Non-small cell lung cancer, CNS metastases

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Note: these are studies of regimens tested in patients with NSCLC and CNS metastases, or subgroups of more general studies that focused on patients with CNS metastases. Please see the main NSCLC page for other regimens.
Last updated on 2024-12-02:17 regimens on this page
19 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.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Non-Small Cell Lung Cancer and NCCN Guidelines - Central Nervous System Cancers.
=All lines of therapy=
==Cisplatin & Vinorelbine (CVb)==
CVb: Cisplatin & Vinorelbine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robinet et al. 2001 (GFPC 95-1)	1995-1997 	Phase 3 (C)	CVb & concurrent WBRT	Did not meet primary endpoint of OS6
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 to 120 minutes once on day 1
*Vinorelbine (Navelbine) 30 mg/m2 IV over 10 to 20 minutes once per day on days 1, 8, 15, 22
28-day cycle for 6 cycles
====Subsequent treatment====
*WBRT
===References===
#GFPC 95-1: Robinet G, Thomas P, Breton JL, Léna H, Gouva S, Dabouis G, Bennouna J, Souquet PJ, Balmes P, Thiberville L, Fournel P, Quoix E, Riou R, Rebattu P, Pérol M, Paillotin D, Mornex F. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59-67. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==Dexamethasone monotherapy==
===Regimen===
Study 	Evidence 	Comparator 	Comparative Efficacy	Comparative Toxicity
Mulvenna et al. 2016 (QUARTZ)	Phase 3 (E-de-esc)	Dexamethasone & WBRT	 	Inconclusive whether non-inferior QALYs (primary endpoint)QALYs: 41.7 vs 46.4 days
====Supportive therapy====
*Dexamethasone (Decadron) (dose not specified)
One course
===References===
#QUARTZ: Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. link to original article link to PMC article EuroPMC ISRCTN3826061
==Dexamethasone & WBRT==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy	Comparative Toxicity
Mulvenna et al. 2016 (QUARTZ)	2007-03-02 to 2014-08-29	Phase 3 (C)	Dexamethasone	 	Inconclusive whether non-inferior QALYs(primary endpoint)QALYs:46.4 vs 41.7 days (difference -4.7 days, 90% CI -12.7 to 3.3)
====Radiotherapy====
*WBRT, 2000 cGy in 5 fractions
====Supportive therapy====
*Dexamethasone (Decadron) (dose not specified)
One course
===References===
#QUARTZ: Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. link to original article link to PMC article EuroPMC ISRCTN3826061
==Teniposide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Postmus et al. 2000	1989-1995 	Phase 3 (C)	Teniposide & RT	Might have shorter OS
====Chemotherapy====
*Teniposide (Vumon) 120 mg/m2 IV over 60 minutes once per day on days 1, 3, 5
21-day cycle for up to 12 cycles
===References===
#Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G; European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000 Oct 1;18(19):3400-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Teniposide & WBRT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Postmus et al. 2000	1989-1995 	Phase 3 (E-esc)	Teniposide	Might have longer OS
====Chemotherapy====
*Teniposide (Vumon) 120 mg/m2 IV over 60 minutes once per day on days 1, 3, 5
21-day cycle for up to 12 cycles
====Radiotherapy====
*WBRT, 3000 cGy in 10 fractions, started within 3 weeks of initiation of teniposide
One course
===References===
#Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G; European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000 Oct 1;18(19):3400-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Whole brain irradiation==
WBRT: Whole-Brain Radiation Therapy
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Neuhaus et al. 2009 	2001-10 to 2004-08-06 	Phase 3 (C)	Topotecan & WBRT	Did not meet primary endpoint of OS
Yang et al. 2021 (ENTER)	2013-08-07 to 2016-11-25	Phase 3 (C)	Erlotinib & WBRT	Did not meet primary endpoint of intracranial PFS
====Radiotherapy====
*Whole-brain irradiation
One course
===References===
#Neuhaus T, Ko Y, Muller RP, Grabenbauer GG, Hedde JP, Schueller H, Kocher M, Stier S, Fietkau R. A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer. Br J Cancer. 2009 Jan 27;100(2):291-7. Epub 2009 Jan 6. link to original article link to PMC article EuroPMC
#ENTER: Yang Z, Zhang Y, Li R, Yisikandaer A, Ren B, Sun J, Li J, Chen L, Zhao R, Zhang J, Xia X, Liao Z, Carbone DP. Whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases: a multicenter, open-label, randomized, controlled phase III trial. Neuro Oncol. 2021 Jun 1;23(6):967-978. link to original article link to PMC article EuroPMC NCT01887795
##HRQoL analysis: Tang F, Zhang J, Xu Z, Zhang Y, Zhang X, Peng Y, Yang Z. Health-related quality of life analysis from ENTER, a randomized, controlled phase III trial of whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases. Transl Lung Cancer Res. 2024 Dec;13(12):3289-3302. link to original article link to EuroPMC
=ALK-mutated, all lines of therapy=
==Alectinib monotherapy==
===Regimen variant #1, 300 mg twice per day===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hida et al. 2017 (J-ALEX)	2013-2015 	Phase 3 (E-switch-ic)	Crizotinib	Longer TTP1 (secondary endpoint)
1Reported CNS efficacy is based on the 2018 update.
