Non-small cell lung cancer, EGFR-mutated

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Eric K. Singhi, MD
MD Anderson Cancer Center
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Amit Kulkarni, MBBS
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Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.
There are several related dedicated pages:

45 regimens on this page
56 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

ESMO

IASLC

NCCN

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 if different primary endpoint of major pathological response

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

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 if different primary endpoint of MPR

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

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

Chemotherapy

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

Chemotherapy

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. IMPACTNSCLC: Tada H, Mitsudomi T, Misumi T, Sugio K, Tsuboi M, Okamoto I, Iwamoto Y, Sakakura N, Sugawara S, Atagi S, Takahashi T, Hayashi H, Okada M, Inokawa H, Yoshioka H, Takahashi K, Higashiyama M, Yoshino I, Nakagawa K; West Japan Oncology Group. Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT). J Clin Oncol. 2022 Jan 20;40(3):231-241. Epub 2021 Nov 2. link to original article 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 (primary endpoint)
Median DFS: 28.7 vs 18 mo
(HR 0.60, 95% CI 0.42-0.87)

Biomarker eligibility criteria

  • Biomarker: EGFR exon 19 deletion and exon 21 L858R activating mutations

Preceding treatment

Targeted therapy

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

Targeted therapy

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) 2015-11 to 2019-02 Phase 3 (E-RT-esc) Placebo Superior DFS1 (primary endpoint)
DFS48: 73% vs 38%
(HR 0.27, 95% CI 0.21-0.34)

Superior OS2 (secondary endpoint)
OS60: 85% vs 73%
(HR 0.49, 95.03% CI 0.33-0.73)

1Reported efficacy is based on the January 2023 update.
2Reported efficacy is based on the June 2023 update.

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R mutation, alone or in combination with other EGFR mutations

Preceding treatment

Targeted therapy

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
    1. Update: Herbst RS, Wu YL, John T, Grohe C, Majem M, Wang J, Kato T, Goldman JW, Laktionov K, Kim SW, Yu CJ, Vu HV, Lu S, Lee KY, Mukhametshina G, Akewanlop C, de Marinis F, Bonanno L, Domine M, Shepherd FA, Urban D, Huang X, Bolanos A, Stachowiak M, Tsuboi M. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol. 2023 Apr 1;41(10):1830-1840. Epub 2023 Jan 31. link to original article link to PMC article PubMed
    2. Update: Tsuboi M, Herbst RS, John T, Kato T, Majem M, Grohé C, Wang J, Goldman JW, Lu S, Su WC, de Marinis F, Shepherd FA, Lee KH, Le NT, Dechaphunkul A, Kowalski D, Poole L, Bolanos A, Rukazenkov Y, Wu YL; ADAURA Investigators. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023 Jul 13;389(2):137-147. Epub 2023 Jun 4. link to original article PubMed

Advanced or metastatic disease, platinum-exposed

Amivantamab monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Park et al. 2021 (CHRYSALIS) 2016-2020 Phase 1 (RT)

Note: Dosing details are from the FDA announcement.

Biomarker eligibility criteria

  • EGFR exon 20 insertion

Targeted therapy

  • Amivantamab (Rybrevant) by the following weight-based criteria:
    • Less than 80 kg: 1050 mg IV once on day 1
    • 80 kg or more: 1400 mg IV once on day 1

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

References

  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) 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

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

Continued indefinitely


Regimen variant #2, 40 mg/day

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2012 (LUX-Lung 2) 2007-2009 Phase 2 (RT) ORR: 61%
Sequist et al. 2013 (LUX-Lung 3) 2009-2011 Phase 3 (E-RT-switch-ooc) Cisplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 11.1 vs 6.9 mo
(HR 0.58, 95% CI 0.43-0.78)
Wu et al. 2014 (LUX-Lung 6) 2010-04-27 to 2011-11-16 Phase 3 (E-RT-switch-ooc) Cisplatin & Gemcitabine Superior PFS (primary endpoint)
Median PFS: 11 vs 5.6 mo
(HR 0.28, 95% CI 0.20-0.39)
Park et al. 2016 (LUX-Lung 7) 2011-2013 Randomized Phase 2 (E-switch-ic) Gefitinib Superior PFS (co-primary endpoint)
Median PFS: 11 vs 10.9 mo
(HR 0.73, 95% CI 0.57-0.95)

