Non-small cell lung cancer, EGFR-mutated - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. Is there a regimen missing from this list? See the EGFRm NSCLC page for current regimens.
Last updated on 2024-12-02:12 regimens on this page
19 variants on this page
=Adjuvant therapy=
==Cisplatin & Vinorelbine (CVb)==
CVb: Cisplatin & Vinorelbine
===Regimen variant #1, 75/25===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zhong et al. 2017 (ADJUVANT/CTONG1104)	2011-2014 	Phase 3 (C)	Gefinitib 	Shorter DFSMedian DFS: 18 vs 28.7 mo(HR 1.67, 95% CI 1.15-2.38)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or EGFR p.L858R
====Preceding treatment====
*Complete surgical resection, within 6 to 12 weeks
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
===Regimen variant #2, 80/25===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tada et al. 2021 (IMPACTNSCLC)	2011-2015 	Phase 3 (C)	Gefinitib 	Did not meet primary endpoint of DFS
Note: this trial should not be confused by those with the same name in prostate cancer and colon cancer.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or EGFR p.L858R
====Preceding treatment====
*Complete surgical resection, within 3 to 8 weeks
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
===References===
#ADJUVANT/CTONG1104: Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, Wang J, Fei K, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yan HH, Yang XN, Zhou Q, Wu YL; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. Epub 2017 Nov 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01405079
##Update: Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Wei YC, Liu YY, Chen C, Cheng Y, Yin R, Yang F, Ren SX, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yang JJ, Yan HH, Yang XN, Liu SY, Zhou Q, Wu YL. Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021 Mar 1;39(7):713-722. Epub 2020 Dec 17. link to original article link to PMC article EuroPMC
#IMPACTNSCLC: Tada H, Mitsudomi T, Misumi T, Sugio K, Tsuboi M, Okamoto I, Iwamoto Y, Sakakura N, Sugawara S, Atagi S, Takahashi T, Hayashi H, Okada M, Inokawa H, Yoshioka H, Takahashi K, Higashiyama M, Yoshino I, Nakagawa K; West Japan Oncology Group. Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT). J Clin Oncol. 2022 Jan 20;40(3):231-241. Epub 2021 Nov 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000006252
=Advanced or metastatic disease, platinum-exposed=
==Mobocertinib monotherapy==
===Regimen===
{| class="wikitable" style="color:white; background-color:#404040"
|FDA-recommended dose
|-
Study 	Dates of enrollment	Evidence
Riely et al. 2021 (AP32788-15-101)	2016-2020 	Phase 1/2 (RT)
Note: this was the dose used in the phase 2 portion.
====Biomarker eligibility criteria====
*EGFR exon 20 insertion mutations
====Targeted therapy====
*Mobocertinib (Exkivity) 160 mg PO once per day on days 1 to 28
28-day cycles
===References===
#AP32788-15-101: Riely GJ, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Costa DB, Tsao AS, Patel JD, Gadgeel SM, Bazhenova L, Zhu VW, West HL, Mekhail T, Gentzler RD, Nguyen D, Vincent S, Zhang S, Lin J, Bunn V, Jin S, Li S, Jänne PA. Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial. Cancer Discov. 2021 Jul;11(7):1688-1699. Epub 2021 Feb 25. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02716116
##Update: Zhou C, Ramalingam SS, Kim TM, Kim SW, Yang JC, Riely GJ, Mekhail T, Nguyen D, Garcia Campelo MR, Felip E, Vincent S, Jin S, Griffin C, Bunn V, Lin J, Lin HM, Mehta M, Jänne PA. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol. 2021 Dec 1;7(12):e214761. Epub 2021 Dec 16. Erratum in: JAMA Oncol. 2022 Feb 24. link to original article link to PMC article EuroPMC
=Advanced or metastatic disease, EGFR inhibitor-naive=
==Carboplatin & Docetaxel (DCb)==
DCb: Docetaxel & Carboplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011 	Phase 3 (C)	Erlotinib 	Shorter PFSMedian PFS: 5.2 vs 9.7 mo(HR 2.70, 95% CI 1.85-4.00)
====Biomarker eligibility criteria====
*Biomarker: EGFR activating mutation with exon 19 deletion or p.L858R mutation in exon 21
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
===References===
#EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00446225