This is the PMDA-approved dose in Japan.
====Biomarker eligibility criteria====
*Gene ALK positive
====Targeted therapy====
*Alectinib (Alecensa) 300 mg PO twice per day
Continued indefinitely
===Regimen variant #2, 600 mg twice per day===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Peters et al. 2017 (ALEX)	2014-2016 	Phase 3 (E-switch-ic)	Crizotinib	Longer TTP1 (secondary endpoint)
1Reported CNS efficacy is based on the 2018 update.
====Biomarker eligibility criteria====
*Gene ALK positive
====Targeted therapy====
*Alectinib (Alecensa) 600 mg PO twice per day
Continued indefinitely
===References===
#J-ALEX: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39. Epub 2017 May 10. link to original articledosing details in abstract have been reviewed by our editorsEuroPMC JapicCTI-132316
##Subgroup analysis: Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:37-40. Epub 2018 Apr 17. link to original article EuroPMC
#ALEX: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Epub 2017 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02075840
##Subgroup analysis: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Pérol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nüesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. link to original article link to PMC article EuroPMC
==Ceritinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Shaw et al. 2014 (ASCEND-1)	2011-2013 	Phase 1, >20 pts in this dosing cohort
Note: CNS efficacy is based on the 2016 update.
====Biomarker eligibility criteria====
*ALK-rearranged
====Targeted therapy====
*Ceritinib (Zykadia) 750 mg PO once per day on days 1 to 21, taken on an empty stomach
21-day cycles
===References===
#ASCEND-1: Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01283516
##Update: Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Sutradhar S, Li S, Szczudlo T, Yovine A, Shaw AT. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016 Apr;17(4):452-463. Epub 2016 Mar 11. link to original article link to PMC article EuroPMC
==Crizotinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hida et al. 2017 (J-ALEX)	2013-2015 	Phase 3 (C)	Alectinib 	Shorter TTP1 (secondary endpoint)
Peters et al. 2017 (ALEX)	2014-2016 	Phase 3 (C)	Alectinib 	Shorter TTP2 (secondary endpoint)
1Reported CNS efficacy for J-ALEX is based on the 2018 update.
2Reported CNS efficacy for ALEX is based on the 2018 update.
====Biomarker eligibility criteria====
*Gene ALK positive
====Targeted therapy====
*Crizotinib (Xalkori) 250 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#J-ALEX: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39. Epub 2017 May 10. link to original articledosing details in abstract have been reviewed by our editorsEuroPMC JapicCTI-132316
##Subgroup analysis: Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:37-40. Epub 2018 Apr 17. link to original article EuroPMC
#ALEX: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Epub 2017 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02075840
##Subgroup analysis: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Pérol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nüesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. link to original article link to PMC article EuroPMC
=EGFR-mutated, all lines of therapy=
==Afatinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sequist et al. 2013 (LUX-Lung 3)	2009-2011 	Phase 3 (E-switch-ooc)	Cisplatin & Pemetrexed 	Seems to have longer PFS1 (secondary endpoint)
Wu et al. 2014 (LUX-Lung 6) 	2010-04-27 to 2011-11-16	Phase 3 (E-switch-ooc)	Cisplatin & Gemcitabine	Seems to have longer PFS1 (secondary endpoint)
1Reported CNS-specific efficacy is based on the 2016 subgroup analysis.