Biomarker eligibility criteria

  • LUX-Lung 2: activating EGFR mutations within exons 18–21
  • LUX-Lung 3 & LUX-Lung 6: Activating EGFR mutation with exon 19 deletions, L858R, insertions in exon 20, L861Q, G719S, G719A, G719C, T790M, or S768I
  • LUX-Lung 7: Activating EGFR mutation with exon 19 deletion and/or L858R

Targeted therapy

  • Afatinib (Gilotrif) 40 mg PO once per day, taken 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")

Continued indefinitely

Dose and schedule modifications

  • In LUX-Lung 3, patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.

References

  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. Epub 2015 Jan 12. 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. Epub 2016 Jan 25. 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. Epub 2014 Jan 15. 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. Epub 2015 Jan 12. 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. Epub 2016 Jan 25. 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 (CTONG1706) 2017-08 to 2018-12 Phase 3 (E-esc) Gefitinib Superior PFS (primary endpoint)
Median PFS: 13.7 vs 10.2 mo
(HR 0.71, 95% CI 0.54-0.95)

Biomarker eligibility criteria

  • EGFR exon 19 deletion or exon 21 L858R mutation

Targeted therapy

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 (E-switch-ic) 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

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 Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022 Sep 20;40(27):3162-3171. Epub 2022 May 17. link to original article contains dosing details in abstract link to PMC article 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

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) 2008-08-24 to 2009-07-17 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

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

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
Superior PFS (primary endpoint)
Median PFS: 7.6 vs 6 mo
(HR 0.57, 95% CI 0.47-0.69)

Seems to have superior OS (secondary endpoint)
Median OS: 18.3 vs 15.2 mo
(HR 0.79, 95% CI 0.64-0.99)

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

Chemotherapy

Targeted therapy

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

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

Carboplatin & Pemetrexed

Regimen variant #1, 4 cycles of carboplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (PAPILLON) 2020-12 to 2022-11 Phase 3 (C) Carboplatin, Pemetrexed, Amivantamab Inferior PFS

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

Biomarker eligibility criteria

  • EGFR exon 20 insertions

Chemotherapy

21-day cycles


Regimen variant #2, 6 cycles of carboplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patil et al. 2017 2012-2016 Phase 3 (C) Gefitinib Inferior PFS

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

Biomarker eligibility criteria

  • Activating EGFR mutation in exons 18, 19, or 21

Chemotherapy

21-day cycles

References

  1. 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 contains dosing details in manuscript PubMed
  2. PAPILLON: Zhou C, Tang KJ, Cho BC, Liu B, Paz-Ares L, Cheng S, Kitazono S, Thiagarajan M, Goldman JW, Sabari JK, Sanborn RE, Mansfield AS, Hung JY, Boyer M, Popat S, Mourão Dias J, Felip E, Majem M, Gumus M, Kim SW, Ono A, Xie J, Bhattacharya A, Agrawal T, Shreeve SM, Knoblauch RE, Park K, Girard N; PAPILLON Investigators. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023 Nov 30;389(22):2039-2051. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT04538664

Carboplatin, Pemetrexed, Amivantamab

Regimen variant #1, lower-dose amivantamab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (PAPILLON) 2020-12 to 2022-11 Phase 3 (E-esc) Carboplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 11.4 vs 6.7 mo
(HR 0.40, 95% CI 0.30-0.53)

Note: This amivantamab dosage was for patients weighing less than 80 kg.

Biomarker eligibility criteria

  • EGFR exon 20 insertions

Chemotherapy

Targeted therapy

  • Amivantamab (Rybrevant) as follows:
    • Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8 & 15
    • Cycle 2: 1400 mg IV once on day 1
    • Cycle 3 onwards: 1750 mg IV once on day 1

21-day cycles


Regimen variant #2, higher-dose amivantamab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (PAPILLON) 2020-12 to 2022-11 Phase 3 (E-esc) Carboplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 11.4 vs 6.7 mo
(HR 0.40, 95% CI 0.30-0.53)

Note: This amivantamab dosage was for patients weighing 80 kg or more.

