Non-small cell lung cancer, EGFR-mutated

Page editor		Section editor
	Eric K. Singhi, MD MD Anderson Cancer Center Houston, TX esinghimd		Amit Kulkarni, MBBS University of Minnesota Minneapolis, MN AmitKulkarniMD

Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.
There are several related dedicated pages:

• Site-specific:
  • NSCLC, CNS metastases

37 regimens on this page 47 variants on this page

Guidelines

ASCO

• 2022: Singh et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline

ESMO

• 2022: Passaro et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer

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

Neoadjuvant therapy

Carboplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (NeoADAURA)	2020-ongoing	Phase 3 (C)	1a. Pem-Carbo & Osimertinib 1b. Pem-Cis & Osimertinib 2. Osimertinib	TBD

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

1. 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 & Osimertinib 1b. Pem-Cis & Osimertinib 2. Osimertinib	TBD

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

1. NeoADAURA: NCT04351555

Adjuvant therapy

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen variant #1, 75/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhong et al. 2017 (ADJUVANT/CTONG1104)	2011-2014	Phase 3 (C)	Gefinitib	Inferior DFS

Biomarker eligibility criteria

• EGFR exon 19 deletion or EGFR p.L858R

Preceding treatment

• Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #2, 80/25

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tada et al. 2021 (IMPACTNSCLC)	2011-2015	Phase 3 (C)	Gefinitib	Did not meet primary endpoint of DFS

Note: this trial should not be confused by those with the same name in prostate cancer and colon cancer.

Biomarker eligibility criteria

• EGFR exon 19 deletion or EGFR p.L858R

Preceding treatment

• Complete surgical resection, within 3 to 8 weeks

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. 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 contains dosing details in abstract PubMed NCT01405079
   1. 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 PubMed
2. IMPACT_NSCLC: Tada H, Mitsudomi T, Misumi T, Sugio K, Tsuboi M, Okamoto I, Iwamoto Y, Sakakura N, Sugawara S, Atagi S, Takahashi T, Hayashi H, Okada M, Inokawa H, Yoshioka H, Takahashi K, Higashiyama M, Yoshino I, Nakagawa K; West Japan Oncology Group. Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT). J Clin Oncol. 2022 Jan 20;40(3):231-241. Epub 2021 Nov 2. link to original article contains dosing details in manuscript PubMed UMIN000006252

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	Superior DFS 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

1. 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 contains dosing details in abstract PubMed NCT01405079
   1. 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 PubMed

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 & Pemetrexed 1b. Cisplatin & Vinorelbine	Superior 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

2-year course

References

1. 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 contains dosing details in abstract PubMed NCT02448797

Osimertinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2020 (ADAURA) ESMO-MCBS (A)	2015-2019	Phase 3 (E-RT-esc)	Placebo	Superior DFS (primary endpoint) DFS24: 90% vs 44% (HR 0.17, 99.06% CI 0.11-0.26)

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

3-year course

References

1. 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 contains dosing details in manuscript PubMed NCT02511106

Advanced or metastatic disease, platinum-exposed

Amivantamab monotherapy

Regimen variant #1

FDA-recommended dose

Study	Dates of enrollment	Evidence
Park et al. 2021 (CHRYSALIS) ESMO-MCBS (3)	2016-2020	Phase 1 (RT)

Note: Dosing details are from the FDA announcement. This is the recommended dose for patients weighing less than 80 kg.

Biomarker eligibility criteria

• EGFR exon 20 insertion

Targeted therapy

• Amivantamab (Rybrevant) 1050 mg IV once on day 1

7-day cycle for 4 cycles, then 14-day cycles

Regimen variant #2

FDA-recommended dose

Study	Dates of enrollment	Evidence
Park et al. 2021 (CHRYSALIS) ESMO-MCBS (3)	2016-2020	Phase 1 (RT)

Note: Dosing details are from the FDA announcement. This is the recommended dose for patients weighing 80 kg or more.

