Difference between revisions of "CNS carcinoma"
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{| class="wikitable" style="text-align:center; width:50%;" | {| class="wikitable" style="text-align:center; width:50%;" | ||
| − | !colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c"|'''Section editor''' | + | ! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor''' |
|- | |- | ||
| − | |style="background-color:#F0F0F0"|[[File:SeemaNagpal.jpg|frameless|upright=0.3|center]] | + | | style="background-color:#F0F0F0" |[[File:SeemaNagpal.jpg|frameless|upright=0.3|center]] |
|<big>[[User:Seemanagpal|Seema Nagpal, MD]]<br>Stanford University<br>Palo Alto, CA</big> | |<big>[[User:Seemanagpal|Seema Nagpal, MD]]<br>Stanford University<br>Palo Alto, CA</big> | ||
|- | |- | ||
| Line 14: | Line 14: | ||
=Guidelines= | =Guidelines= | ||
==[http://www.asco.org/ ASCO]== | ==[http://www.asco.org/ ASCO]== | ||
| + | |||
*'''2018:''' Ramakrishna et al. [https://ascopubs.org/doi/full/10.1200/JCO.2018.79.2713 Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/29939840 PubMed] | *'''2018:''' Ramakrishna et al. [https://ascopubs.org/doi/full/10.1200/JCO.2018.79.2713 Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/29939840 PubMed] | ||
| + | |||
===Older=== | ===Older=== | ||
| + | |||
*'''2014:''' Ramakrishna et al. [https://ascopubs.org/doi/full/10.1200/JCO.2013.54.0955 Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline] [https://www.ncbi.nlm.nih.gov/pubmed/24799487 PubMed] | *'''2014:''' Ramakrishna et al. [https://ascopubs.org/doi/full/10.1200/JCO.2013.54.0955 Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline] [https://www.ncbi.nlm.nih.gov/pubmed/24799487 PubMed] | ||
==EANO/ESMO== | ==EANO/ESMO== | ||
| + | |||
*'''2017:''' Le Rhun et al. [https://www.esmo.org/Guidelines/Neuro-Oncology/EANO-ESMO-Leptomeningeal-Metastasis-Clinical-Practice-Guidelines EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours] | *'''2017:''' Le Rhun et al. [https://www.esmo.org/Guidelines/Neuro-Oncology/EANO-ESMO-Leptomeningeal-Metastasis-Clinical-Practice-Guidelines EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours] | ||
==[https://www.nccn.org/ NCCN]== | ==[https://www.nccn.org/ NCCN]== | ||
| + | |||
*[https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf NCCN Guidelines - Central Nervous System Cancers] | *[https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf NCCN Guidelines - Central Nervous System Cancers] | ||
| Line 33: | Line 38: | ||
===Regimen {{#subobject:d377ed|Variant=1}}=== | ===Regimen {{#subobject:d377ed|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://www.redjournal.org/article/S0360-3016(07)04231-9/fulltext Knisely et al. 2007 (RTOG 0118)] | |[https://www.redjournal.org/article/S0360-3016(07)04231-9/fulltext Knisely et al. 2007 (RTOG 0118)] | ||
| − | |style="background-color:#1a9851"|Phase III (C) | + | | style="background-color:#1a9851" |Phase III (C) |
|Thalidomide & WBRT | |Thalidomide & WBRT | ||
| − | |style="background-color:#ffffbf"|Did not meet primary endpoint of OS | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of OS |
|- | |- | ||
|} | |} | ||
====Radiotherapy==== | ====Radiotherapy==== | ||
| + | |||
*[[External_beam_radiotherapy|Whole-brain irradiation]] 2.50-Gy fractions x 15 (total dose: 37.5 Gy) | *[[External_beam_radiotherapy|Whole-brain irradiation]] 2.50-Gy fractions x 15 (total dose: 37.5 Gy) | ||
| Line 50: | Line 56: | ||
===References=== | ===References=== | ||
| − | # '''RTOG 0118:''' Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ Jr, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):79-86. Epub 2007 Dec 31. [https://www.redjournal.org/article/S0360-3016(07)04231-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18164847 PubMed] | + | |
| + | #'''RTOG 0118:''' Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ Jr, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):79-86. Epub 2007 Dec 31. [https://www.redjournal.org/article/S0360-3016(07)04231-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18164847 PubMed] | ||
=Breast cancer, HER2-positive, all lines of therapy= | =Breast cancer, HER2-positive, all lines of therapy= | ||
| Line 60: | Line 67: | ||
===Regimen {{#subobject:653bef|Variant=1}}=== | ===Regimen {{#subobject:653bef|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)] | |[https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ic) | + | | style="background-color:#1a9851" |Phase III (E-switch-ic) |
|[[#Capecitabine_.26_Trastuzumab|Capecitabine & Trastuzumab]] | |[[#Capecitabine_.26_Trastuzumab|Capecitabine & Trastuzumab]] | ||
| − | |style="background-color:#ffffbf"|Did not meet primary endpoint of CNS metastases as first site of relapse | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of CNS metastases as first site of relapse |
|- | |- | ||
|} | |} | ||
| + | |||
| + | ====== Biomarkers ====== | ||
| + | |||
| + | * Gene HER2 [[Biomarkers#Genes#Her2|Positive]] | ||