Biomarker eligibility criteria

  • EGFR exon 20 insertions

Chemotherapy

Targeted therapy

  • Amivantamab (Rybrevant) as follows:
    • Cycle 1: 350 mg IV once on day 1, then 1400 mg IV once on day 2, then 1750 mg IV once per day on days 8 & 15
    • Cycle 2: 1750 mg IV once on day 1
    • Cycle 3 onwards: 2100 mg IV once on day 1

21-day cycles

References

  1. PAPILLON: Zhou C, Tang KJ, Cho BC, Liu B, Paz-Ares L, Cheng S, Kitazono S, Thiagarajan M, Goldman JW, Sabari JK, Sanborn RE, Mansfield AS, Hung JY, Boyer M, Popat S, Mourão Dias J, Felip E, Majem M, Gumus M, Kim SW, Ono A, Xie J, Bhattacharya A, Agrawal T, Shreeve SM, Knoblauch RE, Park K, Girard N; PAPILLON Investigators. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023 Nov 30;389(22):2039-2051. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT04538664

Carboplatin, Pemetrexed, Osimertinib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Planchard et al. 2023 (FLAURA2) 2020-06-01 to 2021-12-22 Phase 3 (E-RT-esc) Osimertinib Superior PFS (primary endpoint)
PFS24: 57% vs 41%
(HR 0.62, 95% CI 0.49-0.79)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. FLAURA2: Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Epub 2023 Nov 8. link to original article contains dosing details in manuscript PubMed NCT04035486

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

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

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) 2010-04-27 to 2011-11-16 Phase 3 (C) Afatinib Inferior PFS

Biomarker eligibility criteria

  • EGFR mutation-positive

Chemotherapy

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

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

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. Epub 2014 Jan 15. 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. Epub 2015 Jan 12. 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. Epub 2016 Jan 25. 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
Superior PFS (primary endpoint)
Median PFS: 7.6 vs 6 mo
(HR 0.57, 95% CI 0.47-0.69)

Seems to have superior OS (secondary endpoint)
Median OS: 18.3 vs 15.2 mo
(HR 0.79, 95% CI 0.64-0.99)

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

Chemotherapy

Targeted therapy

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

Supportive therapy

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

Supportive therapy

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. Epub 2015 Jan 12. 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. Epub 2016 Jan 25. 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

Cisplatin, Pemetrexed, Osimertinib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Planchard et al. 2023 (FLAURA2) 2020-06-01 to 2021-12-22 Phase 3 (E-RT-esc) Osimertinib Superior PFS (primary endpoint)
PFS24: 57% vs 41%
(HR 0.62, 95% CI 0.49-0.79)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. FLAURA2: Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Epub 2023 Nov 8. link to original article contains dosing details in manuscript PubMed NCT04035486

Dacomitinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ramalingam et al. 2012 (A7471028) 2008-2009 Randomized Phase 2 (E-switch-ic) Erlotinib Seems to have superior PFS (primary endpoint)
Median PFS: 2.9 vs 1.9 mo
(HR 0.66, 95% CI 0.47-0.91)
Ramalingam et al. 2014 (ARCHER 1009) 2011-2013 Phase 3 (E-switch-ic) Erlotinib Did not meet primary endpoint of PFS
Median PFS: 2.6 vs 2.6 mo
(HR 0.94, 95% CI 0.80-1.10)
Wu et al. 2017 (ARCHER 1050) 2013-2015 Phase 3 (E-RT-switch-ic) Gefitinib 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

28-day cycles

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 contains dosing details in manuscript 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 contains dosing details in manuscript 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 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