==Carboplatin & Gemcitabine (GCb)==
GC: Gemcitabine & Carboplatin
GCa: Gemcitabine & Carboplatin
GCb: Gemcitabine & Carboplatin
===Regimen variant #1, 5/1000===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC) 	2007-2011 	Phase 3 (C)	Erlotinib 	Shorter PFSMedian PFS: 5.2 vs 9.7 mo(HR 2.70, 95% CI 1.85-4.00)
Zhou et al. 2011 (CTONG-0802)	2008-08-24 to 2009-07-17	Phase 3 (C)	Erlotinib 	Shorter PFSMedian PFS: 4.6 vs 13.1 mo(HR 6.25, 95% CI 3.85-10.00)
====Biomarker eligibility criteria====
*Biomarker: EGFR activating mutation with exon 19 deletion or p.L858R mutation in exon 21
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 4 cycles
===Regimen variant #2, 5/1250===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	2009-04-29 to 2010-09-09	Phase 3 (C)	1a. Carboplatin & Gemcitabine/Erlotinib1b. GC/Erlotinib	Shorter PFSMedian PFS: 6 vs 7.6 mo(HR 1.75, 95% CI 1.45-2.13)Seems to have shorter OSMedian OS: 15.2 vs 18.3 mo(HR 1.27, 95% CI 1.01-1.56)
Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm. 
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
===References===
#CTONG-0802: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. Epub 2011 Jul 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00874419
##Update: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00446225
#FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00883779
==Carboplatin & Paclitaxel (CP)==
CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
TC: Taxol (Paclitaxel) & Carboplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Maemondo et al. 2010 (NEJ002)	2006-2009 	Phase 3 (C)	Gefitinib 	Shorter PFSMedian PFS: 5.4 vs 10.8 mo(HR 3.33, 95% CI 2.44-4.55)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for at least 3 cycles
===References===
#NEJ002: Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000000376
##HRQoL analysis: Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, Isobe H, Harada M, Kinoshita I, Okinaga S, Kato T, Harada T, Gemma A, Saijo Y, Yokomizo Y, Morita S, Hagiwara K, Nukiwa T. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Oncologist. 2012;17(6):863-70. Epub 2012 May 11. link to original article link to PMC article EuroPMC
##Update: Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013 Jan;24(1):54-9. Epub 2012 Sep 11. link to original article EuroPMC
==Carboplatin & Pemetrexed==
===Regimen variant #1, 4 cycles of carboplatin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2023 (PAPILLON)	2020-12 to 2022-11 	Phase 3 (C)	Carboplatin, Pemetrexed, Amivantamab	Shorter PFSMedian PFS: 6.7 vs 11.4 mo(HR 2.50, 95% CI 1.89-3.33)
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*EGFR exon 20 insertions
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 6 cycles of carboplatin===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Patil et al. 2017	2012-2016 	Phase 3 (C)	Gefitinib 	Shorter PFSMedian PFS: 5.6 vs 8.4 mo(HR 1.52, 95% CI 1.18-1.96)
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*Activating EGFR mutation in exons 18, 19, or 21
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 5 IV over 30 minutes once on day 1, given second
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
21-day cycles
===References===
#Patil VM, Noronha V, Joshi A, Choughule AB, Bhattacharjee A, Kumar R, Goud S, More S, Ramaswamy A, Karpe A, Pande N, Chandrasekharan A, Goel A, Talreja V, Mahajan A, Janu A, Purandare N, Prabhash K. Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open. 2017 Apr 27;2(1):e000168. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
#PAPILLON: Zhou C, Tang KJ, Cho BC, Liu B, Paz-Ares L, Cheng S, Kitazono S, Thiagarajan M, Goldman JW, Sabari JK, Sanborn RE, Mansfield AS, Hung JY, Boyer M, Popat S, Mourão Dias J, Felip E, Majem M, Gumus M, Kim SW, Ono A, Xie J, Bhattacharya A, Agrawal T, Shreeve SM, Knoblauch RE, Park K, Girard N; PAPILLON Investigators. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023 Nov 30;389(22):2039-2051. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04538664
==Cisplatin & Docetaxel (DC)==
DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin
