Non-small cell lung cancer, EGFR-mutated

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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.
There are several related dedicated pages:
*Histology-specific:
**NSCLC, Nonsquamous
**NSCLC, Squamous
*Site-specific:
**NSCLC, CNS metastases
Last updated on 2024-12-02:38 regimens on this page
55 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ASCO==
*2023: Jaiyesimi et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2022.3 EuroPMC
**2022: Singh et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline EuroPMC
==ESMO==
*2024: Lee et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with oncogene-addicted metastatic non-small-cell lung cancer EuroPMC
*2023: Hendriks et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
*2022: Passaro et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer EuroPMC
==IASLC==
*2016: Tan et al. The International Association for the Study of Lung Cancer consensus statement on optimizing management of EGFR mutation–positive non–small cell lung cancer: Status in 2016 EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Non-Small Cell Lung Cancer.
=Neoadjuvant therapy=
==Carboplatin & Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (NeoADAURA)	2020-ongoing 	Phase 3 (C)	1a. Pem-Carbo & Osimertinib1b. Pem-Cis & Osimertinib2. Osimertinib	TBD if different primary endpoint of major pathological response
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgical resection
===References===
#NeoADAURA: NCT04351555
==Cisplatin & Pemetrexed==
Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (NeoADAURA)	2020-ongoing 	Phase 3 (C)	1a. Pem-Carbo & Osimertinib1b. Pem-Cis & Osimertinib2. Osimertinib	TBD if different primary endpoint of major pathological response
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgical resection
===References===
#NeoADAURA: NCT04351555
=Adjuvant therapy=
==Gefitinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhong et al. 2017 (ADJUVANT/CTONG1104)	2011-2014 	Phase 3 (E-switch-ooc)	Cisplatin & Vinorelbine	Longer DFS (primary endpoint)Median DFS: 28.7 vs 18 mo(HR 0.60, 95% CI 0.42-0.87)
====Biomarker eligibility criteria====
*Biomarker: EGFR exon 19 deletion and exon 21 L858R activating mutations
====Preceding treatment====
*Surgery
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day
24-month course
===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
==Icotinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
He et al. 2021 (EVIDENCE)	2015-06-08 to 2019-08-02	Phase 3 (E-switch-ooc)	1a. Cisplatin & Pemetrexed1b. Cisplatin & Vinorelbine	Longer DFS (primary endpoint)Median DFS: 47 vs 22.1 mo(HR 0.36, 95% CI 0.24-0.55)
Note: this drug is only approved in China; eligible patients had stage IIIB/IV lung adenocarcinoma.
====Biomarker eligibility criteria====
*EGFR exon 19 or 21 mutations
====Preceding treatment====
*Complete resection, within 8 weeks
====Targeted therapy====
*Icotinib (Conmana) 125 mg PO three times per day
28-day cycle for 26 cycles (2 years)
===References===
#EVIDENCE: He J, Su C, Liang W, Xu S, Wu L, Fu X, Zhang X, Ge D, Chen Q, Mao W, Xu L, Chen C, Hu B, Shao G, Hu J, Zhao J, Liu X, Liu Z, Wang Z, Xiao Z, Gong T, Lin W, Li X, Ye F, Liu Y, Ma H, Huang Y, Zhou J, Wang Z, Fu J, Ding L, Mao L, Zhou C. Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial. Lancet Respir Med. 2021 Sep;9(9):1021-1029. Epub 2021 Jul 21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02448797
==Osimertinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wu et al. 2020 (ADAURA)	2015-11 to 2019-02 	Phase 3 (E-RT-esc)	Placebo 	Longer DFS1 (primary endpoint)DFS48: 73% vs 38%(HR 0.27, 95% CI 0.21-0.34)Longer OS2 (secondary endpoint)OS60: 85% vs 73%(HR 0.49, 95.03% CI 0.33-0.73)
1Reported efficacy is based on the January 2023 update.
2Reported efficacy is based on the June 2023 update.
Note: "Most patients with stage II to IIIA disease (76%) and approximately a quarter of the patients with stage IB disease (26%) received adjuvant platinum-based chemotherapy" (prior to osimertinib)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R mutation, alone or in combination with other EGFR mutations
====Preceding treatment====
*Complete resection
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day
28-day cycle for 39 cycles (3 years)
===References===
#ADAURA: Wu YL, Tsuboi M, He J, John T, Grohe C, Majem M, Goldman JW, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Hodge R, Atasoy A, Rukazenkov Y, Herbst RS; ADAURA Investigators. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Oct 29;383(18):1711-1723. Epub 2020 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02511106
##HRQoL analysis: Majem M, Goldman JW, John T, Grohe C, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Li S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Atagi S, Zeng L, Kulkarni D, Medic N, Tsuboi M, Herbst RS, Wu YL. Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial. Clin Cancer Res. 2022 Jun;28(11):2286-2296. link to original article link to EuroPMC
##Update: Herbst RS, Wu YL, John T, Grohe C, Majem M, Wang J, Kato T, Goldman JW, Laktionov K, Kim SW, Yu CJ, Vu HV, Lu S, Lee KY, Mukhametshina G, Akewanlop C, de Marinis F, Bonanno L, Domine M, Shepherd FA, Urban D, Huang X, Bolanos A, Stachowiak M, Tsuboi M. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol. 2023 Apr 1;41(10):1830-1840. Epub 2023 Jan 31. link to original article link to PMC article EuroPMC
##Update: Tsuboi M, Herbst RS, John T, Kato T, Majem M, Grohé C, Wang J, Goldman JW, Lu S, Su WC, de Marinis F, Shepherd FA, Lee KH, Le NT, Dechaphunkul A, Kowalski D, Poole L, Bolanos A, Rukazenkov Y, Wu YL; ADAURA Investigators. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023 Jul 13;389(2):137-147. Epub 2023 Jun 4. link to original article EuroPMC
##HRQoL analysis: John T, Grohé C, Goldman JW, Shepherd FA, de Marinis F, Kato T, Wang Q, Su WC, Choi JH, Sriuranpong V, Melotti B, Fidler MJ, Chen J, Albayaty M, Stachowiak M, Taggart S, Wu YL, Tsuboi M, Herbst RS, Majem M. Three-Year Safety, Tolerability, and Health-Related Quality of Life Outcomes of Adjuvant Osimertinib in Patients With Resected Stage IB to IIIA EGFR-Mutated NSCLC: Updated Analysis From the Phase 3 ADAURA Trial. J Thorac Oncol. 2023 Sep;18(9):1209-1221. Epub 2023 May 24. link to original article EuroPMC
=Maintenance after definitive therapy for inoperable disease=
==Osimertinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lu et al. 2024 (LAURA)	2018-08 to 2022-07 	Phase 3 (E-RT-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 39.1 vs 5.6 mo(HR 0.16, 95% CI 0.10-0.24)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R mutation, alone or in combination with other EGFR mutations
====Preceding treatment====
*Platinum-based chemoradiotherapy induction
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day
Continued indefinitely
===References===
#LAURA: Lu S, Kato T, Dong X, Ahn MJ, Quang LV, Soparattanapaisarn N, Inoue T, Wang CL, Huang M, Yang JC, Cobo M, Özgüroğlu M, Casarini I, Khiem DV, Sriuranpong V, Cronemberger E, Takahashi T, Runglodvatana Y, Chen M, Huang X, Grainger E, Ghiorghiu D, van der Gronde T, Ramalingam SS; LAURA Trial Investigators. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med. 2024 Aug 15;391(7):585-597. Epub 2024 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03521154
##Update: Lu S, Ahn MJ, Reungwetwattana T, Özgüroğlu M, Kato T, Yang JC, Huang M, Fujiki F, Inoue T, Quang LV, Sriuranpong V, Vicente D, Fuentes C, Chaudhry AA, Poole L, Armenteros Monterroso E, Rukazenkov Y, van der Gronde T, Ramalingam SS. Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study. Ann Oncol. 2024 Dec;35(12):1116-1125. Epub 2024 Sep 16. link to original article EuroPMC
=Advanced or metastatic disease, platinum-exposed=
==Amivantamab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Park et al. 2021 (CHRYSALIS)	2016-2020 	Phase 1 (RT)
Note: Dosing details are from the FDA announcement.
====Biomarker eligibility criteria====
*EGFR exon 20 insertion
====Targeted therapy====
*Amivantamab (Rybrevant) by the following weight-based criteria:
**Less than 80 kg: 1050 mg IV once on day 1
**80 kg or more: 1400 mg IV once on day 1
7-day cycle for 4 cycles, then 14-day cycles
===References===
#CHRYSALIS: Park K, Haura EB, Leighl NB, Mitchell P, Shu CA, Girard N, Viteri S, Han JY, Kim SW, Lee CK, Sabari JK, Spira AI, Yang TY, Kim DW, Lee KH, Sanborn RE, Trigo J, Goto K, Lee JS, Yang JC, Govindan R, Bauml JM, Garrido P, Krebs MG, Reckamp KL, Xie J, Curtin JC, Haddish-Berhane N, Roshak A, Millington D, Lorenzini P, Thayu M, Knoblauch RE, Cho BC. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol. 2021 Oct 20;39(30):3391-3402. Epub 2021 Aug 2. link to original article link to PMC article EuroPMC NCT02609776
=Advanced or metastatic disease, EGFR inhibitor-naive=
==Afatinib monotherapy==
===Regimen variant #1, 30 mg/day===
FDA-recommended dose
Note: This is the FDA-recommended dose for patients with "severe renal impairment".