| + | * Alterations Method score > 2.2 by fluorescence in situ hybridization and/or 3+ amplification by immunohistochemistry or chromogenic/silver in situ hybridization) | ||
| + | |||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | ||
*[[Lapatinib (Tykerb)]] 1250 mg PO once per day | *[[Lapatinib (Tykerb)]] 1250 mg PO once per day | ||
| Line 78: | Line 92: | ||
===References=== | ===References=== | ||
| − | # '''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605838 PubMed] | + | |
| + | #'''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605838 PubMed] | ||
==Capecitabine & Trastuzumab {{#subobject:677608|Regimen=1}}== | ==Capecitabine & Trastuzumab {{#subobject:677608|Regimen=1}}== | ||
| Line 88: | Line 103: | ||
===Regimen {{#subobject:e14cab|Variant=1}}=== | ===Regimen {{#subobject:e14cab|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)] | |[https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)] | ||
| − | |style="background-color:#1a9851"|Phase III (C) | + | | style="background-color:#1a9851" |Phase III (C) |
|[[#Capecitabine_.26_Lapatinib|Capecitabine & Lapatanib]] | |[[#Capecitabine_.26_Lapatinib|Capecitabine & Lapatanib]] | ||
| − | |style="background-color:#ffffbf"|Did not meet primary endpoint of CNS metastases as first site of relapse | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of CNS metastases as first site of relapse |
|- | |- | ||
|} | |} | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | *[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | ||
*[[Trastuzumab (Herceptin)]] as follows: | *[[Trastuzumab (Herceptin)]] as follows: | ||
| Line 108: | Line 124: | ||
===References=== | ===References=== | ||
| − | # '''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25605838 PubMed] | + | |
| + | #'''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.57.1794 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25605838 PubMed] | ||
=Non-small cell lung cancer, all lines of therapy= | =Non-small cell lung cancer, all lines of therapy= | ||
| Line 118: | Line 135: | ||
===Regimen {{#subobject:6a5b0e|Variant=1}}=== | ===Regimen {{#subobject:6a5b0e|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 20%"|Study | + | ! style="width: 20%" |Study |
| − | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 20%"|Comparator | + | ! style="width: 20%" |Comparator |
| − | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
| − | !style="width: 20%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] | + | ! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] |
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-de-esc) | + | | style="background-color:#1a9851" |Phase III (E-de-esc) |
|[[#Dexamethasone_.26_WBRT|Dexamethasone & WBRT]] | |[[#Dexamethasone_.26_WBRT|Dexamethasone & WBRT]] | ||
| | | | ||
| Line 132: | Line 149: | ||
|} | |} | ||
====Supportive therapy==== | ====Supportive therapy==== | ||
| + | |||
*[[Dexamethasone (Decadron)]] | *[[Dexamethasone (Decadron)]] | ||
===References=== | ===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. [https://www.sciencedirect.com/science/article/pii/S014067361630825X link to SD article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27604504 PubMed] | + | |
| + | #'''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. [https://www.sciencedirect.com/science/article/pii/S014067361630825X link to SD article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27604504 PubMed] | ||
==Dexamethasone & WBRT {{#subobject:04a6d4|Regimen=1}}== | ==Dexamethasone & WBRT {{#subobject:04a6d4|Regimen=1}}== | ||
| Line 144: | Line 163: | ||
===Regimen {{#subobject:da6414|Variant=1}}=== | ===Regimen {{#subobject:da6414|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 20%"|Study | + | ! style="width: 20%" |Study |
| − | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 20%"|Comparator | + | ! style="width: 20%" |Comparator |
| − | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
| − | !style="width: 20%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] | + | ! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] |
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)] | ||
| − | |style="background-color:#1a9851"|Phase III (C) | + | | style="background-color:#1a9851" |Phase III (C) |
|[[#Dexamethasone_monotherapy|Dexamethasone]] | |[[#Dexamethasone_monotherapy|Dexamethasone]] | ||
| | | | ||
| Line 158: | Line 177: | ||
|} | |} | ||
====Radiotherapy==== | ====Radiotherapy==== | ||
| + | |||
*[[External beam radiotherapy|WBRT]], 20 Gy in 5 fractions | *[[External beam radiotherapy|WBRT]], 20 Gy in 5 fractions | ||
====Supportive medications==== | ====Supportive medications==== | ||
| + | |||
*[[Dexamethasone (Decadron)]] | *[[Dexamethasone (Decadron)]] | ||
===References=== | ===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. [https://www.sciencedirect.com/science/article/pii/S014067361630825X link to SD article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27604504 PubMed] | + | |