Biomarker eligibility criteria

• EGFR exon 20 insertion

Targeted therapy

• Amivantamab (Rybrevant) 1400 mg IV once on day 1

7-day cycle for 4 cycles, then 14-day cycles

References

1. 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 PubMed NCT02609776

Mobocertinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Riely et al. 2021 (AP32788-15-101) ESMO-MCBS (2)	2016-2020	Phase 1/2 (RT)

Note: this was the dose used in the phase 2 portion.

Biomarker eligibility criteria

• EGFR exon 20 insertion mutations

Targeted therapy

• Mobocertinib (Exkivity) 160 mg PO once per day

28-day cycles

References

1. AP32788-15-101: Riely GJ, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Costa DB, Tsao AS, Patel JD, Gadgeel SM, Bazhenova L, Zhu VW, West HL, Mekhail T, Gentzler RD, Nguyen D, Vincent S, Zhang S, Lin J, Bunn V, Jin S, Li S, Jänne PA. Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial. Cancer Discov. 2021 Jul;11(7):1688-1699. Epub 2021 Feb 25. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02716116
   1. Update: Zhou C, Ramalingam SS, Kim TM, Kim SW, Yang JC, Riely GJ, Mekhail T, Nguyen D, Garcia Campelo MR, Felip E, Vincent S, Jin S, Griffin C, Bunn V, Lin J, Lin HM, Mehta M, Jänne PA. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol. 2021 Dec 1;7(12):e214761. Epub 2021 Dec 16. Erratum in: JAMA Oncol. 2022 Feb 24. link to original article link to PMC article PubMed

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) ESMO-MCBS (4)	2009-2011	Phase 3 (E-RT-switch-ooc)	Cisplatin & Pemetrexed	Superior PFS Median PFS: 11.1 vs 6.9 mo (HR 0.58, 95% CI 0.43-0.78)
Wu et al. 2014 (LUX-Lung 6)	2010-2011	Phase 3 (E-RT-switch-ooc)	Cisplatin & Gemcitabine	Superior PFS 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	Superior PFS 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, given 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")
  • In LUX-Lung 3, patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed NCT00525148
   1. 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 PubMed
2. LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00949650
   1. HRQoL analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed
   2. Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
   3. 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 PubMed
   4. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
3. LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article contains dosing details in manuscript PubMed NCT01121393
   1. Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
   2. 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 PubMed
   3. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
4. 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 contains dosing details in abstract PubMed NCT01466660

Apatinib & Gefitinib

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhao et al. 2021 (CTOG1706)	2016-NR in abstract	Phase 3 (E-esc)	Gefitinib	Superior PFS Median PFS: 13.7 vs 10.2 mo (HR 0.71, 95% CI 0.54-0.95)

Targeted therapy

• Apatinib (Aitan) 500 mg PO once per day
• Gefitinib (Iressa) 250 mg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in abstract PubMed NCT02824458

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 (C)	Gefitinib	Superior PFS Median 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

1. 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 MetastaticNon-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 contains dosing details in abstract PubMed NCT03849768

Carboplatin & Docetaxel

DCb: Docetaxel & Carboplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011	Phase 3 (C)	Erlotinib	Inferior PFS

Biomarker eligibility criteria

• Biomarker: EGFR activating mutation with exon 19 deletion or p.L858R mutation in exon 21

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT00446225

Carboplatin & Gemcitabine (GCb)

GC: Gemcitabine & Carboplatin
GCa: Gemcitabine & Carboplatin
GCb: Gemcitabine & Carboplatin

Regimen variant #1, 5/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011	Phase 3 (C)	Erlotinib	Inferior PFS
Zhou et al. 2011 (CTONG-0802)	2008-2009	Phase 3 (C)	Erlotinib	Inferior PFS

Biomarker eligibility criteria

• Biomarker: EGFR activating mutation with exon 19 deletion or p.L858R mutation in exon 21

