NTRK

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2 regimens on this page
2 variants on this page


Guidelines

JSCO/ESMO/ASCO/JSMO/TOS

All lines of therapy

Entrectinib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Drilon et al. 2017 (ALKA-372-001) 2012-2016 Phase 1 (RT)
Drilon et al. 2017 (STARTRK-1) 2012-2016 Phase 1 (RT)
Doebele et al. 2020 (STARTRK-2) 2015-NR Phase 2 (RT)

Note: this is the MTD used in the phase 2 portion; it is also the FDA-recommended dose for adults. Doebele et al. 2020 appears to be the first manuscript reporting the results of STARTRK-2.

Targeted therapy

Continued indefinitely

References

  1. ALKA-372-001: Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017 Apr;7(4):400-409. Epub 2017 Feb 9. link to original article link to PMC article PubMed EudraCT 2012-000148-88
    1. Pooled update: Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-282. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020 Feb;21(2):e70. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. Erratum in: Lancet Oncol. 2020 Aug;21(8):e372. link to original article link to PMC article PubMed
    2. Pooled update: Dziadziuszko R, Krebs MG, De Braud F, Siena S, Drilon A, Doebele RC, Patel MR, Cho BC, Liu SV, Ahn MJ, Chiu CH, Farago AF, Lin CC, Karapetis CS, Li YC, Day BM, Chen D, Wilson TR, Barlesi F. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. Epub 2021 Mar 1. link to original article link to PMC article PubMed
  2. STARTRK-1: Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017 Apr;7(4):400-409. Epub 2017 Feb 9. link to original article link to PMC article PubMed NCT02097810
    1. Pooled update: Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-282. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020 Feb;21(2):e70. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. Erratum in: Lancet Oncol. 2020 Aug;21(8):e372. link to original article link to PMC article PubMed
    2. Pooled update: Dziadziuszko R, Krebs MG, De Braud F, Siena S, Drilon A, Doebele RC, Patel MR, Cho BC, Liu SV, Ahn MJ, Chiu CH, Farago AF, Lin CC, Karapetis CS, Li YC, Day BM, Chen D, Wilson TR, Barlesi F. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. Epub 2021 Mar 1. link to original article link to PMC article PubMed
  3. STARTRK-2: Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-282. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020 Feb;21(2):e70. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. Erratum in: Lancet Oncol. 2020 Aug;21(8):e372. link to original article link to PMC article PubMed NCT02568267
    1. Pooled update: Dziadziuszko R, Krebs MG, De Braud F, Siena S, Drilon A, Doebele RC, Patel MR, Cho BC, Liu SV, Ahn MJ, Chiu CH, Farago AF, Lin CC, Karapetis CS, Li YC, Day BM, Chen D, Wilson TR, Barlesi F. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. Epub 2021 Mar 1. link to original article link to PMC article PubMed

Larotrectinib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Drilon et al. 2018 (LOXO-TRK-14001) 2015-2017 Phase 1 (RT)
Drilon et al. 2018 (SCOUT) 2015-2017 Phase 1/2 (RT)
Drilon et al. 2018 (NAVIGATE) 2015-2017 Phase 2 (RT)

Note: these three trials are all reported in a single publication; the doses here are the FDA-recommended doses.

Targeted therapy

  • Larotrectinib (Vitrakvi) by the following age-based criteria:
    • Adults: 100 mg PO twice per day
    • Pediatrics: 100 mg/m2 (maximum dose of 100 mg) PO twice per day

Continued indefinitely

References

  1. LOXO-TRK-14001: 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. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018 Feb 22;378(8):731-739. link to original article contains dosing details in abstract link to PMC article PubMed NCT02122913
    1. Update: Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA 3rd, Doebele RC. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb 1;30(2):325-331. link to original article link to PMC article PubMed
    2. Pooled update: Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. Epub 2020 Feb 24. link to original article link to PMC article PubMed
  2. SCOUT: 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. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018 Feb 22;378(8):731-739. link to original article contains dosing details in abstract link to PMC article PubMed NCT02637687
    1. Pooled update: Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. Epub 2020 Feb 24. link to original article link to PMC article PubMed
  3. NAVIGATE: 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. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018 Feb 22;378(8):731-739. link to original article contains dosing details in abstract link to PMC article PubMed NCT02576431
    1. Pooled update: Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. Epub 2020 Feb 24. link to original article link to PMC article PubMed