====Targeted therapy====
*Afatinib (Gilotrif) 30 mg PO once per day
Continued indefinitely
===Regimen variant #2, 40 mg/day===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2012 (LUX-Lung 2) 	2007-2009 	Phase 2 (RT) 	 	ORR: 61%
Sequist et al. 2013 (LUX-Lung 3)	2009-2011 	Phase 3 (E-RT-switch-ooc) 	Cisplatin & Pemetrexed 	Longer PFS (primary endpoint)Median PFS: 11.1 vs 6.9 mo(HR 0.58, 95% CI 0.43-0.78)
Wu et al. 2014 (LUX-Lung 6) 	2010-04-27 to 2011-11-16	Phase 3 (E-RT-switch-ooc) 	Cisplatin & Gemcitabine	Longer PFS (primary endpoint)Median PFS: 11 vs 5.6 mo(HR 0.28, 95% CI 0.20-0.39)
Park et al. 2016 (LUX-Lung 7) 	2011-2013 	Randomized Phase 2 (E-switch-ic)	Gefitinib 	Longer PFS (co-primary endpoint)Median PFS: 11 vs 10.9 mo(HR 0.73, 95% CI 0.57-0.95)
====Biomarker eligibility criteria====
*LUX-Lung 2: activating EGFR mutations within exons 18–21
*LUX-Lung 3 & LUX-Lung 6: Activating EGFR mutation with exon 19 deletions, L858R, insertions in exon 20, L861Q, G719S, G719A, G719C, T790M, or S768I
*LUX-Lung 7: Activating EGFR mutation with exon 19 deletion and/or L858R
====Targeted therapy====
*Afatinib (Gilotrif) 40 mg PO once per day, taken 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")
Continued indefinitely
====Dose and schedule modifications====
*In LUX-Lung 3 & LUX-Lung 7, 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.
===References===
#LUX-Lung 2: Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012 May;13(5):539-48. Epub 2012 Mar 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00525148
##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
#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
#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
#LUX-Lung 7: Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kölbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89. Epub 2016 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01466660
==Anlotinib & Gefitinib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zhou et al. 2024 (FL-ALTER)	2019-04 to 2021-08 	Phase 3 (E-esc)	Gefitinib 	Longer PFS (primary endpoint)Median PFS: 14.8 vs 11.2 mo(HR 0.64, 95% CI 0.48-0.80)
====Targeted therapy====
*Anlotinib (Fukewei) 12 mg PO once per day on days 1 to 14
*Gefitinib (Iressa) 250 mg PO once per day on days 1 to 14
21-day cycles
===References===
#FL-ALTER: Zhou HQ, Zhang YX, Chen G, Yu QT, Zhang H, Wu GW, Wu D, Lin YC, Zhu JF, Chen JH, Hu XH, Lan B, Zhou ZQ, Lin HF, Wang ZB, Lei XL, Pan SM, Chen LM, Zhang J, Kong TD, Yao JC, Zheng X, Li F, Zhang L, Fang WF. Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial. Signal Transduct Target Ther. 2024 Aug 13;9(1):215. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04028778
==Apatinib & Gefitinib==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zhao et al. 2021 (CTONG1706)	2017-08 to 2018-12 	Phase 3 (E-esc)	Gefitinib 	Longer PFS (primary endpoint)Median PFS: 13.7 vs 10.2 mo(HR 0.71, 95% CI 0.54-0.95)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or exon 21 L858R mutation
====Targeted therapy====
*Apatinib (Aitan) 500 mg PO once per day
*Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
===References===
#CTONG1706: Zhao H, Yao W, Min X, Gu K, Yu G, Zhang Z, Cui J, Miao L, Zhang L, Yuan X, Fang Y, Fu X, Hu C, Zhu X, Fan Y, Yu Q, Wu G, Jiang O, Du X, Liu J, Gu W, Hou Z, Wang Q, Zheng R, Zhou X, Zhang L. Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706). J Thorac Oncol. 2021 Sep;16(9):1533-1546. Epub 2021 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02824458
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==Aumolertinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Lu et al. 2022 (AENEAS)	2018-11-30 to 2019-09-06	Phase 3 (E-switch-ic)	Gefitinib 	Longer PFSMedian PFS: 19.3 vs 9.9 mo(HR 0.46, 95% CI 0.36-0.60)
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or L858R
====Targeted therapy====
*Aumolertinib (Amelie) 110 mg PO once per day
Continued indefinitely
===References===
#AENEAS: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Jie W, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Sun C, Wei H, Li C, Ali SM, Miller VA, Wu Q. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022 Sep 20;40(27):3162-3171. Epub 2022 May 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03849768
##Subgroup analysis: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Weng J, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Wei H, Wei J, Zhang Z, Wu Q. Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS). Cancer Commun (Lond). 2024 Sep;44(9):1005-1017. Epub 2024 Jul 17. link to original article link to PMC article EuroPMC
==Carboplatin & Gemcitabine/Erlotinib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	2009-04-29 to 2010-09-09	Phase 3 (E-esc)	1a. Carboplatin & Gemcitabine1b. Cisplatin & Gemcitabine	Longer PFS (primary endpoint)Median PFS: 7.6 vs 6 mo(HR 0.57, 95% CI 0.47-0.69)Seems to have longer OS (secondary endpoint)Median OS: 18.3 vs 15.2 mo(HR 0.79, 95% CI 0.64-0.99)
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
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 15 to 28
28-day cycle for 6 cycles
===References===
#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, Pemetrexed, Amivantamab==
===Regimen variant #1, lower-dose amivantamab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2023 (PAPILLON)	2020-12 to 2022-11 	Phase 3 (E-RT-esc)	Carboplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 11.4 vs 6.7 mo(HR 0.40, 95% CI 0.30-0.53)
Note: This amivantamab dosage was for patients weighing less than 80 kg.
====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
====Targeted therapy====
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8 & 15
**Cycle 2: 1400 mg IV once on day 1
**Cycle 3 onwards: 1750 mg IV once on day 1
21-day cycles
===Regimen variant #2, higher-dose amivantamab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2023 (PAPILLON)	2020-12 to 2022-11 	Phase 3 (E-RT-esc)	Carboplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 11.4 vs 6.7 mo(HR 0.40, 95% CI 0.30-0.53)
Note: This amivantamab dosage was for patients weighing 80 kg or more.
====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
====Targeted therapy====
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1400 mg IV once on day 2, then 1750 mg IV once per day on days 8 & 15
**Cycle 2: 1750 mg IV once on day 1
**Cycle 3 onwards: 2100 mg IV once on day 1
21-day cycles
===References===
#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
==Carboplatin, Osimertinib, Pemetrexed==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Planchard et al. 2023 (FLAURA2)	2020-06-01 to 2021-12-22	Phase 3 (E-RT-esc)	Osimertinib	Longer PFS (primary endpoint)PFS24: 57% vs 41%(HR 0.62, 95% CI 0.49-0.79)
====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
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day on days 1 to 21
21-day cycles
===References===
#FLAURA2: Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Epub 2023 Nov 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04035486
##Subgroup analysis: Jänne PA, Planchard D, Kobayashi K, Cheng Y, Lee CK, Valdiviezo N, Laktionov K, Yang TY, Yu Y, Kato T, Jiang L, Chewaskulyong B, Lucien Geater S, Maurel JM, Rojas C, Takahashi T, Havel L, Shepherd FA, Tanaka K, Ghiorghiu D, Amin NP, Armenteros-Monterroso E, Huang X, Chaudhry AA, Yang JC. CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2024 Mar 1;42(7):808-820. Epub 2023 Dec 2. link to original article link to PMC article EuroPMC
==Cisplatin & Gemcitabine/Erlotinib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	2009-04-29 to 2010-09-09	Phase 3 (E-esc)	1a. Carboplatin & Gemcitabine1b. Cisplatin & Gemcitabine	Longer PFS (primary endpoint)Median PFS: 7.6 vs 6 mo(HR 0.57, 95% CI 0.47-0.69)Seems to have longer OS (secondary endpoint)Median OS: 18.3 vs 15.2 mo(HR 0.79, 95% CI 0.64-0.99)
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
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 15 to 28
28-day cycle for 6 cycles
===References===
#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
==Cisplatin, Osimertinib, Pemetrexed==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Planchard et al. 2023 (FLAURA2)	2020-06-01 to 2021-12-22	Phase 3 (E-RT-esc)	Osimertinib	Longer PFS (primary endpoint)PFS24: 57% vs 41%(HR 0.62, 95% CI 0.49-0.79)
====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
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day on days 1 to 21
21-day cycles
===References===
#FLAURA2: Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Epub 2023 Nov 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04035486
==Dacomitinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ramalingam et al. 2012 (A7471028) 	2008-2009 	Randomized Phase 2 (E-switch-ic)	Erlotinib 	Seems to have longer PFS (primary endpoint)Median PFS: 2.9 vs 1.9 mo(HR 0.66, 95% CI 0.47-0.91)
Ramalingam et al. 2014 (ARCHER 1009)	2011-2013 	Phase 3 (E-switch-ic) 	Erlotinib 	Did not meet primary endpoint of PFSMedian PFS: 2.6 vs 2.6 mo(HR 0.94, 95% CI 0.80-1.10)
Wu et al. 2017 (ARCHER 1050) 	2013-2015 	Phase 3 (E-RT-switch-ic) 	Gefitinib 	Longer PFS (primary endpoint)Median PFS: 14.7 vs 9.2 mo(HR 0.59, 95% CI 0.47-0.74)Seems to have longer OS1 (secondary endpoint)Median OS: 34.1 vs 27 mo(HR 0.75, 95% CI 0.59-0.95)
1Reported efficacy for OS in ARCHER 1050 is based on the 2021 update.