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 4 cycles

Regimen variant #2, 5/1250

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	2009-04-29 to 2010-09-09	Phase 3 (C)	1a. Carboplatin & Gemcitabine/Erlotinib 1b. GC/Erlotinib	Seems to have inferior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

28-day cycle for 4 cycles

References

1. 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 PubMed NCT00874419
   1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in abstract PubMed NCT00446225
3. 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 contains dosing details in abstract PubMed NCT00883779

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 & Gemcitabine 1b. Cisplatin & Gemcitabine	Seems to have superior OS 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 4 cycles

References

1. 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 contains dosing details in abstract PubMed NCT00883779

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
TC: Taxol (Paclitaxel) & Carboplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Maemondo et al. 2010 (NEJ002)	2006-2009	Phase 3 (C)	Gefitinib	Inferior PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for at least 3 cycles

References

1. 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 contains dosing details in manuscript PubMed UMIN000000376
   1. 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 PubMed
   2. 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 PubMed

Cisplatin & Docetaxel (DC)

DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin

Regimen variant #1, 75/75

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011	Phase 3 (C)	Erlotinib	Inferior PFS

Biomarker eligibility criteria

• EGFR exon 19 deletion or p.L858R mutation

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for up to 4 cycles

Regimen variant #2, 80/60

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mitsudomi et al. 2009 (WJTOG3405)	2006-2009	Phase 3 (C)	Gefitinib	Inferior PFS

Biomarker eligibility criteria

• EGFR exon 19 deletion or p.L858R mutation

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 90 minutes once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1, given first

21-day cycle for 3 to 6 cycles

References

1. 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 contains dosing details in manuscript PubMed UMIN000000539
   1. 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 PubMed
2. 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 contains dosing details in abstract PubMed NCT00446225

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

Regimen variant #1, 75/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2014 (LUX-Lung 6)	2010-2011	Phase 3 (C)	Afatinib	Inferior PFS

Biomarker eligibility criteria

• EGFR mutation-positive

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 75/1250 q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC)	2007-2011	Phase 3 (C)	Erlotinib	Inferior PFS
Wu et al. 2015 (ENSURE)	2011-03 to 2012-06	Phase 3 (C)	Erlotinib	Inferior PFS

Biomarker eligibility criteria

• EURTAC: EGFR exon 19 deletion or p.L858R mutation in exon 21

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 2 hours once per day on days 1 & 8

21-day cycle for up to 4 cycles

Regimen variant #3, 75/1250 q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2013 (FASTACT-2)	2009-04-29 to 2010-09-09	Phase 3 (C)	1a. Carboplatin & Gemcitabine/Erlotinib 1b. GC/Erlotinib	Seems to have inferior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

28-day cycle for 4 cycles

References

1. 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 contains dosing details in abstract PubMed NCT00446225
2. 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 contains dosing details in abstract PubMed NCT00883779
3. LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article contains dosing details in manuscript PubMed NCT01121393
   1. Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
   2. 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 PubMed
   3. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
4. 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 contains dosing details in manuscript PubMed NCT01342965

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 & Gemcitabine 1b. Cisplatin & Gemcitabine	Seems to have superior OS 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 4 cycles

References

1. 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 contains dosing details in abstract PubMed NCT00883779

Cisplatin & Pemetrexed

Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed

Regimen variant #1, limited duration

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sequist et al. 2013 (LUX-Lung 3)	2009-2011	Phase 3 (C)	Afatinib	Inferior PFS

Biomarker eligibility criteria

• Activating mutations in EGFR

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (as described in JMDB):
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
• 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 (Alimta)."

21-day cycle for 4 to 6 cycles

Regimen variant #2, with maintenance

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shi et al. 2017 (CONVINCE)	2013-01 to 2014-08	Phase 3 (C)	Icotinib	Inferior PFS

Biomarker eligibility criteria

• EGFR exon 19/21 mutations

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Supportive therapy

• (as described in JMDB):
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
• 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 (Alimta)."