===Regimen variant #1, 75/75===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011 	Phase 3 (C)	Erlotinib 	Shorter PFSMedian PFS: 5.2 vs 9.7 mo(HR 2.70, 95% CI 1.85-4.00)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R mutation
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
===Regimen variant #2, 80/60===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Mitsudomi et al. 2009 (WJTOG3405)	2006-2009 	Phase 3 (C)	Gefitinib 	Shorter PFSMedian PFS: 6.3 vs 9.2 mo(HR 2.04, 95% CI 1.41-2.94)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R mutation
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 90 minutes once on day 1, given second
*Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1, given first
21-day cycle for 3 to 6 cycles
===References===
#WJTOG3405: Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Thoracic Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121-8. Epub 2009 Dec 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000000539
##Update: Yoshioka H, Shimokawa M, Seto T, Morita S, Yatabe Y, Okamoto I, Tsurutani J, Satouchi M, Hirashima T, Atagi S, Shibata K, Saito H, Toyooka S, Yamamoto N, Nakagawa K, Mitsudomi T. Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. Ann Oncol. 2019 Dec 1;30(12):1978-1984. link to original article EuroPMC
#EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00446225
==Cisplatin & Gemcitabine (GC)==
GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)
===Regimen variant #1, 75/1000===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Wu et al. 2014 (LUX-Lung 6)	2010-04-27 to 2011-11-16	Phase 3 (C)	Afatinib 	Shorter PFS
====Biomarker eligibility criteria====
*EGFR mutation-positive
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
===Regimen variant #2, 75/1250 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011 	Phase 3 (C)	Erlotinib 	Shorter PFSMedian PFS: 5.2 vs 9.7 mo(HR 2.70, 95% CI 1.85-4.00)
Wu et al. 2015 (ENSURE) 	2011-03 to 2012-06 	Phase 3 (C)	Erlotinib 	Shorter PFS
====Biomarker eligibility criteria====
*EURTAC: EGFR exon 19 deletion or p.L858R mutation in exon 21
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 30 minutes once on day 1
*Gemcitabine (Gemzar) 1250 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycle for up to 4 cycles
===Regimen variant #3, 75/1250 q4wk===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	2009-04-29 to 2010-09-09	Phase 3 (C)	1a. Carboplatin & Gemcitabine/Erlotinib1b. GC/Erlotinib	Shorter PFSMedian PFS: 6 vs 7.6 mo(HR 1.75, 95% CI 1.45-2.13)Seems to have shorter OSMedian OS: 15.2 vs 18.3 mo(HR 1.27, 95% CI 1.01-1.56)
Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm. 
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
===References===
#EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00446225
#FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00883779
#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. Epub 2014 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01121393
##Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. Epub 2015 Jan 12. link to original article EuroPMC
##Pooled subgroup analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article EuroPMC
##Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. Epub 2016 Jan 25. link to original article EuroPMC
#ENSURE: Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, Huang C, Qin S, Zhu Y, Pan H, Liang H, Li E, Jiang G, How SH, Fernando MC, Zhang Y, Xia F, Zuo Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015 Sep;26(9):1883-9. Epub 2015 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01342965
==Cisplatin & Pemetrexed==
Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed
===Regimen variant #1, limited duration===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sequist et al. 2013 (LUX-Lung 3)	2009-2011 	Phase 3 (C)	Afatinib 	Shorter PFS
====Biomarker eligibility criteria====
*Activating mutations in EGFR
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given second
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
====Supportive therapy====
*(as described in JMDB):
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
*Folic acid (Folate) 1 mg PO once per day
*In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for pemetrexed."