====Biomarker eligibility criteria====
*A7471028 & ARCHER 1009: None
*ARCHER 1050: Activating mutations in EGFR
====Targeted therapy====
*Dacomitinib (Vizimpro) 45 mg PO once per day on days 1 to 28
28-day cycles
===References===
#A7471028: Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012 Sep 20;30(27):3337-44. Epub 2012 Jul 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00769067
#ARCHER 1009: Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15.link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01360554
#ARCHER 1050: Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. Epub 2017 Sep 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774721
##Update: Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Lee M, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Wu YL. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018 Aug 1;36(22):2244-2250. Epub 2018 Jun 4. link to original article EuroPMC
##Update: Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Chawla A, Rosell R, Corral J, Migliorino MR, Pluzanski A, Noonan K, Tang Y, Pastel M, Wilner KD, Wu YL. Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. Drugs. 2021 Feb;81(2):257-266. link to original article link to PMC article EuroPMC
==Erlotinib monotherapy==
===Regimen variant #1, 150 mg/d===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rossell et al. 2012 (EURTAC) 	2007-2011 	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Docetaxel1b. Carboplatin & Gemcitabine1c. Cisplatin & Docetaxel1d. Cisplatin & Gemcitabine	Longer PFS (primary endpoint)Median PFS: 9.7 vs 5.2 mo(HR 0.37, 95% CI 0.25-0.54)
Zhou et al. 2011 (CTONG-0802) 	2008-08-24 to 2009-07-17	Phase 3 (E-switch-ooc) 	Carboplatin & Gemcitabine 	Longer PFS (primary endpoint)Median PFS: 13.1 vs 4.6 mo(HR 0.16, 95% CI 0.10-0.26)
Ramalingam et al. 2012 (A7471028) 	2008-2009 	Randomized Phase 2 (C) 	Dacomitinib 	Seems to have shorter PFS (primary endpoint)Median PFS: 1.9 vs 2.9 mo(HR 1.52, 95% CI 1.10-2.13)
Yang et al. 2017 (CTONG 0901) 	2009-2014 	Phase 3 (E-switch-ic) 	Gefitinib 	Might have longer PFS (primary endpoint)Median PFS: 13 vs 10.4 mo(HR 0.81, 95% CI 0.62-1.05)
Seto et al. 2014 (JO25567) 	2011-2012 	Randomized Phase 2 (C) 	Erlotinib & Bevacizumab 	Shorter PFS1 (primary endpoint)Median PFS: 9.8 vs 16.4 mo(HR 1.92, 95% CI 1.32-2.86)Did not meet secondary endpoint of OS1Median OS: 47 vs 47.4 mo(HR 1.23, 95% CI 0.81-1.89)
Wu et al. 2015 (ENSURE) 	2011-03 to 2012-06 	Phase 3 (E-switch-ooc) 	Cisplatin & Gemcitabine 	Longer PFS (primary endpoint)Median PFS: 11.0 vs 5.5 mo(HR 0.34, 95% CI 0.22-0.51)Did not meet secondary endpoint of OSMedian OS: 26.3 vs 25.5 mo(HR 0.91, 95% CI 0.63-1.31)
Ramalingam et al. 2014 (ARCHER 1009)	2011-2013 	Phase 3 (C) 	Dacomitinib 	Did not meet primary endpoint of PFS
Soria et al. 2017 (FLAURA) 	2014-2016 	Phase 3 (C) 	Osimertinib 	Shorter PFSMedian PFS: 10.2 vs 18.9 mo(HR 2.17, 95% CI 1.75-2.70)Seems to have shorter OS2Median OS: 31.8 vs 38.6 mo(HR 1.25, 95% CI 1.00-1.56)
Saito et al. 2019 (NEJ026) 	2015-06-03 to 2016-08-31	Phase 3 (C) 	Erlotinib & Bevacizumab 	Seems to have shorter PFS (primary endpoint)Median PFS: 13.3 vs 16.9 mo(HR 1.64, 95% CI 1.14-2.38)Did not meet secondary endpoint of OS3Median OS: 46.2 vs 50.7 mo(HR 0.99, 95% CI 0.67-1.47)
Nakagawa et al. 2019 (RELAY) 	2016-01-28 to 2018-02-01	Phase 3 (C) 	Erlotinib & Ramucirumab 	Shorter PFSMedian PFS: 12.4 vs 19.4 mo(HR 1.69, 95% CI 1.32-2.17)
Kelly et al. 2019 (SOLARNSCLC) 	2016-02-11 to 2017-12-21	Phase 3 (C) 	Naquotinib 	Did not meet primary endpoint of PFSMedian PFS: 9.6 vs 9.3 mo(HR 0.62)
Zhou et al. 2021 (ARTEMIS-CTONG1509)	2016-05 to 2017-07 	Phase 3 (C) 	Erlotinib & Bevacizumab 	Shorter PFSMedian PFS: 11.2 vs 17.9 mo(HR 1.82, 95% CI 1.37-2.44)
Piccirillo et al. 2022 (BEVERLY) 	2016-2019 	Phase 3 (C) 	Erlotinib & Bevacizumab 	Shorter PFSMedian PFS: 9.6 vs 15.4 mo(HR 1.52, 95% CI 1.09-2.13)
1Reported efficacy for JO25567 is based on the 2020 update.
2Reported efficacy for FLAURA is based on the 2019 update.
3Reported efficacy for OS for NEJ026 is based on the 2021 update.
Note: these are all trials restricted to patients with EGFR-mutated lung cancer. Some trials of erlotinib in unselected populations nevertheless had high rates of EGFR-mutated lung cancers, due to the nature of the populations studied. See the main NSCLC page for these trials. SOLAR should not be confused with the trial by the same name in gastric cancer.
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 28
28-day cycles
===Regimen variant #2, low-dose===
Study 	Dates of enrollment	Evidence
Yeo et al. 2010	2004-2010 	Retrospective
====Targeted therapy====
*Erlotinib (Tarceva) 25 mg PO once per day on days 1 to 21
21-day cycles
===References===
#Retrospective: Yeo WL, Riely GJ, Yeap BY, Lau MW, Warner JL, Bodio K, Huberman MS, Kris MG, Tenen DG, Pao W, Kobayashi S, Costa DB. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol. 2010 Jul;5(7):1048-53. link to PMC article EuroPMC
#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 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
#A7471028: Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012 Sep 20;30(27):3337-44. Epub 2012 Jul 2. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC NCT00769067
#JO25567: Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Erratum in: Lancet Oncol. 2014 Oct;15(11):e475. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-111390
#ARCHER 1009: Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01360554
#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
#CTONG 0901: Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, Wang Z, Xu CR, Su J, Wang BC, Jiang BY, Bai XY, Zhong WZ, Yang XN, Wu YL. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017 Feb 28;116(5):568-574. Epub 2017 Jan 19. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01024413
#FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02296125
##Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article EuroPMC
##Update: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. Epub 2019 Nov 21. link to original article EuroPMC
#NEJ026: Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Gemma A, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):625-635. Epub 2019 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000017069
##Update: Kawashima Y, Fukuhara T, Saito H, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Seike M, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Respir Med. 2022 Jan;10(1):72-82. Epub 2021 Aug 26. link to original article EuroPMC
#SOLAR: Kelly RJ, Shepherd FA, Krivoshik A, Jie F, Horn L. A phase 3, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small cell lung cancer. Ann Oncol. 2019 Jul 1;30(7):1127-1133. Epub 2019 May 9. link to original article link to PMC article EuroPMC NCT02588261
#RELAY: Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. Epub 2019 Oct 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02411448
##PRO analysis: Yoh K, Atagi S, Reck M, Garon EB, Ponce Aix S, Moro-Sibilot D, Winfree KB, Frimodt-Moller B, Zimmermann A, Visseren-Grul C, Nakagawa K; RELAY investigators. Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. Curr Med Res Opin. 2020 Oct;36(10):1667-1675. Epub 2020 Aug 28. link to original article EuroPMC
#ARTEMIS-CTONG1509: Zhou Q, Xu CR, Cheng Y, Liu YP, Chen GY, Cui JW, Yang N, Song Y, Li XL, Lu S, Zhou JY, Ma ZY, Yu SY, Huang C, Shu YQ, Wang Z, Yang JJ, Tu HY, Zhong WZ, Wu YL. Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study. Cancer Cell. 2021 Sep 13;39(9):1279-1291.e3. Epub 2021 Aug 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02759614
#BEVERLY: Piccirillo MC, Bonanno L, Garassino MC, Esposito G, Dazzi C, Cavanna L, Burgio MA, Rosetti F, Rizzato S, Morgillo F, Cinieri S, Veccia A, Papi M, Tonini G, Gebbia V, Ricciardi S, Pozzessere D, Ferro A, Proto C, Costanzo R, D'Arcangelo M, Proietto M, Gargiulo P, Di Liello R, Arenare L, De Marinis F, Crinò L, Ciardiello F, Normanno N, Gallo C, Perrone F, Gridelli C, Morabito A. Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial. J Thorac Oncol. 2022 Sep;17(9):1086-1097. Epub 2022 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02633189
==Erlotinib & Bevacizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Seto et al. 2014 (JO25567) 	2011-2012 	Randomized Phase 2 (E-esc)	Erlotinib 	Longer PFS1 (primary endpoint)Median PFS: 16.4 vs 9.8 mo(HR 0.52, 95% CI 0.35-0.76)Did not meet secondary endpoint of OS1Median OS: 47.4 vs 47 mo(HR 0.81, 95% CI 0.53-1.23)
Saito et al. 2019 (NEJ026) 	2015-06-03 to 2016-08-31	Phase 3 (E-esc) 	Erlotinib 	Seems to have longer PFS (primary endpoint)Median PFS: 16.9 vs 13.3 mo(HR 0.61, 95% CI 0.42-0.88)Did not meet secondary endpoint of OS2Median OS: 50.7 vs 46.2 mo(HR 1.01, 95% CI 0.68-1.49)
Zhou et al. 2021 (ARTEMIS-CTONG1509)	2016-05 to 2017-07 	Phase 3 (E-esc) 	Erlotinib 	Longer PFS (primary endpoint)Median PFS: 17.9 vs 11.2 mo(HR 0.55, 95% CI 0.41-0.73)
Piccirillo et al. 2022 (BEVERLY) 	2016-2019 	Phase 3 (E-esc) 	Erlotinib 	Longer PFS (primary endpoint)Median PFS: 15.4 vs 9.6 mo(HR 0.66, 95% CI 0.47-0.92)
1Reported efficacy for JO25567 is based on the 2020 update.
2Reported efficacy for OS for NEJ026 is based on the 2021 update.
