Difference between revisions of "Malignant solid neoplasm, NTRK-mutated"

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=Guidelines=
 
=Guidelines=
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'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 
==JSCO/ESMO/ASCO/JSMO/TOS==
 
==JSCO/ESMO/ASCO/JSMO/TOS==
 
*'''2020:''' Yoshino et al. [https://doi.org/10.1016/j.annonc.2020.03.299 JSCO—ESMO—ASCO—JSMO—TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions]
 
*'''2020:''' Yoshino et al. [https://doi.org/10.1016/j.annonc.2020.03.299 JSCO—ESMO—ASCO—JSMO—TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions]
 
=All lines of therapy=
 
=All lines of therapy=
 
==Entrectinib monotherapy {{#subobject:bcja91|Regimen=1}}==
 
==Entrectinib monotherapy {{#subobject:bcja91|Regimen=1}}==
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{| class="wikitable" style="float:right; margin-left: 5px;"
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<div class="toccolours" style="background-color:#eeeeee">
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===Regimen variant #1, pediatric dosing {{#subobject:ejhgk3|Variant=1}}===
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{| class="wikitable" style="color:white; background-color:#404040"
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|<small>'''FDA-recommended dose'''</small>
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|-
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|}
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{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
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!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
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|-
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9527518/ Desai et al. 2022 (STARTRK-NG)]
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|2016-05 to 2020-09
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| style="background-color:#91cf61" |Phase 1/2 (RT)
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:ehac84|Variant=1}}===
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''Note: these are the FDA-recommended doses based on age and BSA.''
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<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Entrectinib (Rozlytrek)]] by the following age- and BSA-based criteria:
 +
**Older than 1 month old up to 6 months old: 250 mg/m<sup>2</sup> PO once per day on days 1 to 28
 +
**Older than 6 months old AND BSA up to 0.50: 300 mg/m<sup>2</sup> PO once per day on days 1 to 28
 +
**Older than 6 months old AND BSA between 0.51 to 0.80: 200 mg PO once per day on days 1 to 28
 +
**Older than 6 months old AND BSA between 0.81 to 1.10: 300 mg PO once per day on days 1 to 28
 +
**Older than 6 months old AND BSA between 1.11 to 1.50: 400 mg PO once per day on days 1 to 28
 +
**Older than 6 months old AND BSA 1.51 or more: 600 mg PO once per day on days 1 to 28
 +
'''28-day cycles'''
 +
</div></div><br>
 +
 
 +
<div class="toccolours" style="background-color:#eeeeee">
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===Regimen variant #3, flat dose {{#subobject:ehac84|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
 
|<small>'''FDA-recommended dose'''</small>
 
|<small>'''FDA-recommended dose'''</small>
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{| class="wikitable" style="width: 60%; text-align:center;"  
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
−
!style="width: 33%"|Years of enrollment
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!style="width: 33%"|Dates of enrollment
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ Drilon et al. 2017 (ALKA-372-001)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ Drilon et al. 2017 (ALKA-372-001)]
−
|2012-2016
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
| style="background-color:#91cf61" |Phase I
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|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-209-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2012-2018
 +
| style="background-color:#91cf61" |Phase 1 (RT)
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ Drilon et al. 2017 (STARTRK-1)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ Drilon et al. 2017 (STARTRK-1)]
−
|2012-2016
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
| style="background-color:#91cf61" |Phase I (RT)
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|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-209-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2012-2018
 +
| style="background-color:#91cf61" |Phase 1 (RT)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630/ Doebele et al. 2020 (STARTRK-2)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
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|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-209-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2015 to not reported
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 
|-
 
|-
 
|}
 
|}
−
''Note: this is the MTD used in the phase 2 portion; it is also the FDA-recommended dose for adults.''
+
''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.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Entrectinib (Rozlytrek)]] 600 mg PO once per day
 