21-day cycle for 4 to 6 cycles
===Regimen variant #2, with maintenance===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shi et al. 2017 (CONVINCE)	2013-01 to 2014-08 	Phase 3 (C)	Icotinib 	Shorter PFS
====Biomarker eligibility criteria====
*EGFR exon 19/21 mutations
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Supportive therapy====
*(as described in JMDB):
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
*Folic acid (Folate) 1 mg PO once per day
*In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for pemetrexed."
21-day cycles
===References===
#LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00949650
##HRQoL analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. Epub 2015 Jan 12. link to original article EuroPMC
##Pooled subgroup analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article EuroPMC
##Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. Epub 2016 Jan 25. link to original article EuroPMC
#CONVINCE: Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01719536
=Advanced or metastatic disease, EGFR p.T790M mutation=
==Carboplatin & Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mok et al. 2016 (AURA3)	2014-08 to 2015-09 	Phase 3 (C)	Osimertinib	Shorter PFSMedian PFS: 4.4 vs 10.1 mo(HR 3.33, 95% CI 2.44-4.35)Did not meet secondary endpoint of OS1Median OS: 22.5 vs 26.8 mo(HR 1.15, 95% CI 0.89-1.49)
1Reported OS efficacy is based on the 2020 update.
====Prior treatment criteria====
*Progression after first-line EGFR TKI therapy
====Biomarker eligibility criteria====
*EGFR p.T790M mutation
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
====Supportive therapy====
*(Ardizzoni et al. 2012 contained more details):
*Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
*Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
*Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for 4 to 6 cycles
====Subsequent treatment====
*Optional pemetrexed maintenance
===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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02151981
##PRO analysis: Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-Reported Symptoms and Impact of Treatment With Osimertinib Versus Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The AURA3 Trial. J Clin Oncol. 2018 Jun 20;36(18):1853-1860. Epub 2018 May 7. link to original article EuroPMC
##Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article EuroPMC
##Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Nov;31(11):1536-1544. Epub 2020 Aug 27. link to original article EuroPMC
==Cisplatin & Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mok et al. 2016 (AURA3)	2014-08 to 2015-09 	Phase 3 (C)	Osimertinib	Shorter PFSMedian PFS: 4.4 vs 10.1 mo(HR 3.33, 95% CI 2.44-4.35)Did not meet secondary endpoint of OS1Median OS: 22.5 vs 26.8 mo(HR 1.15, 95% CI 0.89-1.49)
1Reported OS efficacy is based on the 2020 update.
====Prior treatment criteria====
*Progression after first-line EGFR TKI therapy
====Biomarker eligibility criteria====
*EGFR p.T790M mutation
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Supportive therapy====
*(as described in Scagliotti et al. 2008):
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
*Folic acid (Folate) 1 mg PO once per day
*In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for pemetrexed."
21-day cycle for 4 to 6 cycles
====Subsequent treatment====
*AURA3, patients without disease progression after 4 cycles: Optional pemetrexed maintenance
===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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02151981
##PRO analysis: Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-Reported Symptoms and Impact of Treatment With Osimertinib Versus Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The AURA3 Trial. J Clin Oncol. 2018 Jun 20;36(18):1853-1860. Epub 2018 May 7. link to original article EuroPMC
##Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article EuroPMC
##Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Nov;31(11):1536-1544. Epub 2020 Aug 27. link to original article EuroPMC
==Docetaxel & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Nie et al. 2018 (QingdaoCH20161101)	2015-04 to 2016-05 	Phase 3 (C)	Osimertinib	Shorter PFS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*EGFR p.T790M mutation
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===References===
#QingdaoCH20161101: Nie K, Zhang Z, Zhang C, Geng C, Zhang L, Xu X, Liu S, Wang S, Zhuang X, Lan K, Ji Y. Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:5-11. Epub 2018 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02959749
Category:Non-small cell lung cancer regimens
Category:Historical regimens
Category:Biomarker-specific pages
Category:Lung cancers