21-day cycles

References

1. LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00949650
   1. HRQoL analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed
   2. Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
   3. 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 PubMed
   4. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
2. 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 contains dosing details in manuscript PubMed NCT01719536

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 superior PFS 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 PFS Median PFS: 2.6 vs 2.6 mo (HR 0.94, 95% CI 0.80-1.10)
Wu et al. 2017 (ARCHER 1050) ESMO-MCBS (3)	2013-2015	Phase 3 (E-RT-switch-ic)	Gefitinib	Superior PFS (primary endpoint) Median PFS: 14.7 vs 9.2 mo (HR 0.59, 95% CI 0.47-0.74) Seems to have superior 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

Continued indefinitely

References

1. 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 PubMed NCT00769067
2. 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 PubMed NCT01360554
3. 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 PubMed NCT01774721
   1. 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 PubMed
   2. 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 PubMed

Erlotinib monotherapy

Regimen variant #1, 150 mg/d

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rossell et al. 2012 (EURTAC) ESMO-MCBS (4)	2007-2011	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Docetaxel 1b. Carboplatin & Gemcitabine 1c. Cisplatin & Docetaxel 1d. Cisplatin & Gemcitabine	Superior PFS Median PFS: 9.7 vs 5.2 mo (HR 0.37, 95% CI 0.25-0.54)
Zhou et al. 2011 (CTONG-0802) ESMO-MCBS (4)	2008-2009	Phase 3 (E-switch-ooc)	Carboplatin & Gemcitabine	Superior PFS 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 inferior PFS
Yang et al. 2017 (CTONG 0901)	2009-2014	Phase 3 (C)	Gefitinib	Did not meet primary endpoint of PFS
Seto et al. 2014 (JO25567)	2011-2012	Randomized Phase 2 (C)	Erlotinib & Bevacizumab	Inferior PFS
Wu et al. 2015 (ENSURE)	2011-03 to 2012-06	Phase 3 (E-switch-ooc)	Cisplatin & Gemcitabine	Superior PFS Median PFS: 11.0 vs 5.5 mo (HR 0.34, 95% CI 0.22-0.51)
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	Seems to have inferior OS1
Saito et al. 2019 (NEJ026)	2015-06-03 to 2016-08-31	Phase 3 (C)	Erlotinib & Bevacizumab	Seems to have inferior PFS
Nakagawa et al. 2019 (RELAY)	2016-01-28 to 2018-02-01	Phase 3 (C)	Erlotinib & Ramucirumab	Inferior PFS
Kelly et al. 2019 (SOLARNSCLC)	2016-02-11 to 2017-12-21	Phase 3 (C)	Naquotinib	Did not meet primary endpoint of PFS
Zhou et al. 2021 (ARTEMIS-CTONG1509)	2016-05 to 2017-07	Phase 3 (C)	Erlotinib & Bevacizumab	Inferior PFS
Piccirillo et al. 2022 (BEVERLY)	2016-2019	Phase 3 (C)	Erlotinib & Bevacizumab	Inferior PFS

¹Reported efficacy for FLAURA is based on the 2019 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

Continued indefinitely

Regimen variant #2, low-dose

Study	Evidence
Yeo et al. 2010	Retrospective

Targeted therapy

• Erlotinib (Tarceva) 25 mg PO once per day

21-day cycles

References

1. 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 PubMed
2. 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 contains dosing details in abstract PubMed NCT00874419
   1. 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 PubMed
3. 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 contains dosing details in abstract PubMed NCT00446225
4. 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 contains dosing details in abstract PubMed NCT00769067
5. 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 contains dosing details in abstract PubMed JapicCTI-111390
6. 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 contains dosing details in abstract PubMed NCT01360554
7. 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 contains dosing details in manuscript PubMed NCT01342965
8. 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 contains dosing details in abstract link to PMC article PubMed NCT01024413
9. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains dosing details in manuscript PubMed NCT02296125
   1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
   2. 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 PubMed
10. 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 contains dosing details in abstract PubMed UMIN000017069
    1. 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 PubMed
11. 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 PubMed NCT02588261
12. 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 contains dosing details in abstract PubMed NCT02411448
13. 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 contains dosing details in manuscript PubMed NCT02759614
14. 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 contains dosing details in manuscript PubMed NCT02633189