====Biomarker eligibility criteria====
*Gene EGFR mutation (Leu858Arg, exon 19 deletions, or other)
====Targeted therapy====
*Afatinib (Gilotrif) 40 mg PO once per day, taken 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")
Continued indefinitely
====Dose and schedule modifications====
*LUX-Lung 3: Afatinib (Gilotrif) could be increased to 50 mg PO once per day if patients did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.
===References===
#LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00949650
##HRQoL analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article EuroPMC
##Pooled subgroup analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article EuroPMC
##Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article EuroPMC
#LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01121393
##Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article EuroPMC
##Pooled subgroup analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article EuroPMC
##Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article EuroPMC
==Aumolertinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Lu et al. 2022 (AENEAS)	2018-11-30 to 2019-09-06	Phase 3 (E-switch-ic)	Gefitinib 	Longer CNS-PFS1 (secondary endpoint)Median CNS-PFS: 29 vs 8.3 mo(HR 0.31, 95% CI 0.17-0.56)
Reported efficacy is based on the 2024 subgroup analysis.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or L858R
====Targeted therapy====
*Aumolertinib (Amelie) 110 mg PO once per day
Continued indefinitely
===References===
#AENEAS: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Jie W, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Sun C, Wei H, Li C, Ali SM, Miller VA, Wu Q. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022 Sep 20;40(27):3162-3171. Epub 2022 May 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03849768
##Subgroup analysis: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Weng J, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Wei H, Wei J, Zhang Z, Wu Q. Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS). Cancer Commun (Lond). 2024 Sep;44(9):1005-1017. Epub 2024 Jul 17. link to original article link to PMC article EuroPMC
==Cisplatin, Gefitinib, Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hou et al. 2023 (GAP BRAIN)	2016-2021 	Phase 3 (E-esc)	Gefitinib 	Longer intracranial PFS (primary endpoint)Median intracranial PFS: 15.6 vs 9.1 mo(HR 0.36, 95% CI 0.25-0.53)Seems to have longer OS (secondary endpoint)Median OS: 35 vs 28.9 mo(HR 0.65, 95% CI 0.43-0.99)
====Biomarker eligibility criteria====
* EGFR exon 19 deletion or exon 21 L858R mutation
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4 up to 6: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day on days 1 to 28
28-day cycles
===References===
#GAP BRAIN: Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01951469
==Furmonertinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Shi et al. 2022 (FURLONG)	2019-05-30 to 2019-12-05	Phase 3 (E-switch-ic)	Gefitinib 	Longer CNS-PFS1 (secondary endpoint)Median CNS-PFS: 20.8 vs 9.8 mo(HR 0.40, 95% CI 0.23-0.71)
1Reported efficacy is based on the 2022 subgroup analysis.
====Biomarker eligibility criteria====
*FURLONG: EGFR exon 19 deletion or EGFR p.L858R mutation
====Targeted therapy====
*Furmonertinib (Ivesa) 80 mg PO once per day on days 1 to 21
21-day cycles
===References===
#FURLONG: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C; FURLONG investigators. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 2022 Nov;10(11):1019-1028. Epub 2022 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03787992
##Subgroup analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C. Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study. J Thorac Oncol. 2022 Nov;17(11):1297-1305. Epub 2022 Aug 3. link to original article EuroPMC
##PRO analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Hu J, Liu F, Jiang Y, Ge N. Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. Lancet Reg Health West Pac. 2024 Jun 17;48:101122. link to original article link to PMC article EuroPMC
==Gefitinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hou et al. 2023 (GAP BRAIN)	2016-2021 	Phase 3 (C)	1a. Cisplatin, Gefitinib, Pemetrexed1b. Gefitinib, Nedaplatin, Pemetrexed	Shorter intracranial PFS
Lu et al. 2022 (AENEAS) 	2018-11-30 to 2019-09-06	Phase 3 (C)	Aumolertinib 	Shorter CNS-PFS1
Shi et al. 2022 (FURLONG) 	2019-05-30 to 2019-12-05	Phase 3 (C)	Furmonertinib 	Shorter CNS-PFS2 (secondary endpoint)Median CNS-PFS: 9.8 vs 20.8 mo(HR 2.50, 95% CI 1.41-4.35)
1Reported efficacy for AENEAS is based on the 2024 subgroup analysis.