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 21
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#JO25567: Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Erratum in: Lancet Oncol. 2014 Oct;15(11):e475. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-111390
##Update: Yamamoto N, Seto T, Nishio M, Goto K, Yamamoto N, Okamoto I, Yamanaka T, Tanaka M, Takahashi K, Fukuoka M. Erlotinib plus bevacizumab vs erlotinib monotherapy as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer: Survival follow-up results of the randomized JO25567 study. Lung Cancer. 2021 Jan;151:20-24. Epub 2020 Nov 20. link to original article EuroPMC
#NEJ026: Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Gemma A, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):625-635. Epub 2019 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000017069
##Update: Kawashima Y, Fukuhara T, Saito H, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Seike M, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Respir Med. 2022 Jan;10(1):72-82. Epub 2021 Aug 26. link to original article EuroPMC
#ARTEMIS-CTONG1509: Zhou Q, Xu CR, Cheng Y, Liu YP, Chen GY, Cui JW, Yang N, Song Y, Li XL, Lu S, Zhou JY, Ma ZY, Yu SY, Huang C, Shu YQ, Wang Z, Yang JJ, Tu HY, Zhong WZ, Wu YL. Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study. Cancer Cell. 2021 Sep 13;39(9):1279-1291.e3. Epub 2021 Aug 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02759614
#BEVERLY: Piccirillo MC, Bonanno L, Garassino MC, Esposito G, Dazzi C, Cavanna L, Burgio MA, Rosetti F, Rizzato S, Morgillo F, Cinieri S, Veccia A, Papi M, Tonini G, Gebbia V, Ricciardi S, Pozzessere D, Ferro A, Proto C, Costanzo R, D'Arcangelo M, Proietto M, Gargiulo P, Di Liello R, Arenare L, De Marinis F, Crinò L, Ciardiello F, Normanno N, Gallo C, Perrone F, Gridelli C, Morabito A. Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial. J Thorac Oncol. 2022 Sep;17(9):1086-1097. Epub 2022 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02633189
==Erlotinib & Ramucirumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Nakagawa et al. 2019 (RELAY)	2016-01-28 to 2018-02-01	Phase 3 (E-RT-esc)	Erlotinib 	Longer PFS (primary endpoint)Median PFS: 19.4 vs 12.4 mo(HR 0.59, 95% CI 0.46-0.76)
Note: the FDA-recommended dose is only provided for ramucirumab.
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 14
*Ramucirumab (Cyramza) 10 mg/kg IV once on day 1
14-day cycles
===References===
#RELAY: Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. Epub 2019 Oct 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02411448
##PRO analysis: Yoh K, Atagi S, Reck M, Garon EB, Ponce Aix S, Moro-Sibilot D, Winfree KB, Frimodt-Moller B, Zimmermann A, Visseren-Grul C, Nakagawa K; RELAY investigators. Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. Curr Med Res Opin. 2020 Oct;36(10):1667-1675. Epub 2020 Aug 28. link to original article EuroPMC
==Furmonertinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Shi et al. 2022 (FURLONG)	2019-05-30 to 2019-12-05	Phase 3 (E-switch-ic)	Gefitinib 	Longer PFS (primary endpoint)Median PFS: 20.8 vs 11.1 mo(HR 0.44, 95% CI 0.34-0.58)
====Biomarker eligibility criteria====
*FURLONG: EGFR exon 19 deletion or EGFR p.L858R mutation
====Targeted therapy====
*Furmonertinib (Ivesa) 80 mg PO once per day on days 1 to 21
21-day cycles
===References===
#FURLONG: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C; FURLONG investigators. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 2022 Nov;10(11):1019-1028. Epub 2022 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03787992
##Subgroup analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C. Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study. J Thorac Oncol. 2022 Nov;17(11):1297-1305. Epub 2022 Aug 3. link to original article EuroPMC
##PRO analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Hu J, Liu F, Jiang Y, Ge N. Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. Lancet Reg Health West Pac. 2024 Jun 17;48:101122. link to original article link to PMC article EuroPMC
==GCP==
GCP: Gefitinib, Carboplatin, Pemetrexed
===Regimen variant #1, 4 cycles of carboplatin===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Noronha et al. 2019	2016-2018 	Phase 3 (E-esc)	Gefitinib 	Longer PFS (primary endpoint)Median PFS: 16 vs 8 mo(HR 0.51, 95% CI 0.39-0.66)Longer OS (secondary endpoint)Median OS: NYR vs 17 mo(HR 0.45, 95% CI 0.31-0.65)
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day on days 1 to 21
====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
Hosomi et al. 2019 (NEJ009)	2011-2015 	Phase 3 (E-esc)	Gefitinib 	Longer OS (co-primary endpoint)Median OS: 50.9 vs 38.8 mo(HR 0.72, 95% CI 0.55-0.95)
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
===References===
#NEJ009: Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, Takahashi K, Fujita Y, Harada T, Minato K, Takamura K, Hagiwara K, Kobayashi K, Nukiwa T, Inoue A; North-East Japan Study Group. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol. 2020 Jan 10;38(2):115-123. Epub 2019 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000006340
#Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, Janu A, Purandare N, Kumar R, More S, Goud S, Kadam N, Daware N, Bhattacharjee A, Shah S, Yadav A, Trivedi V, Behel V, Dutt A, Banavali SD, Prabhash K. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol. 2020 Jan 10;38(2):124-136. Epub 2019 Aug 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2016/08/007149
==Gefitinib monotherapy==
===Regimen variant #1, continuous===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Mitsudomi et al. 2009 (WJTOG3405)	2006-2009 	Phase 3 (E-switch-ooc)	Cisplatin & Docetaxel 	Longer PFS (primary endpoint)Median PFS: 9.2 vs 6.3 mo(HR 0.49, 95% CI 0.34-0.71)
Maemondo et al. 2010 (NEJ002) 	2006-2009 	Phase 3 (E-switch-ooc)	Carboplatin & Paclitaxel	Longer PFS (primary endpoint)Median PFS: 10.8 vs 5.4 mo(HR 0.30, 95% CI 0.22-0.41)
Urata et al. 2016 (WJOG 5108L) 	2009-2012 	Phase 3 (E-switch-ic) 	Erlotinib 	Inconclusive whether non-inferior PFS
Yang et al. 2017 (CTONG 0901) 	2009-2014 	Phase 3 (C) 	Erlotinib 	Might have shorter PFSMedian PFS: 10.4 vs 13 mo(HR 1.23, 95% CI 0.95-1.61)
Douillard et al. 2014 (IFUM) 	2010-2012 	Phase 4 (RT) 	 	ORR: 70% (95% CI: 60.5–78)
Park et al. 2016 (LUX-Lung 7) 	2011-2013 	Randomized Phase 2 (C)	Afatinib 	Shorter PFSMedian PFS: 10.9 vs 11 mo(HR 1.37, 95% CI 1.05-1.75)
Hosomi et al. 2019 (NEJ009) 	2011-2015 	Phase 3 (C) 	GCP 	Shorter OSMedian OS: 38.8 vs 50.9 mo(HR 1.39, 95% CI 1.05-1.82)
Cheng et al. 2016 (JMIT) 	2012-2013 	Randomized Phase 2 (C)	P+G 	Seems to have shorter PFS (primary endpoint)Median PFS: 10.9 vs 15.8 mo(aHR 1.47, 95% CI 1.04-2.08)
Patil et al. 2017 	2012-2016 	Phase 3 (E-switch-ooc)	Carboplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 8.4 vs 5.6 mo(HR 0.66, 95% CI 0.51-0.85)
Wu et al. 2017 (ARCHER 1050) 	2013-2015 	Phase 3 (C) 	Dacomitinib 	Seems to have shorter OS1 (secondary endpoint)Median OS: 27 vs 34.1 mo(HR 1.33, 95% CI 1.05-1.69)Shorter PFS (primary endpoint)Median PFS: 9.2 vs 14.7 mo(HR 1.69, 95% CI 1.35-2.13)
Soria et al. 2017 (FLAURA) 	2014-2016 	Phase 3 (C) 	Osimertinib 	Shorter PFSMedian PFS: 10.2 vs 18.9 mo(HR 2.17, 95% CI 1.75-2.70)Seems to have shorter OS2Median OS: 31.8 vs 38.6 mo(HR 1.25, 95% CI 1.00-1.56)
Noronha et al. 2019 	2016-2018 	Phase 3 (C) 	GCP 	Shorter PFS (primary endpoint)Median PFS: 8 vs 16 mo(HR 1.96, 95% CI 1.52-2.56)Shorter OS (secondary endpoint)Median OS: 17 vs NYR mo(HR 2.22, 95% CI 1.54-3.23)
Zhao et al. 2021 (CTONG1706) 	2017-08 to 2018-12 	Phase 3 (C) 	Apatinib & Gefitinib 	Shorter PFSMedian PFS: 10.2 vs 13.7 mo(HR 1.41, 95% CI 1.05-1.85)
Lu et al. 2022 (AENEAS) 	2018-11-30 to 2019-09-06	Phase 3 (C) 	Aumolertinib 	Shorter PFSMedian PFS: 9.9 vs 19.3 mo(HR 2.17, 95% CI 1.67-2.78)
Shi et al. 2022 (FURLONG) 	2019-05-30 to 2019-12-05	Phase 3 (C) 	Furmonertinib 	Shorter PFSMedian PFS: 11.1 vs 20.8 mo(HR 2.27, 95% CI 1.72-2.94)
Cho et al. 2023 (LASER301) 	2020-02 to 2021-09 	Phase 3 (C) 	Lazertinib 	Shorter PFSMedian PFS: 9.7 vs 20.6 mo(HR 2.22, 95% CI 1.72-2.94)
1Reported efficacy for ARCHER 1050 is based on the 2021 update.
2Reported efficacy for FLAURA is based on the 2019 update.
Note: these are all trials restricted to EGFR-mutated lung cancer, with the exception of WJOG 5108L, which nevertheless had 72% EGFR-mutated patients.
