CNS carcinoma
Section editor | |
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Seema Nagpal, MD Stanford University Palo Alto, CA |
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Guidelines
ASCO
- 2022: Ramakrishna et al. Management of Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases
Older
- 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
- 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
- 2021: Le Rhun et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours
- 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
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WBRT: Whole-Brain Radiation Therapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Knisely et al. 2007 (RTOG 0118) | 2002-2004 | Phase 3 (C) | Thalidomide & WBRT | Did not meet primary endpoint of OS |
Radiotherapy
- Whole-brain irradiation 2.5 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 NCT00033254
Breast cancer, HER2-positive, all lines of therapy
Capecitabine & Lapatinib
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Pivot et al. 2015 (CEREBEL) | 2009-2012 | Phase 3 (E-switch-ic) | Capecitabine & Trastuzumab | Did not meet primary endpoint of CNS metastases as first site of relapse |
Biomarker eligibility criteria
- Gene: HER2 Positive
- Clinical Trial Eligibility: 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
Targeted therapy
- 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 NCT00820222
Capecitabine & Trastuzumab (XH)
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XH: Xeloda (Capecitabine) & Herceptin
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Pivot et al. 2015 (CEREBEL) | 2009-2012 | Phase 3 (C) | Capecitabine & Lapatanib | Did not meet primary endpoint of CNS metastases as first site of relapse |
Biomarker eligibility criteria
- Gene HER2 Positive
- Clinical Trial Eligibility: score > 2.2 by fluorescence in situ hybridization and/or 3+ amplification by immunohistochemistry or chromogenic/silver in situ hybridization
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- 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 NCT00820222
Capecitabine & Trastuzumab (XH) & Tucatinib
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Murthy et al. 2019 (HER2CLIMB) | 2016-2019 | Phase 3 (E-RT-esc) | XH | Superior OS Median OS: 21.9 vs 17.4 mo (HR 0.66, 95% CI 0.50-0.88) |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Tucatinib (Tukysa) 300 mg PO twice per day
- 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
- HER2CLIMB: Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. link to original article contains verified protocol PubMed NCT02614794
- Subgroup analysis: Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. link to original article link to PMC article PubMed
Non-small cell lung cancer, all lines of therapy
Cisplatin & Vinorelbine (CVb)
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CVb: Cisplatin & Vinorelbine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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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
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 contains protocol PubMed
Dexamethasone monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
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Mulvenna et al. 2016 (QUARTZ) | Phase 3 (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 original article link to PMC article PubMed
Dexamethasone & WBRT
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Regimen
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
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Mulvenna et al. 2016 (QUARTZ) | Phase 3 (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 original article link to PMC article PubMed
Teniposide & WBRT
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Postmus et al. 2000 | 1989-1995 | Phase 3 (E-esc) | Teniposide | Might have superior OS |
Chemotherapy
Radiotherapy
- WBRT, 30 Gy in 10 fractions
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 PubMed
Whole brain irradiation
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WBRT: Whole-Brain Radiation Therapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Yang et al. 2021 (ENTER) | 2013-NR in abstract | Phase 3 (C) | Erlotinib & WBRT | Did not meet primary endpoint of intracranial PFS |
Radiotherapy
One course
References
- 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 PubMed NCT01887795
Non-small cell lung cancer, ALK-mutated, all lines of therapy
Alectinib monotherapy
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Regimen variant #1, 300 mg twice per day
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Hida et al. 2017 (J-ALEX) | 2013-2015 | Phase 3 (E-switch-ic) | Crizotinib | Superior TTP1 |
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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Peters et al. 2017 (ALEX) | 2014-2016 | Phase 3 (E-switch-ic) | Crizotinib | Superior TTP1 |
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 articlecontains protocolPubMed 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 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 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 PubMed
Ceritinib monotherapy
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Regimen
Study | Evidence |
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Shaw et al. 2014 (ASCEND-1) | Phase I, >20 pts in this dosing cohort |
Note: CNS efficacy is based on the 2016 update.
Targeted therapy
- 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 | Years 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 superior PFS1 |
Wu et al. 2014 (LUX-Lung 6) | 2010-2011 | Phase 3 (E-switch-ooc) | Cisplatin & Gemcitabine | Seems to have superior PFS1 |
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, 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 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 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
- Pooled 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 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 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 PubMed
- Pooled 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 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
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Yang et al. 2017 (BRAIN) | 2012-2015 | Phase 3 (E-switch-ooc) | WBRT | Seems to have superior intracranial PFS |
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 contains protocol PubMed NCT01724801
Osimertinib monotherapy
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Regimen variant #1, 80 mg/day
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Goss et al. 2018 (AURA extension) | 2013-NR | Phase 2 | ||
Mok et al. 2016 (AURA3) | 2014-2015 | Phase 3 (E-switch-ooc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Seems to have superior ORR1 |
Soria et al. 2017 (FLAURA) | 2014-2016 | Phase 3 (E-switch-ic) | 1. Erlotinib 2. Gefitinib |
Seems to have superior PFS2 |
Goss et al. 2018 (AURA2) | 2014-NR | Phase 2 | ||
Yamaguchi et al. 2021 (WJOG9116L) | 2016-2019 | Phase 2 |
1Reported efficacy reported for AURA3 is based on the 2018 subgroup analysis.
2Reported 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.
Biomarker eligibility criteria
Targeted therapy
- Osimertinib (Tagrisso) 80 mg PO once per day
Continued indefinitely
Regimen variant #2, 160 mg/day
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Yang et al. 2019 (BLOOM) | 2015-2017 | Phase I, >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
Targeted therapy
- Osimertinib (Tagrisso) 160 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 NCT02151981
- 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
- AURA extension; AURA2: 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 NCT01802632; NCT02094261
- 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 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 PubMed
- 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 PubMed NCT02228369
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