| + | #'''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. [https://www.sciencedirect.com/science/article/pii/S014067361630825X link to SD article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27604504 PubMed] | ||
=Non-small cell lung cancer, ALK-mutated, all lines of therapy= | =Non-small cell lung cancer, ALK-mutated, all lines of therapy= | ||
| Line 174: | Line 196: | ||
===Variant #1, 300 mg twice per day {{#subobject:9cef11|Variant=1}}=== | ===Variant #1, 300 mg twice per day {{#subobject:9cef11|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltext Hida et al. 2017 (J-ALEX)] | |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltext Hida et al. 2017 (J-ALEX)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ic) | + | | style="background-color:#1a9851" |Phase III (E-switch-ic) |
|Crizotinib | |Crizotinib | ||
| − | |style="background-color:#1a9850"|Superior TTP (*) | + | | style="background-color:#1a9850" |Superior TTP (*) |
|- | |- | ||
|} | |} | ||
''This is the PMDA-approved dose in Japan. CNS efficacy is based on the 2018 update.'' | ''This is the PMDA-approved dose in Japan. CNS efficacy is based on the 2018 update.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Alectinib (Alecensa)]] 300 mg PO twice per day | *[[Alectinib (Alecensa)]] 300 mg PO twice per day | ||
| Line 193: | Line 216: | ||
===Variant #2, 600 mg twice per day {{#subobject:92a408|Variant=1}}=== | ===Variant #2, 600 mg twice per day {{#subobject:92a408|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1704795 Peters et al. 2017 (ALEX)] | |[https://www.nejm.org/doi/full/10.1056/NEJMoa1704795 Peters et al. 2017 (ALEX)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ic) | + | | style="background-color:#1a9851" |Phase III (E-switch-ic) |
|Crizotinib | |Crizotinib | ||
| − | |style="background-color:#1a9850"|Superior TTP (*) | + | | style="background-color:#1a9850" |Superior TTP (*) |
|- | |- | ||
|} | |} | ||
''CNS efficacy is based on the 2018 update.'' | ''CNS efficacy is based on the 2018 update.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Alectinib (Alecensa)]] 600 mg PO twice per day | *[[Alectinib (Alecensa)]] 600 mg PO twice per day | ||
| Line 211: | Line 235: | ||
===References=== | ===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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltext link to original article]'''contains protocol'''[https://www.ncbi.nlm.nih.gov/pubmed/28501140 PubMed] | + | |
| − | ## '''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. [https://www.sciencedirect.com/science/article/pii/S016950021830343X link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/29858024 PubMed] | + | #'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltext link to original article]'''contains protocol'''[https://www.ncbi.nlm.nih.gov/pubmed/28501140 PubMed] |
| − | # '''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1704795 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28586279 PubMed] | + | ##'''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. [https://www.sciencedirect.com/science/article/pii/S016950021830343X link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/29858024 PubMed] |
| − | ## '''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. [https://academic.oup.com/annonc/article/29/11/2214/5095692 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30215676 PubMed] | + | #'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1704795 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28586279 PubMed] |
| + | ##'''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. [https://academic.oup.com/annonc/article/29/11/2214/5095692 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30215676 PubMed] | ||
==Ceritinib monotherapy {{#subobject:d35518|Regimen=1}}== | ==Ceritinib monotherapy {{#subobject:d35518|Regimen=1}}== | ||
| Line 223: | Line 248: | ||
===Regimen {{#subobject:a93389|Variant=1}}=== | ===Regimen {{#subobject:a93389|Variant=1}}=== | ||
{| class="wikitable" style="width: 50%; text-align:center;" | {| class="wikitable" style="width: 50%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079055/ Shaw et al. 2014 (ASCEND-1)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079055/ Shaw et al. 2014 (ASCEND-1)] | ||
| Line 232: | Line 257: | ||
''Note: CNS efficacy is based on the 2016 update.'' | ''Note: CNS efficacy is based on the 2016 update.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Ceritinib (Zykadia)]] 750 mg PO once per day on an empty stomach | *[[Ceritinib (Zykadia)]] 750 mg PO once per day on an empty stomach | ||
| Line 237: | Line 263: | ||
===References=== | ===References=== | ||
| − | # '''Phase I:''' 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1311107 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079055/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24670165 PubMed] | + | |