====Biomarker eligibility criteria====
*FURLONG: EGFR exon 19 deletion or EGFR p.L858R mutation
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
===Regimen variant #2, 2 out of 3 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2024 (FL-ALTER)	2019-04 to 2021-08 	Phase 3 (C)	Anlotinib & Gefitinib	Shorter PFSMedian PFS: 11.2 vs 14.8 mo(HR 1.56, 95% CI 1.25-2.08)
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day on days 1 to 14
21-day 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
#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
#IFUM: Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, Milenkova T. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014 Jan 7;110(1):55-62. Epub 2013 Nov 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01203917
#LUX-Lung 7: Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kölbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89. Epub 2016 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01466660
#WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000002014
#JMIT: Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Wang X, Enatsu S, Puri T, Orlando M, Yang JC. Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016 Sep 20;34(27):3258-66. Epub 2016 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01469000
#CTONG 0901: Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, Wang Z, Xu CR, Su J, Wang BC, Jiang BY, Bai XY, Zhong WZ, Yang XN, Wu YL. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017 Feb 28;116(5):568-574. Epub 2017 Jan 19. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01024413
#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
#ARCHER 1050: Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. Epub 2017 Sep 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774721
##Update: Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Lee M, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Wu YL. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018 Aug 1;36(22):2244-2250. Epub 2018 Jun 4. link to original article EuroPMC
##Update: Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Chawla A, Rosell R, Corral J, Migliorino MR, Pluzanski A, Noonan K, Tang Y, Pastel M, Wilner KD, Wu YL. Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. Drugs. 2021 Feb;81(2):257-266. link to original article link to PMC article EuroPMC
#FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02296125
##Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article EuroPMC
##Update: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. Epub 2019 Nov 21. link to original article EuroPMC
#NEJ009: Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, Takahashi K, Fujita Y, Harada T, Minato K, Takamura K, Hagiwara K, Kobayashi K, Nukiwa T, Inoue A; North-East Japan Study Group. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol. 2020 Jan 10;38(2):115-123. Epub 2019 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000006340
#Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, Janu A, Purandare N, Kumar R, More S, Goud S, Kadam N, Daware N, Bhattacharjee A, Shah S, Yadav A, Trivedi V, Behel V, Dutt A, Banavali SD, Prabhash K. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol. 2020 Jan 10;38(2):124-136. Epub 2019 Aug 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2016/08/007149
#CTONG1706: Zhao H, Yao W, Min X, Gu K, Yu G, Zhang Z, Cui J, Miao L, Zhang L, Yuan X, Fang Y, Fu X, Hu C, Zhu X, Fan Y, Yu Q, Wu G, Jiang O, Du X, Liu J, Gu W, Hou Z, Wang Q, Zheng R, Zhou X, Zhang L. Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706). J Thorac Oncol. 2021 Sep;16(9):1533-1546. Epub 2021 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02824458
#AENEAS: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Jie W, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Sun C, Wei H, Li C, Ali SM, Miller VA, Wu Q. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022 Sep 20;40(27):3162-3171. Epub 2022 May 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03849768
##Subgroup analysis: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Weng J, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Wei H, Wei J, Zhang Z, Wu Q. Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS). Cancer Commun (Lond). 2024 Sep;44(9):1005-1017. Epub 2024 Jul 17. link to original article link to PMC article EuroPMC
#FURLONG: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C; FURLONG investigators. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 2022 Nov;10(11):1019-1028. Epub 2022 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03787992
##Subgroup analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Liu F, Jiang Y, Gu C. Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study. J Thorac Oncol. 2022 Nov;17(11):1297-1305. Epub 2022 Aug 3. link to original article EuroPMC
##PRO analysis: Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, Liu J, Cao L, Cheng Y, Zhao H, Zhang S, Zang A, Cui J, Feng J, Yang N, Hu J, Liu F, Jiang Y, Ge N. Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. Lancet Reg Health West Pac. 2024 Jun 17;48:101122. link to original article link to PMC article EuroPMC
#LASER301: Cho BC, Ahn MJ, Kang JH, Soo RA, Reungwetwattana T, Yang JC, Cicin I, Kim DW, Wu YL, Lu S, Lee KH, Pang YK, Zimina A, Fong CH, Poddubskaya E, Sezer A, How SH, Danchaivijitr P, Kim Y, Lim Y, An T, Lee H, Byun HM, Zaric B. Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301. J Clin Oncol. 2023 Sep 10;41(26):4208-4217. Epub 2023 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04248829
#FL-ALTER: Zhou HQ, Zhang YX, Chen G, Yu QT, Zhang H, Wu GW, Wu D, Lin YC, Zhu JF, Chen JH, Hu XH, Lan B, Zhou ZQ, Lin HF, Wang ZB, Lei XL, Pan SM, Chen LM, Zhang J, Kong TD, Yao JC, Zheng X, Li F, Zhang L, Fang WF. Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial. Signal Transduct Target Ther. 2024 Aug 13;9(1):215. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04028778
==Gefitinib & Pemetrexed==
P+G: Pemetrexed and Gefitinib
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cheng et al. 2016 (JMIT)	2012-2013 	Randomized Phase 2 (E-esc)	Gefitinib 	Seems to have longer PFS (primary endpoint)Median PFS: 15.8 vs 10.9 mo(aHR 0.68, 95% CI 0.48-0.96)
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day on days 1 to 21
====Chemotherapy====
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===References===
#JMIT: Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Wang X, Enatsu S, Puri T, Orlando M, Yang JC. Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016 Sep 20;34(27):3258-66. Epub 2016 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01469000
==Icotinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Shi et al. 2017 (CONVINCE)	2013-01 to 2014-08 	Phase 3 (E-switch-ooc)	Cisplatin & Pemetrexed x 4, then Pemetrexed maintenance	Longer PFS (primary endpoint)Median PFS: 11.2 vs 7.9 mo(HR 0.61, 95% CI 0.43-0.87)
Lu et al. 2023 (IBIO-103) 	2019-12-24 to 2020-12-18	Phase 3 (C) 	Befotertinib 	Shorter PFS (primary endpoint)Median PFS: 13.8 vs 22.1 mo(HR 2.04, 95% CI 1.47-2.78)
Note: this drug is only approved in China; eligible patients in CONVINCE had stage IIIB/IV lung adenocarcinoma.
====Biomarker eligibility criteria====
*CONVINCE: EGFR exon 19 or 21 mutations
*Lu et al. 2023: EGFR exon 19 deletions or exon 21 Leu858Arg mutation
====Targeted therapy====
*Icotinib (Conmana) 125 mg PO three times per day
Continued indefinitely
===References===
#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
#IBIO-103: Lu S, Zhou J, Jian H, Wu L, Cheng Y, Fan Y, Fang J, Chen G, Zhang Z, Lv D, Jiang L, Wu R, Jin X, Zhang X, Zhang J, Xie C, Sun G, Huang D, Cui J, Guo R, Han Z, Chen Z, Liang J, Zhuang W, Hu X, Zang A, Zhang Y, Cang S, Lan Y, Chen X, Liu L, Li X, Chen J, Ma R, Guo Y, Sun P, Tian P, Pan Y, Liu Z, Cao P, Ding L, Wang Y, Yuan X, Wu P. Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study. Lancet Respir Med. 2023 Oct;11(10):905-915. Epub 2023 May 24. link to original article EuroPMC NCT04206072
==Lazertinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cho et al. 2023 (LASER301)	2020-02 to 2021-09 	Phase 3 (E-switch-ic)	Gefitinib 	Longer PFS (primary endpoint)Median PFS: 20.6 vs 9.7 mo(HR 0.45, 95% CI 0.34-0.58)
====Targeted therapy====
*Lazertinib (Leclaza) 240 mg PO once per day
Continued indefinitely
===References===
#LASER301: Cho BC, Ahn MJ, Kang JH, Soo RA, Reungwetwattana T, Yang JC, Cicin I, Kim DW, Wu YL, Lu S, Lee KH, Pang YK, Zimina A, Fong CH, Poddubskaya E, Sezer A, How SH, Danchaivijitr P, Kim Y, Lim Y, An T, Lee H, Byun HM, Zaric B. Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301. J Clin Oncol. 2023 Sep 10;41(26):4208-4217. Epub 2023 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04248829
==Lazertinib & Amivantamab==