*[[Entrectinib (Rozlytrek)]] 600 mg PO once per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# '''Phase 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. [http://cancerdiscovery.aacrjournals.org/content/7/4/400.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28183697 PubMed] NCT02097810; EudraCT 2012-000148-88
+
# '''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. [https://doi.org/10.1158/2159-8290.CD-16-1237 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28183697/ PubMed] EudraCT 2012-000148-88
−
## '''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. [https://doi.org/10.1016/s1470-2045(19)30691-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31838007 PubMed]
+
## '''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. [https://doi.org/10.1016/s1470-2045(19)30691-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31838007/ PubMed]
 +
##'''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. [https://doi.org/10.1200/jco.20.03025 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078299/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33646820/ PubMed]
 +
# '''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. [https://doi.org/10.1158/2159-8290.CD-16-1237 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28183697/ PubMed] [https://clinicaltrials.gov/study/NCT02097810 NCT02097810]
 +
## '''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. [https://doi.org/10.1016/s1470-2045(19)30691-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31838007/ PubMed]
 +
##'''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. [https://doi.org/10.1200/jco.20.03025 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078299/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33646820/ PubMed]
 +
# '''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. [https://doi.org/10.1016/s1470-2045(19)30691-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31838007/ PubMed] [https://clinicaltrials.gov/study/NCT02568267 NCT02568267]
 +
##'''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. [https://doi.org/10.1200/jco.20.03025 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078299/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33646820/ PubMed]
 +
#'''STARTRK-NG:''' Desai AV, Robinson GW, Gauvain K, Basu EM, Macy ME, Maese L, Whipple NS, Sabnis AJ, Foster JH, Shusterman S, Yoon J, Weiss BD, Abdelbaki MS, Armstrong AE, Cash T, Pratilas CA, Corradini N, Marshall LV, Farid-Kapadia M, Chohan S, Devlin C, Meneses-Lorente G, Cardenas A, Hutchinson KE, Bergthold G, Caron H, Chow Maneval E, Gajjar A, Fox E. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. 2022 Oct 3;24(10):1776-1789. [https://doi.org/10.1093/neuonc/noac087 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9527518/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/35395680/ PubMed] [https://clinicaltrials.gov/study/NCT02650401 NCT02650401]
 +
#'''TAPISTRY:''' [https://clinicaltrials.gov/study/NCT04589845 NCT04589845]
  
 
==Larotrectinib monotherapy {{#subobject:e0d17a|Regimen=1}}==
 
==Larotrectinib monotherapy {{#subobject:e0d17a|Regimen=1}}==
−
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<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:392a4b|Variant=1}}===
 
===Regimen {{#subobject:392a4b|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
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{| class="wikitable" style="width: 60%; text-align:center;"  
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 33%"|Dates of enrollment
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
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|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ Drilon et al. 2018 (SCOUT)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ Drilon et al. 2018 (SCOUT)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-143-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 
|2015-2017
 
|2015-2017
−
|style="background-color:#91cf61"|Phase I/II (RT)
+
|style="background-color:#91cf61"|Phase 1/2 (RT)
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ Drilon et al. 2018 (NAVIGATE)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ Drilon et al. 2018 (NAVIGATE)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-143-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 
|2015-2017
 
|2015-2017
 
|style="background-color:#91cf61"|Phase 2 (RT)
 
|style="background-color:#91cf61"|Phase 2 (RT)
Line 73: Line 132:
 
|}
 
|}
 
''Note: these three trials are all reported in a single publication; the doses here are the FDA-recommended doses.''
 
''Note: these three trials are all reported in a single publication; the doses here are the FDA-recommended doses.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Larotrectinib (Vitrakvi)]] as follows:
+
*[[Larotrectinib (Vitrakvi)]] by the following age- and BSA-based criteria:
−
**Adults: 100 mg PO twice per day
+
**Adults and children with BSA of at least 1 m<sup>2</sup>: 100 mg PO twice per day
−
**Pediatrics: 100 mg/m<sup>2</sup> (maximum dose of 100 mg) PO twice per day
+
**Children with BSA less than 1 m<sup>2</sup>: 100 mg/m<sup>2</sup> PO twice per day
−
 
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
 +
</div></div>
  
 
===References===
 
===References===
 +
# '''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. [https://doi.org/10.1056/NEJMoa1714448 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29466156/ PubMed] [https://clinicaltrials.gov/study/NCT02122913 NCT02122913]
 +
##'''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. [https://doi.org/10.1093/annonc/mdy539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6386027/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30624546/ PubMed]
 +
##'''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. [https://doi.org/10.1016/s1470-2045(19)30856-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497841/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32105622/ PubMed]
 