| − | ## '''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00614-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063047/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26973324 PubMed] | + | #'''Phase I:''' 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1311107 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079055/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24670165 PubMed] |
| + | ##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00614-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063047/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26973324 PubMed] | ||
=Non-small cell lung cancer, EGFR-mutated, all lines of therapy= | =Non-small cell lung cancer, EGFR-mutated, all lines of therapy= | ||
| Line 248: | Line 275: | ||
===Regimen {{#subobject:130d4a|Variant=1}}=== | ===Regimen {{#subobject:130d4a|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[http://jco.ascopubs.org/content/31/27/3327.long Sequist et al. 2013 (LUX-Lung 3)] | |[http://jco.ascopubs.org/content/31/27/3327.long Sequist et al. 2013 (LUX-Lung 3)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ooc) | + | | style="background-color:#1a9851" |Phase III (E-switch-ooc) |
|[[Non-small_cell_lung_cancer#Cisplatin_.26_Pemetrexed_2|Cisplatin & Pemetrexed]] | |[[Non-small_cell_lung_cancer#Cisplatin_.26_Pemetrexed_2|Cisplatin & Pemetrexed]] | ||
| style="background-color:#91cf60" |Seems to have superior PFS (*) | | style="background-color:#91cf60" |Seems to have superior PFS (*) | ||
|- | |- | ||
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70604-1/fulltext Wu et al. 2014 (LUX-Lung 6)] | |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70604-1/fulltext Wu et al. 2014 (LUX-Lung 6)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ooc) | + | | style="background-color:#1a9851" |Phase III (E-switch-ooc) |
|[[Non-small cell lung cancer#Cisplatin_.26_Gemcitabine_2|Cisplatin & Gemcitabine]] | |[[Non-small cell lung cancer#Cisplatin_.26_Gemcitabine_2|Cisplatin & Gemcitabine]] | ||
| style="background-color:#91cf60" |Seems to have superior PFS (*) | | style="background-color:#91cf60" |Seems to have superior PFS (*) | ||
| Line 266: | Line 293: | ||
''Note: CNS-specific efficacy is based on the 2016 subgroup analysis.'' | ''Note: CNS-specific efficacy is based on the 2016 subgroup analysis.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Afatinib (Gilotrif)]] 40 mg PO once per day, given 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib") | *[[Afatinib (Gilotrif)]] 40 mg PO once per day, given 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib") | ||
**In '''LUX-Lung 3''', patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event. | **In '''LUX-Lung 3''', patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event. | ||
| Line 272: | Line 300: | ||
===References=== | ===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. [http://jco.ascopubs.org/content/31/27/3327.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23816960 PubMed] | + | |
| − | ## '''Subgroup 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. [http://jco.ascopubs.org/content/31/27/3342.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23816967 PubMed] | + | #'''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. [http://jco.ascopubs.org/content/31/27/3327.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23816960 PubMed] |
| − | ## '''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71173-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25589191 PubMed] | + | ##'''Subgroup 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. [http://jco.ascopubs.org/content/31/27/3342.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23816967 PubMed] |
| − | ## '''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. [http://www.jto.org/article/S1556-0864(15)00220-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26823294 PubMed] | + | ##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71173-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25589191 PubMed] |
| − | # '''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70604-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24439929 PubMed] | + | ##'''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. [http://www.jto.org/article/S1556-0864(15)00220-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26823294 PubMed] |
| − | ## '''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71173-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25589191 PubMed] | + | #'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70604-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24439929 PubMed] |
| − | ## '''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. [http://www.jto.org/article/S1556-0864(15)00220-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26823294 PubMed] | + | ##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71173-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25589191 PubMed] |