Erlotinib & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Seto et al. 2014 (JO25567) ESMO-MCBS (2)	2011-2012	Randomized Phase 2 (E-esc)	Erlotinib	Superior 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 OS1 Median 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 superior 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 OS2 Median 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	Superior PFS 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	Superior PFS 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
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. 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 contains dosing details in abstract PubMed JapicCTI-111390
   1. 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 PubMed
2. 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 contains dosing details in abstract PubMed UMIN000017069
   1. 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 PubMed
3. 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 contains dosing details in manuscript PubMed NCT02759614
4. 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 contains dosing details in manuscript PubMed NCT02633189

Erlotinib & Ramucirumab

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nakagawa et al. 2019 (RELAY) ESMO-MCBS (3)	2016-01-28 to 2018-02-01	Phase 3 (E-RT-esc)	Erlotinib	Superior 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
• Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

14-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02411448

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	Superior PFS 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

21-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT03787992

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	Superior OS 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

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	Superior OS 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

1. 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 contains dosing details in manuscript PubMed UMIN000006340
2. 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 contains dosing details in manuscript PubMed CTRI/2016/08/007149

Gefitinib monotherapy

Regimen

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	Superior PFS 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	Superior PFS 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 (C)	Erlotinib	Inconclusive whether non-inferior PFS
Yang et al. 2017 (CTONG 0901)	2009-2014	Phase 3 (C)	Erlotinib	Did not meet primary endpoint of PFS
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	Inferior PFS
Hosomi et al. 2019 (NEJ009)	2011-2015	Phase 3 (C)	GCP	Inferior OS
Cheng et al. 2016 (JMIT)	2012-2013	Randomized Phase 2 (C)	P+G	Seems to have inferior PFS
Patil et al. 2017	2012-2016	Phase 3 (E-switch-ooc)	Carboplatin & Pemetrexed, then Pem maint.	Superior PFS 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 inferior OS1
Soria et al. 2017 (FLAURA)	2014-2016	Phase 3 (C)	Osimertinib	Seems to have inferior OS2
Noronha et al. 2019	2016-2018	Phase 3 (C)	GCP	Inferior OS
Lu et al. 2022 (AENEAS)	2018-11-30 to 2019-09-06	Phase 3 (C)	Aumolertinib	Inferior PFS
Shi et al. 2022 (FURLONG)	2019-05-30 to 2019-12-05	Phase 3 (C)	Furmonertinib	Inferior PFS

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

21-day cycles

References

1. 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 contains dosing details in manuscript PubMed UMIN000000539
   1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed UMIN000000376
   1. 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 PubMed
   2. 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 PubMed
3. 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 contains dosing details in manuscript link to PMC article PubMed NCT01203917
4. 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 contains dosing details in abstract PubMed NCT01466660
5. 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 contains dosing details in manuscript PubMed UMIN000002014
6. 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 contains dosing details in manuscript PubMed NCT01469000
7. 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 contains dosing details in abstract link to PMC article PubMed NCT01024413
8. 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 PubMed
9. 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 contains dosing details in manuscript PubMed NCT01774721
   1. 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 PubMed
   2. 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 PubMed
10. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains dosing details in manuscript PubMed NCT02296125
    1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
    2. 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 PubMed
11. 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 contains dosing details in manuscript PubMed UMIN000006340
12. 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 contains dosing details in manuscript PubMed CTRI/2016/08/007149
13. 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 MetastaticNon-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 contains dosing details in abstract PubMed NCT03849768
14. 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 contains dosing details in abstract PubMed NCT03787992