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# '''Abstract:''' Hyman DM, Laetsch TW, Kummar S, DuBois SG, Farago AF, Pappo AS, Demetri GD, El-Deiry WS, Lassen UN, Dowlati A, Brose MS. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. [https://doi.org/10.1200/JCO.2017.35.18_suppl.LBA2501 link to abstract] -->
 
# '''Abstract:''' Hyman DM, Laetsch TW, Kummar S, DuBois SG, Farago AF, Pappo AS, Demetri GD, El-Deiry WS, Lassen UN, Dowlati A, Brose MS. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. [https://doi.org/10.1200/JCO.2017.35.18_suppl.LBA2501 link to abstract] -->
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# '''SCOUT; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1714448 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29466156 PubMed] NCT02122913; NCT02637687; NCT02576431
+
# '''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. [https://doi.org/10.1056/NEJMoa1714448 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29466156/ PubMed] [https://clinicaltrials.gov/study/NCT02637687 NCT02637687]
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+
##'''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. [https://doi.org/10.1016/s1470-2045(19)30856-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497841/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32105622/ PubMed]
 +
# '''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. [https://doi.org/10.1056/NEJMoa1714448 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29466156/ PubMed] [https://clinicaltrials.gov/study/NCT02576431 NCT02576431]
 +
##'''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. [https://doi.org/10.1016/s1470-2045(19)30856-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497841/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32105622/ PubMed]
 
[[Category:Malignant solid neoplasm]]
 
[[Category:Malignant solid neoplasm]]
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[[Category:NTRK regimens]]
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[[Category:Malignant solid neoplasm, NTRK-mutated regimens]]
 
[[Category:Biomarker-specific pages]]
 
[[Category:Biomarker-specific pages]]
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[[Category:Site-agnostic regimens]]
 

Latest revision as of 00:12, 23 July 2024

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2 regimens on this page
3 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

JSCO/ESMO/ASCO/JSMO/TOS

All lines of therapy

Entrectinib monotherapy

Regimen variant #1, pediatric dosing

FDA-recommended dose
Study Dates of enrollment Evidence
Desai et al. 2022 (STARTRK-NG) 2016-05 to 2020-09 Phase 1/2 (RT)

Note: these are the FDA-recommended doses based on age and BSA.

Targeted therapy

  • Entrectinib (Rozlytrek) by the following age- and BSA-based criteria:
    • Older than 1 month old up to 6 months old: 250 mg/m2 PO once per day on days 1 to 28
    • Older than 6 months old AND BSA up to 0.50: 300 mg/m2 PO once per day on days 1 to 28
    • Older than 6 months old AND BSA between 0.51 to 0.80: 200 mg PO once per day on days 1 to 28
    • Older than 6 months old AND BSA between 0.81 to 1.10: 300 mg PO once per day on days 1 to 28
    • Older than 6 months old AND BSA between 1.11 to 1.50: 400 mg PO once per day on days 1 to 28
    • Older than 6 months old AND BSA 1.51 or more: 600 mg PO once per day on days 1 to 28

28-day cycles


Regimen variant #3, flat dose

FDA-recommended dose
Study Dates of enrollment Evidence
Drilon et al. 2017 (ALKA-372-001) 2012-2018 Phase 1 (RT)
Drilon et al. 2017 (STARTRK-1) 2012-2018 Phase 1 (RT)
Doebele et al. 2020 (STARTRK-2) 2015 to not reported 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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
  4. STARTRK-NG: Desai AV, Robinson GW, Gauvain K, Basu EM, Macy ME, Maese L, Whipple NS, Sabnis AJ, Foster JH, Shusterman S, Yoon J, Weiss BD, Abdelbaki MS, Armstrong AE, Cash T, Pratilas CA, Corradini N, Marshall LV, Farid-Kapadia M, Chohan S, Devlin C, Meneses-Lorente G, Cardenas A, Hutchinson KE, Bergthold G, Caron H, Chow Maneval E, Gajjar A, Fox E. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. 2022 Oct 3;24(10):1776-1789. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02650401
  5. TAPISTRY: NCT04589845

Larotrectinib monotherapy

Regimen

FDA-recommended dose
Study Dates 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- and BSA-based criteria:
    • Adults and children with BSA of at least 1 m2: 100 mg PO twice per day
    • Children with BSA less than 1 m2: 100 mg/m2 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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
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