| + | ##'''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. [http://www.jto.org/article/S1556-0864(15)00220-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26823294 PubMed] | ||
==Icotinib monotherapy {{#subobject:9720a1|Regimen=1}}== | ==Icotinib monotherapy {{#subobject:9720a1|Regimen=1}}== | ||
| Line 287: | Line 316: | ||
===Regimen {{#subobject:d7253b|Variant=1}}=== | ===Regimen {{#subobject:d7253b|Variant=1}}=== | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30262-X/fulltext Yang et al. 2017 (BRAIN)] | |[https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30262-X/fulltext Yang et al. 2017 (BRAIN)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ooc) | + | | style="background-color:#1a9851" |Phase III (E-switch-ooc) |
|WB-XRT | |WB-XRT | ||
| style="background-color:#91cf60" |Seems to have superior intracranial PFS | | style="background-color:#91cf60" |Seems to have superior intracranial PFS | ||
| Line 300: | Line 329: | ||
''Note: this drug is only approved in China.'' | ''Note: this drug is only approved in China.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Icotinib (Conmana)]] 125 mg PO three times per day | *[[Icotinib (Conmana)]] 125 mg PO three times per day | ||
| Line 305: | Line 335: | ||
===References=== | ===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. [https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30262-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28734822 PubMed] | + | |
| + | #'''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. [https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30262-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28734822 PubMed] | ||
==Osimertinib monotherapy {{#subobject:PYR2|Regimen=1}}== | ==Osimertinib monotherapy {{#subobject:PYR2|Regimen=1}}== | ||
| Line 318: | Line 349: | ||
|} | |} | ||
{| class="wikitable" style="width: 100%; text-align:center;" | {| class="wikitable" style="width: 100%; text-align:center;" | ||
| − | !style="width: 25%"|Study | + | ! style="width: 25%" |Study |
| − | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]] |
| − | !style="width: 25%"|Comparator | + | ! style="width: 25%" |Comparator |
| − | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | + | ! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1612674 Mok et al. 2016 (AURA3)] | |[https://www.nejm.org/doi/full/10.1056/NEJMoa1612674 Mok et al. 2016 (AURA3)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ooc) | + | | style="background-color:#1a9851" |Phase III (E-switch-ooc) |
|1. [[Non-small cell lung cancer#Carboplatin_.26_Pemetrexed_2|Carboplatin & Pemetrexed]]<br> 2. [[Non-small cell lung cancer#Cisplatin_.26_Pemetrexed_3|Cisplatin & Pemetrexed]] | |1. [[Non-small cell lung cancer#Carboplatin_.26_Pemetrexed_2|Carboplatin & Pemetrexed]]<br> 2. [[Non-small cell lung cancer#Cisplatin_.26_Pemetrexed_3|Cisplatin & Pemetrexed]] | ||
| style="background-color:#91cf60" |Seems to have superior ORR (*) | | style="background-color:#91cf60" |Seems to have superior ORR (*) | ||
| Line 334: | Line 365: | ||
|- | |- | ||
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713137 Soria et al. 2017 (FLAURA)] | |[https://www.nejm.org/doi/full/10.1056/NEJMoa1713137 Soria et al. 2017 (FLAURA)] | ||
| − | |style="background-color:#1a9851"|Phase III (E-switch-ic) | + | | style="background-color:#1a9851" |Phase III (E-switch-ic) |
|1. [[Non-small cell lung cancer#Erlotinib_monotherapy|Erlotinib]]<br> 2. [[Non-small cell lung cancer#Gefitinib_monotherapy|Gefitinib]] | |1. [[Non-small cell lung cancer#Erlotinib_monotherapy|Erlotinib]]<br> 2. [[Non-small cell lung cancer#Gefitinib_monotherapy|Gefitinib]] | ||
| style="background-color:#91cf60" |Seems to have superior PFS (*) | | style="background-color:#91cf60" |Seems to have superior PFS (*) | ||
| Line 341: | Line 372: | ||
''Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation. Efficacy reported for AURA3 is based on the 2018 subgroup analysis. Efficacy reported for FLAURA is based on the 2018 subgroup analysis.'' | ''Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation. Efficacy reported for AURA3 is based on the 2018 subgroup analysis. Efficacy reported for FLAURA is based on the 2018 subgroup analysis.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
| + | |||
*[[Osimertinib (Tagrisso)]] 80 mg PO once per day | *[[Osimertinib (Tagrisso)]] 80 mg PO once per day | ||
| Line 346: | Line 378: | ||
===References=== | ===References=== | ||
| − | # '''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1612674 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27959700 PubMed] | + | |
| − | ## '''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. [https://ascopubs.org/doi/full/10.1200/JCO.2018.77.9363 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30059262 PubMed] | + | #'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1612674 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27959700 PubMed] |