===Regimen variant #1, <80 kg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cho et al. 2024 (MARIPOSA)	2020-11 to 2022-05 	Phase 3 (E-RT-esc)	1. Osimertinib	Longer PFS (primary endpoint)Median PFS: 23.7 vs 16.6 mo(HR 0.70, 95% CI 0.58-0.85)
Cho et al. 2024 (MARIPOSA)	2020-11 to 2022-05 	Phase 3 (E-RT-esc)	2. Lazertinib 	Not reported
====Targeted therapy====
*Lazertinib (Leclaza) as follows:
**Cycle 1: 240 mg PO once per day on days 1 to 28
**Cycle 2 onwards: 240 mg PO once per day on days 1 to 14
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 700 mg IV once on day 2, then 1050 mg IV once per day on days 8, 15, 22
**Cycle 2 onwards: 1050 mg IV once on day 1
28-day course, then 14-day cycles
===Regimen variant #2, more than 80 kg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cho et al. 2024 (MARIPOSA)	2020-11 to 2022-05 	Phase 3 (E-RT-esc)	1. Osimertinib	Longer PFS (primary endpoint)Median PFS: 23.7 vs 16.6 mo(HR 0.70, 95% CI 0.58-0.85)
Cho et al. 2024 (MARIPOSA)	2020-11 to 2022-05 	Phase 3 (E-RT-esc)	2. Lazertinib 	Not reported
====Targeted therapy====
*Lazertinib (Leclaza) as follows:
**Cycle 1: 240 mg PO once per day on days 1 to 28
**Cycle 2 onwards: 240 mg PO once per day on days 1 to 14
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8, 15, 22
**Cycle 2 onwards: 1400 mg IV once on day 1
28-day course, then 14-day cycles
===References===
#MARIPOSA: Cho BC, Lu S, Felip E, Spira AI, Girard N, Lee JS, Lee SH, Ostapenko Y, Danchaivijitr P, Liu B, Alip A, Korbenfeld E, Mourão Dias J, Besse B, Lee KH, Xiong H, How SH, Cheng Y, Chang GC, Yoshioka H, Yang JC, Thomas M, Nguyen D, Ou SI, Mukhedkar S, Prabhash K, D'Arcangelo M, Alatorre-Alexander J, Vázquez Limón JC, Alves S, Stroyakovskiy D, Peregudova M, Şendur MAN, Yazici O, Califano R, Gutiérrez Calderón V, de Marinis F, Passaro A, Kim SW, Gadgeel SM, Xie J, Sun T, Martinez M, Ennis M, Fennema E, Daksh M, Millington D, Leconte I, Iwasawa R, Lorenzini P, Baig M, Shah S, Bauml JM, Shreeve SM, Sethi S, Knoblauch RE, Hayashi H; MARIPOSA Investigators. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024 Oct 24;391(16):1486-1498. Epub 2024 Jun 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04487080
==Osimertinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Soria et al. 2017 (FLAURA) 	2014-2016 	Phase 3 (E-RT-switch-ic)	1a. Erlotinib1b. Gefitinib 	Longer PFS (primary endpoint)Median PFS: 18.9 vs 10.2 mo(HR 0.46, 95% CI 0.37-0.57)Seems to have longer OS1 (secondary endpoint)Median OS: 38.6 vs 31.8 mo(HR 0.80, 95% CI 0.64-1.00)
Planchard et al. 2023 (FLAURA2)	2020-06-01 to 2021-12-22	Phase 3 (C) 	1a. Carboplatin, Osimertinib, Pemetrexed1b. Cisplatin, Osimertinib, Pemetrexed	Shorter PFS (primary endpoint)PFS24: 41% vs 57%(HR 1.61, 95% CI 1.27-2.04)
Cho et al. 2024 (MARIPOSA) 	2020-11 to 2022-05 	Phase 3 (C) 	1. Lazertinib & Amivantamab 	Shorter PFS
Cho et al. 2024 (MARIPOSA) 	2020-11 to 2022-05 	Phase 3 (C) 	2. Lazertinib 	Not directly compared
1Reported efficacy for FLAURA is based on the 2019 update.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R mutation
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day
Continued indefinitely
===References===
#FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02296125
##Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article EuroPMC
##Update: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. Epub 2019 Nov 21. link to original article EuroPMC
#FLAURA2: Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Epub 2023 Nov 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04035486
#MARIPOSA: Cho BC, Lu S, Felip E, Spira AI, Girard N, Lee JS, Lee SH, Ostapenko Y, Danchaivijitr P, Liu B, Alip A, Korbenfeld E, Mourão Dias J, Besse B, Lee KH, Xiong H, How SH, Cheng Y, Chang GC, Yoshioka H, Yang JC, Thomas M, Nguyen D, Ou SI, Mukhedkar S, Prabhash K, D'Arcangelo M, Alatorre-Alexander J, Vázquez Limón JC, Alves S, Stroyakovskiy D, Peregudova M, Şendur MAN, Yazici O, Califano R, Gutiérrez Calderón V, de Marinis F, Passaro A, Kim SW, Gadgeel SM, Xie J, Sun T, Martinez M, Ennis M, Fennema E, Daksh M, Millington D, Leconte I, Iwasawa R, Lorenzini P, Baig M, Shah S, Bauml JM, Shreeve SM, Sethi S, Knoblauch RE, Hayashi H; MARIPOSA Investigators. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024 Oct 24;391(16):1486-1498. Epub 2024 Jun 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04487080
#ECOG-ACRIN EA5182: NCT04181060
=Advanced or metastatic disease, EGFR inhibitor-exposed=
==ABCP==
ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel
===Regimen variant #1, 4 cycles then maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Park et al. 2023 (ATTLAS)	2019-08-27 to 2022-03-11	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 8.48 vs 5.62 mo(HR 0.62, 95% CI 0.45-0.86)
====Prior treatment criteria====
*Progression or intolerance to one or more EGFR TKIs
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 5 or 5.5 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 4: 175 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 6 cycles then maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Park et al. 2023 (ATTLAS)	2019-08-27 to 2022-03-11	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 8.48 vs 5.62 mo(HR 0.62, 95% CI 0.45-0.86)
====Prior treatment criteria====
*Progression or intolerance to one or more EGFR TKIs
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 5 or 5.5 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 6: 175 mg/m2 IV once on day 1
21-day cycles
===References===
#ATTLAS: Park S, Kim TM, Han JY, Lee GW, Shim BY, Lee YG, Kim SW, Kim IH, Lee S, Kim YJ, Park JH, Park SG, Lee KH, Kang EJ, Kim JW, Shin SH, Ock CY, Nam BH, Lee J, Jung HA, Sun JM, Lee SH, Ahn JS, Ahn MJ. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol. 2024 Apr 10;42(11):1241-1251. Epub 2023 Oct 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03991403
==Afatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Katakami et al. 2013 (LUX-Lung 4)	2009-2011 	Phase 2 	ORR: 8% (95% CI: 3-18)
Note: In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants. 
====Prior treatment criteria====
*Progression while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen
====Targeted therapy====
*Afatinib (Gilotrif) 50 mg PO once per day, taken at least 1 hour before eating food
Continued indefinitely
===References===
#LUX-Lung 4: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00711594
==Afatinib & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence
Hata et al. 2018 (ABC Study)	2014-2017 	Phase 2
====Targeted therapy====
*Afatinib (Gilotrif) 30 mg PO once per day on days 1 to 21
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#ABC Study: Hata A, Katakami N, Kaji R, Yokoyama T, Kaneda T, Tamiya M, Inoue T, Kimura H, Yano Y, Tamura D, Morita S, Negoro S; Hanshin Oncology Group F. Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: Multicenter, single-arm, phase 2 trial (ABC Study). Cancer. 2018 Oct 1;124(19):3830-3838. Epub 2018 Sep 7. link to original article EuroPMC UMIN000014710
==Afatinib & Cetuximab==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Janjigian et al. 2014 (BI 1200.71)	2010-2013 	Phase 1b	ORR: 29%
====Targeted therapy====
*Afatinib (Gilotrif) 40 mg PO once per day on days 1 to 14
*Cetuximab (Erbitux) 500 mg IV once on day 1
14-day cycles
===References===
#BI 1200.71: Janjigian YY, Smit EF, Groen HJ, Horn L, Gettinger S, Camidge DR, Riely GJ, Wang B, Fu Y, Chand VK, Miller VA, Pao W. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014 Sep;4(9):1036-45. Epub 2014 Jul 29. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01090011
==Carboplatin & Pemetrexed==
===Regimen variant #1, AUC 5 x 4 with pemetrexed maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Mok et al. 2024 (CheckMate 722) 	2017-03 to 2020-06 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab 	Might have shorter PFS (primary endpoint)Median PFS: 5.4 vs 5.6 mo(HR 1.33, 95% CI 1.00-1.79)
Yang et al. 2024 (KEYNOTE-789) 	2018-07-23 to 2020-08-30	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab1b. Cisplatin, Pemetrexed, Pembrolizumab 	Might have shorter OS (co-primary endpoint)Median OS: 14.7 vs 15.9 mo(HR 1.19, 95% CI 0.98-1.45)Seems to have shorter PFS (co-primary endpoint)Median PFS: 5.5 vs 5.6 mo(HR 1.25, 95% CI 1.03-1.54)
Park et al. 2023 (ATTLAS) 	2019-08-27 to 2022-03-11	Phase 3 (C)	ABCP 	Shorter PFSMedian PFS: 5.62 vs 8.48 mo(HR 1.61, 95% CI 1.16-2.22)
Passaro et al. 2023 (MARIPOSA-2) 	2021-12 to 2023-04 	Phase 3 (C)	1. Carboplatin, Pemetrexed, Amivantamab2. Carboplatin, Lazertinib, Pemetrexed, Amivantamab	Shorter PFS
Fang et al. 2024 (HARMONi-A) 	2022-01 to 2022-11 	Phase 3 (C)	Carboplatin, Pemetrexed, Ivonescimab 	Shorter PFS (primary endpoint)Median PFS: 4.8 vs 7.1 mo(HR 2.17, 95% CI 1.61-2.94)
Awaiting publication (HERTHENA-Lung02)	2022-ongoing 	Phase 3 (C)	Patritumab-DXd 	TBD if different primary endpoint of PFS
Note: this was the lower bound of carboplatin dosing in CheckMate 722.