2Reported efficacy for FURLONG is based on the 2022 subgroup analysis.
====Biomarker eligibility criteria====
* EGFR exon 19 deletion or exon 21 L858R mutation
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
===References===
#AENEAS: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Jie W, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Sun C, Wei H, Li C, Ali SM, Miller VA, Wu Q. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022 Sep 20;40(27):3162-3171. Epub 2022 May 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03849768
##Subgroup analysis: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Weng J, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Wei H, Wei J, Zhang Z, Wu Q. Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS). Cancer Commun (Lond). 2024 Sep;44(9):1005-1017. Epub 2024 Jul 17. link to original article link to PMC article EuroPMC
#FURLONG: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C; FURLONG investigators. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 2022 Nov;10(11):1019-1028. Epub 2022 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03787992
##Subgroup analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C. Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study. J Thorac Oncol. 2022 Nov;17(11):1297-1305. Epub 2022 Aug 3. link to original article EuroPMC
##PRO analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Hu J, Liu F, Jiang Y, Ge N. Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. Lancet Reg Health West Pac. 2024 Jun 17;48:101122. link to original article link to PMC article EuroPMC
#GAP BRAIN: Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01951469
==Gefitinib, Nedaplatin, Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hou et al. 2023 (GAP BRAIN)	2016-2021 	Phase 3 (E-esc)	Gefitinib 	Longer intracranial PFS (primary endpoint)Median intracranial PFS: 15.6 vs 9.1 mo(HR 0.36, 95% CI 0.25-0.53)Seems to have longer OS (secondary endpoint)Median OS: 35 vs 28.9 mo(HR 0.65, 95% CI 0.43-0.99)
====Biomarker eligibility criteria====
* EGFR exon 19 deletion or exon 21 L858R mutation
====Chemotherapy====
*Nedaplatin (Aqupla) as follows:
**Cycles 1 to 4 up to 6: 80 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day on days 1 to 28
28-day cycles
===References===
#GAP BRAIN: Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01951469
==Icotinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yang et al. 2017 (BRAIN)	2012-2015 	Phase 3 (E-switch-ooc)	WBRT 	Longer intracranial PFS (primary endpoint)Median intracranial PFS: 10 vs 4.8 mo(HR 0.56, 95% CI 0.36-0.90)
Note: this drug is only approved in China.
====Biomarker eligibility criteria====
* EGFR Mutation
* Clinical Trial Eligibility: EGFR Exon 19 deletion, EGFR exon 21 L858R, Uncommon EGFR mutations
====Targeted therapy====
*Icotinib (Conmana) 125 mg PO three times per day
Continued indefinitely
===References===
#BRAIN: Yang JJ, Zhou C, Huang Y, Feng J, Lu S, Song Y, Huang C, Wu G, Zhang L, Cheng Y, Hu C, Chen G, Zhang L, Liu X, Yan HH, Tan FL, Zhong W, Wu YL. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med. 2017 Sep;5(9):707-716. Epub 2017 Jul 19. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01724801
==Osimertinib monotherapy==
===Regimen variant #1, 80 mg/day===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jänne et al. 2015 (AURA) 	2013 to not reported	Phase 1/2 (RT) 	 	
Goss et al. 2016 (AURA2) 	2014 	Phase 2 (RT) 	 	
Mok et al. 2016 (AURA3) 	2014-08 to 2015-09 	Phase 3 (E-switch-ooc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Seems to have higher ORR1 (secondary endpoint)
Soria et al. 2017 (FLAURA) 	2014-2016 	Phase 3 (E-switch-ic) 	1a. Erlotinib1b. Gefitinib 	Seems to have longer PFS2 (secondary endpoint)
Yamaguchi et al. 2021 (WJOG9116L)	2016-2019 	Phase 2 	 	
1Reported efficacy for AURA3 is based on the 2018 subgroup analysis.
2Reported efficacy for FLAURA is based on the 2018 subgroup analysis.