| − | # '''Pooled 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. [https://academic.oup.com/annonc/article-abstract/29/3/687/4774219 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29293889 PubMed] | + | ##'''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. [https://ascopubs.org/doi/full/10.1200/JCO.2018.77.9363 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30059262 PubMed] |
| − | # '''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713137 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29151359 PubMed] | + | #'''Pooled 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. [https://academic.oup.com/annonc/article-abstract/29/3/687/4774219 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29293889 PubMed] |
| − | ## '''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. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.3118 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30153097 PubMed] | + | #'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713137 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29151359 PubMed] |
| + | ##'''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. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.3118 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30153097 PubMed] | ||
[[Category:CNS carcinoma regimens]] | [[Category:CNS carcinoma regimens]] | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
[[Category:CNS cancers]] | [[Category:CNS cancers]] | ||
Revision as of 23:48, 8 January 2020
| Section editor | |
|---|---|
 |
Seema Nagpal, MD Stanford University Palo Alto, CA |
1 regimens on this page
1 variants on this page
|
Guidelines
ASCO
- 2018: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update PubMed
Older
- 2014: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline PubMed
EANO/ESMO
- 2017: Le Rhun et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours
NCCN
Unselected all lines of therapy
Whole brain irradiation
| back to top |
WBRT: Whole-Brain Radiation Therapy
Regimen
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Knisely et al. 2007 (RTOG 0118) | Phase III (C) | Thalidomide & WBRT | Did not meet primary endpoint of OS |
Radiotherapy
- Whole-brain irradiation 2.50-Gy fractions x 15 (total dose: 37.5 Gy)
One course
References
- RTOG 0118: Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ Jr, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):79-86. Epub 2007 Dec 31. link to original article contains protocol PubMed
Breast cancer, HER2-positive, all lines of therapy
Capecitabine & Lapatinib
| back to top |
Regimen
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Pivot et al. 2015 (CEREBEL) | Phase III (E-switch-ic) | Capecitabine & Trastuzumab | Did not meet primary endpoint of CNS metastases as first site of relapse |
Biomarkers
- Gene HER2 Positive
- Alterations Method score > 2.2 by fluorescence in situ hybridization and/or 3+ amplification by immunohistochemistry or chromogenic/silver in situ hybridization)
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Lapatinib (Tykerb) 1250 mg PO once per day
21-day cycles
References
- CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article PubMed
Capecitabine & Trastuzumab
| back to top |
XH: Xeloda (Capecitabine) & Herceptin
Regimen
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Pivot et al. 2015 (CEREBEL) | Phase III (C) | Capecitabine & Lapatanib | Did not meet primary endpoint of CNS metastases as first site of relapse |
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
- Trastuzumab (Herceptin) as follows:
- Cycle 1: 8 mg/kg IV once on day 1
- Cycle 2 onwards: 6 mg/kg IV once on day 1
21-day cycles
References
- CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article contains protocol PubMed
Non-small cell lung cancer, all lines of therapy
Dexamethasone monotherapy
| back to top |
Regimen
| Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
|---|---|---|---|---|
| Mulvenna et al. 2016 (QUARTZ) | Phase III (E-de-esc) | Dexamethasone & WBRT | Inconclusive whether non-inferior QALYs |
Supportive therapy
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 SD article link to PMC article PubMed
Dexamethasone & WBRT
| back to top |
Regimen
| Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
|---|---|---|---|---|
| Mulvenna et al. 2016 (QUARTZ) | Phase III (C) | Dexamethasone | Inconclusive whether non-inferior QALYs |
Radiotherapy
- WBRT, 20 Gy in 5 fractions
Supportive medications
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 SD article link to PMC article PubMed
Non-small cell lung cancer, ALK-mutated, all lines of therapy
Alectinib monotherapy
| back to top |
Variant #1, 300 mg twice per day
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Hida et al. 2017 (J-ALEX) | Phase III (E-switch-ic) | Crizotinib | Superior TTP (*) |
This is the PMDA-approved dose in Japan. CNS efficacy is based on the 2018 update.