====Prior treatment criteria====
*MARIPOSA-2: Progression after osimertinib
*HERTHENA-Lung02: Progression after first-line EGFR TKI therapy
*ATTLAS & HARMONi-A: Progression or intolerance to one or more EGFR TKIs
====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, AUC 5 x 6 with pemetrexed maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Park et al. 2023 (ATTLAS)	2019-08-27 to 2022-03-11	Phase 3 (C)	ABCP 	Shorter PFSMedian PFS: 5.62 vs 8.48 mo(HR 1.61, 95% CI 1.16-2.22)
====Prior treatment criteria====
*Progression or intolerance to one or more EGFR TKIs
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #3, AUC 6 x 4 with pemetrexed maintenance===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mok et al. 2024 (CheckMate 722)	2017-03 to 2020-06 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab	Might have shorter PFS (primary endpoint)Median PFS: 5.4 vs 5.6 mo(HR 1.33, 95% CI 1.00-1.79)
Note: this was the upper bound of carboplatin dosing in CheckMate 722.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===References===
#MARIPOSA-2: Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, Wang J, Azuma K, Juan-Vidal O, Cobo M, Felip E, Girard N, Cortot AB, Califano R, Cappuzzo F, Owen S, Popat S, Tan JL, Salinas J, Tomasini P, Gentzler RD, William WN Jr, Reckamp KL, Takahashi T, Ganguly S, Kowalski DM, Bearz A, MacKean M, Barala P, Bourla AB, Girvin A, Greger J, Millington D, Withelder M, Xie J, Sun T, Shah S, Diorio B, Knoblauch RE, Bauml JM, Campelo RG, Cho BC; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. Epub 2023 Oct 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04988295
#CheckMate 722: Mok T, Nakagawa K, Park K, Ohe Y, Girard N, Kim HR, Wu YL, Gainor J, Lee SH, Chiu CH, Kim SW, Yang CT, Wu CL, Wu L, Lin MC, Samol J, Ichikado K, Wang M, Zhang X, Sylvester J, Li S, Forslund A, Yang JC. Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722. J Clin Oncol. 2024 Apr 10;42(11):1252-1264. Epub 2024 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02864251
#ATTLAS: Park S, Kim TM, Han JY, Lee GW, Shim BY, Lee YG, Kim SW, Kim IH, Lee S, Kim YJ, Park JH, Park SG, Lee KH, Kang EJ, Kim JW, Shin SH, Ock CY, Nam BH, Lee J, Jung HA, Sun JM, Lee SH, Ahn JS, Ahn MJ. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol. 2024 Apr 10;42(11):1241-1251. Epub 2023 Oct 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03991403
#HARMONi-A: Fang W, Zhao Y, Luo Y, Yang R, Huang Y, He Z, Zhao H, Li M, Li K, Song Q, Du X, Sun Y, Li W, Xu F, Wang Z, Yang K, Fan Y, Liu B, Zhao H, Hu Y, Jia L, Xu S, Yi T, Lv D, Lan H, Li M, Liang W, Wang Y, Yang H, Jia Y, Chen Y, Lu J, Feng J, Liu C, Zhou M, Zhou J, Liu X, Zhou N, He M, Dong X, Chen H, Chen Y, Su H, Li X, Zhang Z, Yang L, Cheng Y, Chen L, Hou X, Zhang Y, Guo J, Wang Z, Lu H, Wu D, Feng W, Li W, Huang J, Wang Y, Song X, Peng J, Liu L, Guo Y, Li W, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhang L; HARMONi-A Study Investigators. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA. 2024 Aug 20;332(7):561-570. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05184712
#KEYNOTE-789: Yang JC, Lee DH, Lee JS, Fan Y, de Marinis F, Iwama E, Inoue T, Rodríguez-Cid J, Zhang L, Yang CT, de la Mora Jimenez E, Zhou J, Pérol M, Lee KH, Vicente D, Ichihara E, Riely GJ, Luo Y, Chirovsky D, Pietanza MC, Bhagwati N, Lu S. Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Dec;42(34):4029-4039. Epub 2024 Aug 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03515837
#HERTHENA-Lung02: NCT05338970
==Carboplatin, Pemetrexed, Amivantamab==
===Regimen variant #1, lower-dose amivantamab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	1. Carboplatin & Pemetrexed 	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.48, 95% CI 0.36-0.64)
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	2. Carboplatin, Lazertinib, Pemetrexed, Amivantamab	Not formally compared
Note: This amivantamab dosage was for patients weighing less than 80 kg.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R
====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
====Targeted therapy====
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8 & 15
**Cycle 2: 1400 mg IV once on day 1
**Cycle 3 onwards: 1750 mg IV once on day 1
21-day cycles
===Regimen variant #2, higher-dose amivantamab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	1. Carboplatin & Pemetrexed 	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.48, 95% CI 0.36-0.64)
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	2. Carboplatin, Lazertinib, Pemetrexed, Amivantamab	Not formally compared
Note: This amivantamab dosage was for patients weighing 80 kg or more.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R
====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
====Targeted therapy====
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1400 mg IV once on day 2, then 1750 mg IV once per day on days 8 & 15
**Cycle 2: 1750 mg IV once on day 1
**Cycle 3 onwards: 2100 mg IV once on day 1
21-day cycles
===References===
#MARIPOSA-2: Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, Wang J, Azuma K, Juan-Vidal O, Cobo M, Felip E, Girard N, Cortot AB, Califano R, Cappuzzo F, Owen S, Popat S, Tan JL, Salinas J, Tomasini P, Gentzler RD, William WN Jr, Reckamp KL, Takahashi T, Ganguly S, Kowalski DM, Bearz A, MacKean M, Barala P, Bourla AB, Girvin A, Greger J, Millington D, Withelder M, Xie J, Sun T, Shah S, Diorio B, Knoblauch RE, Bauml JM, Campelo RG, Cho BC; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. Epub 2023 Oct 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04988295
==Carboplatin, Pemetrexed, Ivonescimab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Fang et al. 2024 (HARMONi-A)	2022-01 to 2022-11 	Phase 3 (E-RT-esc)	Carboplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 7.1 vs 4.8 mo(HR 0.46, 95% CI 0.34-0.62)
====Prior treatment criteria====
*Progression or intolerance to one or more EGFR TKIs
====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
====Immunotherapy====
*Ivonescimab (Akeso) 20 mg/kg IV once on day 1
21-day cycles
===References===
#HARMONi-A: Fang W, Zhao Y, Luo Y, Yang R, Huang Y, He Z, Zhao H, Li M, Li K, Song Q, Du X, Sun Y, Li W, Xu F, Wang Z, Yang K, Fan Y, Liu B, Zhao H, Hu Y, Jia L, Xu S, Yi T, Lv D, Lan H, Li M, Liang W, Wang Y, Yang H, Jia Y, Chen Y, Lu J, Feng J, Liu C, Zhou M, Zhou J, Liu X, Zhou N, He M, Dong X, Chen H, Chen Y, Su H, Li X, Zhang Z, Yang L, Cheng Y, Chen L, Hou X, Zhang Y, Guo J, Wang Z, Lu H, Wu D, Feng W, Li W, Huang J, Wang Y, Song X, Peng J, Liu L, Guo Y, Li W, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhang L; HARMONi-A Study Investigators. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA. 2024 Aug 20;332(7):561-570. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05184712
==Carboplatin, Lazertinib, Pemetrexed, Amivantamab==
===Regimen variant #1, lower-dose amivantamab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	1. Carboplatin & Pemetrexed 	Longer PFS (primary endpoint)Median PFS: 8.3 vs 4.2 mo(HR 0.44, 95% CI 0.35-0.56)
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	2. Carboplatin, Pemetrexed, Amivantamab	Not formally compared
Note: This amivantamab dosage was for patients weighing less than 80 kg. Due to excess toxicity in this arm, the lazertinib was not started until cycle 5, after a protocol modification.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R
====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
====Targeted therapy====
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8 & 15
**Cycle 2: 1400 mg IV once on day 1
**Cycle 3 onwards: 1750 mg IV once on day 1
*Lazertinib (Leclaza) as follows:
**Cycle 5 onwards: 240 mg PO once per day on days 1 to 21
21-day cycles
===Regimen variant #2, higher-dose amivantamab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	1. Carboplatin & Pemetrexed 	Longer PFS (primary endpoint)Median PFS: 8.3 vs 4.2 mo(HR 0.44, 95% CI 0.35-0.56)
Passaro et al. 2023 (MARIPOSA-2)	2021-12 to 2023-04 	Phase 3 (E-RT-esc)	2. Carboplatin, Pemetrexed, Amivantamab	Not formally compared
Note: This amivantamab dosage was for patients weighing 80 kg or more. Due to excess toxicity in this arm, the lazertinib was not started until cycle 5, after a protocol modification.
====Biomarker eligibility criteria====
*EGFR exon 19 deletion or p.L858R
====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
====Targeted therapy====
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1400 mg IV once on day 2, then 1750 mg IV once per day on days 8 & 15
**Cycle 2: 1750 mg IV once on day 1
**Cycle 3 onwards: 2100 mg IV once on day 1
*Lazertinib (Leclaza) as follows:
**Cycle 5 onwards: 240 mg PO once per day on days 1 to 21
21-day cycles
===References===
#MARIPOSA-2: Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, Wang J, Azuma K, Juan-Vidal O, Cobo M, Felip E, Girard N, Cortot AB, Califano R, Cappuzzo F, Owen S, Popat S, Tan JL, Salinas J, Tomasini P, Gentzler RD, William WN Jr, Reckamp KL, Takahashi T, Ganguly S, Kowalski DM, Bearz A, MacKean M, Barala P, Bourla AB, Girvin A, Greger J, Millington D, Withelder M, Xie J, Sun T, Shah S, Diorio B, Knoblauch RE, Bauml JM, Campelo RG, Cho BC; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. Epub 2023 Oct 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04988295
==Cisplatin & Pemetrexed==
===Regimen variant #1, 70/500 x 4 with pemetrexed maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Park et al. 2023 (ATTLAS)	2019-08-27 to 2022-03-11	Phase 3 (C)	ABCP 	Shorter PFSMedian PFS: 5.62 vs 8.48 mo(HR 1.61, 95% CI 1.16-2.22)
====Prior treatment criteria====
*Progression or intolerance to one or more EGFR TKIs
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 70 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 70/500 x 6 with pemetrexed maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Park et al. 2023 (ATTLAS)	2019-08-27 to 2022-03-11	Phase 3 (C)	ABCP 	Shorter PFSMedian PFS: 5.62 vs 8.48 mo(HR 1.61, 95% CI 1.16-2.22)
====Prior treatment criteria====
*Progression or intolerance to one or more EGFR TKIs
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 70 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #3, 75/500, limited duration===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Soria et al. 2015 (IMPRESS)	2012-03-29 to 2013-12-20	Phase 3 (C)	Cisplatin, Pemetrexed, Gefitinib	Did not meet primary endpoint of PFS
====Prior treatment criteria====
*Progression after first-line gefitinib
====Biomarker eligibility criteria====
*EGFR mutation positive
====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
===Regimen variant #4, 75/500 x 4 with pem maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Mok et al. 2024 (CheckMate 722)	2017-03 to 2020-06 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab 	Might have shorter PFS (primary endpoint)Median PFS: 5.4 vs 5.6 mo(HR 1.33, 95% CI 1.00-1.79)
Yang et al. 2024 (KEYNOTE-789) 	2018-07-23 to 2020-08-30	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab1b. Cisplatin, Pemetrexed, Pembrolizumab	Might have shorter OS (co-primary endpoint)Median OS: 14.7 vs 15.9 mo(HR 1.19, 95% CI 0.98-1.45)Seems to have shorter PFS (co-primary endpoint)Median PFS: 5.5 vs 5.6 mo(HR 1.25, 95% CI 1.03-1.54)
Lu et al. 2022 (ORIENT-31) 	2019-07-11 to 2022-03-31	Phase 3 (C)	1. Cis-Pem & Sintilimab 	Shorter PFS1 (primary endpoint)Median PFS: 4.3 vs 5.5 mo(HR 1.39, 95% CI 1.06-1.82)
Lu et al. 2022 (ORIENT-31) 	2019-07-11 to 2022-03-31	Phase 3 (C)	2. Cis-Pem, Bevacizumab-byva, Sintilimab 	Shorter PFS1 (primary endpoint)Median PFS: 4.3 vs 7.2 mo(HR 1.96, 95% CI 1.49-2.56)
1Reported efficacy for ORIENT-31 is based on the 2023 update.