Note: Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy. CNS efficacy for AURA & AURA2 is best described in Goss et al. 2018.
====Biomarker eligibility criteria====
*AURA3: EGFR T790M
*FLAURA: EGFR exon 19 deletion or EGFR L858R
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day
Continued indefinitely
===Regimen variant #2, 160 mg/day===
Study 	Dates of enrollment	Evidence 	Efficacy
Yang et al. 2019 (BLOOM)	2015-2017 	Phase 1, >20 pts	BICR- LM ORR (62%), DoR 15.2 months
Investigator- LM ORR (41%), DoR 8.3 months
Patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy. BICR- Blinded Independent Central Review, DoR- Duration of Response, ORR-Objective response rate
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or EGFR L858R
====Targeted therapy====
*Osimertinib (Tagrisso) 160 mg PO once per day
Continued indefinitely
===References===
#AURA: Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01802632
##Update: Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, Blackhall F, Haggstrom D, Yoh K, Novello S, Gold K, Hirashima T, Lin CC, Mann H, Cantarini M, Ghiorghiu S, Jänne PA. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol. 2017 Apr 20;35(12):1288-1296. Epub 2017 Feb 21. link to original article EuroPMC
##Pooled subgroup analysis: Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crinò L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Jänne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. link to original article EuroPMC NCT01802632
##Pooled update: Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Jänne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. Epub 2018 Dec 4. link to original article EuroPMC
#AURA2: Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, Han JY, Juan O, Dunphy F, Nishio M, Kang JH, Majem M, Mann H, Cantarini M, Ghiorghiu S, Mitsudomi T. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1643-1652. Epub 2016 Oct 14. link to original article EuroPMC NCT02094261
##Pooled subgroup analysis: Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crinò L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Jänne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. link to original article EuroPMC
##Pooled update: Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Jänne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. Epub 2018 Dec 4. link to original article EuroPMC
#AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02151981
##PRO analysis: Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-Reported Symptoms and Impact of Treatment With Osimertinib Versus Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The AURA3 Trial. J Clin Oncol. 2018 Jun 20;36(18):1853-1860. Epub 2018 May 7. link to original article EuroPMC
##Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article EuroPMC
##Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Nov;31(11):1536-1544. Epub 2020 Aug 27. link to original article EuroPMC
#FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02296125
##Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article EuroPMC
#BLOOM: Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB, Brown AP, Collins B, Chmielecki J, Vishwanathan K, Mendoza-Naranjo A, Ahn MJ. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol. 2020 Feb 20;38(6):538-547. Epub 2019 Dec 6. link to original article link to PMC article EuroPMC NCT02228369
#WJOG9116L: Yamaguchi H, Wakuda K, Fukuda M, Kenmotsu H, Mukae H, Ito K, Chibana K, Inoue K, Miura S, Tanaka K, Ebi N, Suetsugu T, Harada T, Kirita K, Yokoyama T, Nakatani Y, Yoshimura K, Nakagawa K, Yamamoto N, Sugio K. A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L). J Thorac Oncol. 2021 Dec;16(12):2121-2132. Epub 2021 Aug 19. link to original article dosing details in abstract have been reviewed by our editors EuroPMC UMIN000024218
=RET-mutated, first-line therapy=
==Selpercatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2023 (LIBRETTO-431)	2020-03 to 2022-08 	Phase 3 (E-switch-ooc)	1a. Carboplatin & Pemetrexed1b. Carboplatin, Pemetrexed, Pembrolizumab1c. Cisplatin & Pemetrexed1d. Cisplatin, Pemetrexed, Pembrolizumab	Longer PFS (primary endpoint)Median PFS: 24.8 vs 11.2 mo(HR 0.46, 95% CI 0.31-0.70)
====Targeted therapy====
*Selpercatinib (Retevmo) 160 mg PO twice per day on days 1 to 21
21-day cycles
===References===
#LIBRETTO-431: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. Epub 2023 Oct 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04194944
##Subgroup analysis: Pérol M, Solomon BJ, Goto K, Park K, Nadal E, Bria E, Martin C, Bar J, Williams JN, Puri T, Li J, Uh MK, Lin BK, Zhou C. CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Jul 20;42(21):2500-2505. Epub 2024 Jun 3. link to original article EuroPMC
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