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 superior PFS

Targeted therapy

• Gefitinib (Iressa) 250 mg PO once per day

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycles

References

1. 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 contains dosing details in manuscript PubMed 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	Superior PFS Median PFS: 11.2 vs 7.9 mo (HR 0.61, 95% CI 0.43-0.87)

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

Targeted therapy

• Icotinib (Conmana) 125 mg PO three times per day

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed NCT01719536

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)	1. Erlotinib 2. Gefitinib	Seems to have superior OS1 Median OS: 38.6 vs 31.8 mo (HR 0.80, 95% CI 0.64-1.00)

¹Reported efficacy 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

1. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains dosing details in manuscript PubMed NCT02296125
   1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
   2. 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 PubMed
2. ECOG-ACRIN EA5182: NCT04181060
3. MARIPOSA: NCT04487080

Advanced or metastatic disease, EGFR inhibitor-exposed

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, given 1 hour before eating food

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed 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
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. 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 PubMed 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
• Cetuximab (Erbitux) 500 mg IV once on day 1

14-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT01090011

Cisplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Soria et al. 2015 (IMPRESS)	2012-2013	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 (Alimta)
• 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 (Alimta)."

21-day cycle for 4 to 6 cycles

References

1. 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 contains dosing details in manuscript PubMed NCT01544179
   1. 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 PubMed

Advanced or metastatic disease, EGFR p.T790M mutation

Carboplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mok et al. 2016 (AURA3)	2014-2015	Phase 3 (C)	Osimertinib	Inferior PFS

Prior treatment criteria

• Progression after first-line EGFR TKI therapy

Biomarker eligibility criteria

• EGFR p.T790M mutation

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

• Optional pemetrexed maintenance

References

1. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02151981
   1. 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 PubMed
   2. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
   3. 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 PubMed

Cisplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mok et al. 2016 (AURA3)	2014-2015	Phase 3 (C)	Osimertinib	Inferior PFS

Prior treatment criteria

• Progression after first-line EGFR TKI therapy

Biomarker eligibility criteria

• EGFR p.T790M mutation

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Supportive therapy

• (as described in Scagliotti et al. 2008):
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
• 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 (Alimta)."

21-day cycle for 4 to 6 cycles

Subsequent treatment

• AURA3, patients without disease progression after 4 cycles: Optional pemetrexed maintenance

References

1. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02151981
   1. 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 PubMed
   2. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
   3. 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 PubMed

Docetaxel & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nie et al. 2018 (QingdaoCH20161101)	2015-2016	Phase 3 (C)	Osimertinib	Inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Biomarker eligibility criteria

• EGFR p.T790M mutation

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02959749

Osimertinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jänne et al. 2015 (AURA)	2013-NR	Phase 1/2 (RT)
Goss et al. 2016 (AURA2)	2014	Phase 2 (RT)
Mok et al. 2016 (AURA3) ESMO-MCBS (4)	2014-2015	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Superior 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 OS1 Median OS: 26.8 vs 22.5 mo (HR 0.87, 95% CI 0.67-1.12)
Nie et al. 2018 (QingdaoCH20161101)	2015-2016	Phase 3 (E-switch-ooc)	Docetaxel & Bevacizumab	Superior PFS 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 efficacy for OS endpoint in 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

1. 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 contains dosing details in manuscript PubMed NCT01802632
   1. 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 PubMed
   2. 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 PubMed NCT01802632
   3. 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 PubMed
2. 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 PubMed NCT02094261
   1. 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 PubMed
   2. 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 PubMed
3. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02151981
   1. 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 PubMed
   2. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
   3. 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 PubMed
4. 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 contains dosing details in abstract PubMed NCT02959749