====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
21-day cycles
===References===
#IMPRESS: Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):990-8. Epub 2015 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01544179
##Update: Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Shi X, Rukazenkov Y, Haddad V, Thress KS, Soria JC. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses. J Clin Oncol. 2017 Dec 20;35(36):4027-4034. Epub 2017 Oct 2. link to original article EuroPMC
#ORIENT-31: Lu S, Wu L, Jian H, Chen Y, Wang Q, Fang J, Wang Z, Hu Y, Sun M, Han L, Miao L, Ding C, Cui J, Li B, Pan Y, Li X, Ye F, Liu A, Wang K, Cang S, Zhou H, Sun X, Ferry D, Lin Y, Wang S, Zhang W, Zhang C. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022 Sep;23(9):1167-1179. Epub 2022 Jul 28. Erratum in: Lancet Oncol. 2022 Sep;23(9):e404. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03802240
##Update: Lu S, Wu L, Jian H, Cheng Y, Wang Q, Fang J, Wang Z, Hu Y, Han L, Sun M, Miao L, Ding C, Cui J, Wang K, Li B, Li X, Ye F, Liu A, Pan Y, Cang S, Zhou H, Sun X, Shen Y, Wang S, Zhang W, He Y. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2023 Jul;11(7):624-636. Epub 2023 May 5. link to original article EuroPMC
#CheckMate 722: Mok T, Nakagawa K, Park K, Ohe Y, Girard N, Kim HR, Wu YL, Gainor J, Lee SH, Chiu CH, Kim SW, Yang CT, Wu CL, Wu L, Lin MC, Samol J, Ichikado K, Wang M, Zhang X, Sylvester J, Li S, Forslund A, Yang JC. Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722. J Clin Oncol. 2024 Apr 10;42(11):1252-1264. Epub 2024 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02864251
#ATTLAS: Park S, Kim TM, Han JY, Lee GW, Shim BY, Lee YG, Kim SW, Kim IH, Lee S, Kim YJ, Park JH, Park SG, Lee KH, Kang EJ, Kim JW, Shin SH, Ock CY, Nam BH, Lee J, Jung HA, Sun JM, Lee SH, Ahn JS, Ahn MJ. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol. 2024 Apr 10;42(11):1241-1251. Epub 2023 Oct 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03991403
#KEYNOTE-789: Yang JC, Lee DH, Lee JS, Fan Y, de Marinis F, Iwama E, Inoue T, Rodríguez-Cid J, Zhang L, Yang CT, de la Mora Jimenez E, Zhou J, Pérol M, Lee KH, Vicente D, Ichihara E, Riely GJ, Luo Y, Chirovsky D, Pietanza MC, Bhagwati N, Lu S. Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Dec;42(34):4029-4039. Epub 2024 Aug 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03515837
#HERTHENA-Lung02: NCT05338970
==Lazertinib & Amivantamab==
===Regimen variant #1, <80 kg (IV)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leighl et al. 2024 (PALOMA-3NSCLC)	2022-08 to 2023-10 	Phase 3 (C)	Lazertinib & Amivantimab	Non-inferior pharmacokinetics
Note: There is another trial named PALOMA-3 in breast cancer; this one is renamed PALOMA-3NSCLC to avoid confusion.
====Targeted therapy====
*Lazertinib (Leclaza) as follows:
**Cycle 1: 240 mg PO once per day on days 1 to 28
**Cycle 2 onwards: 240 mg PO once per day on days 1 to 14
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 700 mg IV once on day 2, then 1050 mg IV once per day on days 8, 15, 22
**Cycle 2 onwards: 1050 mg IV once on day 1
28-day course, then 14-day cycles
===Regimen variant #2, more than 80 kg (IV)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leighl et al. 2024 (PALOMA-3NSCLC)	2022-08 to 2023-10 	Phase 3 (C)	Lazertinib & Amivantimab	Non-inferior pharmacokinetics
Note: There is another trial named PALOMA-3 in breast cancer; this one is renamed PALOMA-3NSCLC to avoid confusion.
====Targeted therapy====
*Lazertinib (Leclaza) as follows:
**Cycle 1: 240 mg PO once per day on days 1 to 28
**Cycle 2 onwards: 240 mg PO once per day on days 1 to 14
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8, 15, 22
**Cycle 2 onwards: 1400 mg IV once on day 1
28-day course, then 14-day cycles
===Regimen variant #3, <80 kg (SC)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leighl et al. 2024 (PALOMA-3NSCLC)	2022-08 to 2023-10 	Phase 3 (E-switch-ic)	Lazertinib & Amivantimab	Non-inferior pharmacokinetics
Note: There is another trial named PALOMA-3 in breast cancer; this one is renamed PALOMA-3NSCLC to avoid confusion.
====Targeted therapy====
*Lazertinib (Leclaza) as follows:
**Cycle 1: 240 mg PO once per day on days 1 to 28
**Cycle 2 onwards: 240 mg PO once per day on days 1 to 14
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 1600 mg SC once per day on days 1, 8, 15, 22
**Cycle 2 onwards: 1600 mg SC once on day 1
28-day course, then 14-day cycles
===Regimen variant #4, more than 80 kg (SC)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leighl et al. 2024 (PALOMA-3NSCLC)	2022-08 to 2023-10 	Phase 3 (E-switch-ic)	Lazertinib & Amivantimab	Non-inferior pharmacokinetics
Note: There is another trial named PALOMA-3 in breast cancer; this one is renamed PALOMA-3NSCLC to avoid confusion.
====Targeted therapy====
*Lazertinib (Leclaza) as follows:
**Cycle 1: 240 mg PO once per day on days 1 to 28
**Cycle 2 onwards: 240 mg PO once per day on days 1 to 14
*Amivantamab (Rybrevant) as follows:
**Cycle 1: 2240 mg SC once per day on days 1, 8, 15, 22
**Cycle 2 onwards: 2240 mg SC once on day 1
28-day course, then 14-day cycles
===References===
#PALOMA-3NSCLC: Leighl NB, Akamatsu H, Lim SM, Cheng Y, Minchom AR, Marmarelis ME, Sanborn RE, Chih-Hsin Yang J, Liu B, John T, Massutí B, Spira AI, Lee SH, Wang J, Li J, Liu C, Novello S, Kondo M, Tamiya M, Korbenfeld E, Moskovitz M, Han JY, Alexander M, Joshi R, Felip E, Voon PJ, Danchaivijitr P, Hsu PC, Silva Melo Cruz FJ, Wehler T, Greillier L, Teixeira E, Nguyen D, Sabari JK, Qin A, Kowalski D, Şendur MAN, Xie J, Ghosh D, Alhadab A, Haddish-Berhane N, Clemens PL, Lorenzini P, Verheijen RB, Gamil M, Bauml JM, Baig M, Passaro A; PALOMA-3 Investigators. Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study. J Clin Oncol. 2024 Oct 20;42(30):3593-3605. Epub 2024 Jun 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05388669
=Advanced or metastatic disease, EGFR p.T790M mutation=
==Osimertinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jänne et al. 2015 (AURA) 	2013 to not reported	Phase 1/2 (RT) 	 	
Goss et al. 2016 (AURA2) 	2014 	Phase 2 (RT) 	 	
Mok et al. 2016 (AURA3) 	2014-08 to 2015-09 	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 10.1 vs 4.4 mo(HR 0.30, 95% CI 0.23-0.41)Did not meet secondary endpoint of OS1Median OS: 26.8 vs 22.5 mo(HR 0.87, 95% CI 0.67-1.12)
Nie et al. 2018 (QingdaoCH20161101)	2015-04 to 2016-05 	Phase 3 (E-switch-ooc) 	Docetaxel & Bevacizumab 	Longer PFS (primary endpoint)Median PFS: 10.2 vs 3 mo(HR 0.23, 95% CI 0.12-0.38)Did not meet secondary endpoint of OS(HR 0.79, 95% CI 0.38-1.60)
1Reported OS efficacy for AURA3 is based on the 2020 update.
====Prior treatment criteria====
*AURA3: Progression after first-line EGFR TKI therapy
====Biomarker eligibility criteria====
*AURA3: EGFR p.T790M mutation
====Targeted therapy====
*Osimertinib (Tagrisso) 80 mg PO once per day
Continued indefinitely
===References===
#AURA: Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01802632
##Update: Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, Blackhall F, Haggstrom D, Yoh K, Novello S, Gold K, Hirashima T, Lin CC, Mann H, Cantarini M, Ghiorghiu S, Jänne PA. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol. 2017 Apr 20;35(12):1288-1296. Epub 2017 Feb 21. link to original article EuroPMC
##Pooled update: Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crinò L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Jänne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. link to original article EuroPMC NCT01802632
##Pooled update: Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Jänne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. Epub 2018 Dec 4. link to original article EuroPMC
#AURA2: Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, Han JY, Juan O, Dunphy F, Nishio M, Kang JH, Majem M, Mann H, Cantarini M, Ghiorghiu S, Mitsudomi T. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1643-1652. Epub 2016 Oct 14. link to original article EuroPMC NCT02094261
##Pooled subgroup analysis: Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crinò L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Jänne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. link to original article EuroPMC
##Pooled update: Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Jänne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. Epub 2018 Dec 4. link to original article EuroPMC
#AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02151981
##PRO analysis: Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-Reported Symptoms and Impact of Treatment With Osimertinib Versus Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The AURA3 Trial. J Clin Oncol. 2018 Jun 20;36(18):1853-1860. Epub 2018 May 7. link to original article EuroPMC
##Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article EuroPMC
##Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Nov;31(11):1536-1544. Epub 2020 Aug 27. link to original article EuroPMC
#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:Biomarker-specific pages
Category:Non-small cell lung cancers