Chemotherapy
- Alectinib (Alecensa) 300 mg PO twice per day
Continued indefinitely
Variant #2, 600 mg twice per day
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Peters et al. 2017 (ALEX) | Phase III (E-switch-ic) | Crizotinib | Superior TTP (*) |
CNS efficacy is based on the 2018 update.
Chemotherapy
- 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 articlecontains protocolPubMed
- 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 SD article PubMed
- 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 contains verified protocol PubMed
- 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 PubMed
Ceritinib monotherapy
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Regimen
| Study | Evidence |
|---|---|
| Shaw et al. 2014 (ASCEND-1) | Phase I, >20 pts in this dosing cohort |
Note: CNS efficacy is based on the 2016 update.
Chemotherapy
- Ceritinib (Zykadia) 750 mg PO once per day on an empty stomach
21-day cycles
References
- Phase I: 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 contains verified protocol link to PMC article PubMed
- 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 PubMed
Non-small cell lung cancer, EGFR-mutated, all lines of therapy
Afatinib monotherapy
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Regimen
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Sequist et al. 2013 (LUX-Lung 3) | Phase III (E-switch-ooc) | Cisplatin & Pemetrexed | Seems to have superior PFS (*) |
| Wu et al. 2014 (LUX-Lung 6) | Phase III (E-switch-ooc) | Cisplatin & Gemcitabine | Seems to have superior PFS (*) |
Note: CNS-specific efficacy is based on the 2016 subgroup analysis.
Chemotherapy
- Afatinib (Gilotrif) 40 mg PO once per day, given 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")
- In LUX-Lung 3, patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.
Continued indefinitely
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 contains verified protocol PubMed
- Subgroup 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 contains verified protocol PubMed
- 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 PubMed
- 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 PubMed
- 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 contains verified protocol PubMed
- 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 PubMed
- 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 PubMed
Icotinib monotherapy
| back to top |
Regimen
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Yang et al. 2017 (BRAIN) | Phase III (E-switch-ooc) | WB-XRT | Seems to have superior intracranial PFS |
Note: this drug is only approved in China.
Chemotherapy
- 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 contains protocol PubMed
Osimertinib monotherapy
| back to top |
Regimen
| FDA-recommended dose |
| Study | Evidence | Comparator | Comparative Efficacy |
|---|---|---|---|
| Mok et al. 2016 (AURA3) | Phase III (E-switch-ooc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Seems to have superior ORR (*) |
| Goss et al. 2018 (AURA extension; AURA2) | Phase II | ||
| Soria et al. 2017 (FLAURA) | Phase III (E-switch-ic) | 1. Erlotinib 2. Gefitinib |
Seems to have superior PFS (*) |
Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation. Efficacy reported for AURA3 is based on the 2018 subgroup analysis. Efficacy reported for FLAURA is based on the 2018 subgroup analysis.
Chemotherapy
- Osimertinib (Tagrisso) 80 mg PO once per day
Continued indefinitely
References
- 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 contains verified protocol PubMed
- 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 PubMed
- Pooled 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 PubMed
- 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 contains verified protocol PubMed
- 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 PubMed