramanian, R. ; Taylor, M. ; Rudzinski, E. R. ; Meric-Bernstam, F. ; Sohal, D. P.S. ; Ma, P. C. ; Raez, L. E. ; Hechtman, J. F. ; Benayed, R. ; Ladanyi, M. ; Tuch, B. B. ; Ebata, K. ; Cruickshank, S. ; Ku, N. C. ; Cox, M. C. ; Hawkins, D. S. ; Hong, D. S. ; Hyman, D. M. / Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 8. pp. 731-739.
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abstract = "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.",
author = "A. Drilon and Laetsch, {T. W.} and S. Kummar and Dubois, {S. G.} and Lassen, {U. N.} and Demetri, {G. D.} and M. Nathenson and Doebele, {R. C.} and Farago, {A. F.} and Pappo, {A. S.} and B. Turpin and A. Dowlati and Brose, {M. S.} and L. Mascarenhas and N. Federman and J. Berlin and El-Deiry, {W. S.} and C. Baik and J. Deeken and V. Boni and R. Nagasubramanian and M. Taylor and Rudzinski, {E. R.} and F. Meric-Bernstam and Sohal, {D. P.S.} and Ma, {P. C.} and Raez, {L. E.} and Hechtman, {J. F.} and R. Benayed and M. Ladanyi and Tuch, {B. B.} and K. Ebata and S. Cruickshank and Ku, {N. C.} and Cox, {M. C.} and Hawkins, {D. S.} and Hong, {D. S.} and Hyman, {D. M.}",
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TY - JOUR

T1 - Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children

AU - Drilon, A.

AU - Laetsch, T. W.

AU - Kummar, S.

AU - Dubois, S. G.

AU - Lassen, U. N.

AU - Demetri, G. D.

AU - Nathenson, M.

AU - Doebele, R. C.

AU - Farago, A. F.

AU - Pappo, A. S.

AU - Turpin, B.

AU - Dowlati, A.

AU - Brose, M. S.

AU - Mascarenhas, L.

AU - Federman, N.

AU - Berlin, J.

AU - El-Deiry, W. S.

AU - Baik, C.

AU - Deeken, J.

AU - Boni, V.

AU - Nagasubramanian, R.

AU - Taylor, M.

AU - Rudzinski, E. R.

AU - Meric-Bernstam, F.

AU - Sohal, D. P.S.

AU - Ma, P. C.

AU - Raez, L. E.

AU - Hechtman, J. F.

AU - Benayed, R.

AU - Ladanyi, M.

AU - Tuch, B. B.

AU - Ebata, K.

AU - Cruickshank, S.

AU - Ku, N. C.

AU - Cox, M. C.

AU - Hawkins, D. S.

AU - Hong, D. S.

AU - Hyman, D. 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.

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DO - 10.1056/NEJMoa1714448

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JO - New England Journal of Medicine

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