Erlotinib monotherapy

Regimen variant #1, 150 mg/d

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rossell et al. 2012 (EURTAC) 2007-2011 Phase 3 (E-RT-switch-ooc) 1a. Carboplatin & Docetaxel
1b. Carboplatin & Gemcitabine
1c. Cisplatin & Docetaxel
1d. Cisplatin & Gemcitabine
Superior PFS (primary endpoint)
Median PFS: 9.7 vs 5.2 mo
(HR 0.37, 95% CI 0.25-0.54)
Zhou et al. 2011 (CTONG-0802) 2008-08-24 to 2009-07-17 Phase 3 (E-switch-ooc) Carboplatin & Gemcitabine Superior PFS (primary endpoint)
Median PFS: 13.1 vs 4.6 mo
(HR 0.16, 95% CI 0.10-0.26)
Ramalingam et al. 2012 (A7471028) 2008-2009 Randomized Phase 2 (C) Dacomitinib Seems to have inferior PFS
Yang et al. 2017 (CTONG 0901) 2009-2014 Phase 3 (E-switch-ic) 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 (primary endpoint)
Median PFS: 11.0 vs 5.5 mo
(HR 0.34, 95% CI 0.22-0.51)

Did not meet secondary endpoint of OS
Median OS: 26.3 vs 25.5 mo
(HR 0.91, 95% CI 0.63-1.31)
Ramalingam et al. 2014 (ARCHER 1009) 2011-2013 Phase 3 (C) Dacomitinib Did not meet primary endpoint of PFS
Soria et al. 2017 (FLAURA) 2014-2016 Phase 3 (C) Osimertinib 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

28-day cycles


Regimen variant #2, low-dose

Study Evidence
Yeo et al. 2010 Retrospective

Targeted therapy

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
    1. PRO analysis: Yoh K, Atagi S, Reck M, Garon EB, Ponce Aix S, Moro-Sibilot D, Winfree KB, Frimodt-Moller B, Zimmermann A, Visseren-Grul C, Nakagawa K; RELAY investigators. Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. Curr Med Res Opin. 2020 Oct;36(10):1667-1675. Epub 2020 Aug 28. link to original article PubMed
  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) 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 (primary endpoint)
Median PFS: 17.9 vs 11.2 mo
(HR 0.55, 95% CI 0.41-0.73)
Piccirillo et al. 2022 (BEVERLY) 2016-2019 Phase 3 (E-esc) Erlotinib Superior PFS (primary endpoint)
Median PFS: 15.4 vs 9.6 mo
(HR 0.66, 95% CI 0.47-0.92)

1Reported efficacy for JO25567 is based on the 2020 update.
2Reported efficacy for OS for NEJ026 is based on the 2021 update.

Targeted therapy

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) 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

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
    1. PRO analysis: Yoh K, Atagi S, Reck M, Garon EB, Ponce Aix S, Moro-Sibilot D, Winfree KB, Frimodt-Moller B, Zimmermann A, Visseren-Grul C, Nakagawa K; RELAY investigators. Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. Curr Med Res Opin. 2020 Oct;36(10):1667-1675. Epub 2020 Aug 28. link to original article PubMed

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 (primary endpoint)
Median PFS: 20.8 vs 11.1 mo
(HR 0.44, 95% CI 0.34-0.58)

Biomarker eligibility criteria

  • FURLONG: EGFR exon 19 deletion or EGFR p.L858R mutation

Targeted therapy

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 PFS (primary endpoint)
Median PFS: 16 vs 8 mo
(HR 0.51, 95% CI 0.39-0.66)

Superior OS (secondary endpoint)
Median OS: NYR vs 17 mo
(HR 0.45, 95% CI 0.31-0.65)

Targeted therapy

Chemotherapy

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 (co-primary endpoint)
Median OS: 50.9 vs 38.8 mo
(HR 0.72, 95% CI 0.55-0.95)

Targeted therapy

Chemotherapy

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 (primary endpoint)
Median PFS: 9.2 vs 6.3 mo
(HR 0.49, 95% CI 0.34-0.71)
Maemondo et al. 2010 (NEJ002) 2006-2009 Phase 3 (E-switch-ooc) Carboplatin & Paclitaxel Superior PFS (primary endpoint)
Median PFS: 10.8 vs 5.4 mo
(HR 0.30, 95% CI 0.22-0.41)
Urata et al. 2016 (WJOG 5108L) 2009-2012 Phase 3 (E-switch-ic) Erlotinib Inconclusive whether non-inferior PFS
Yang et al. 2017 (CTONG 0901) 2009-2014 Phase 3 (C) Erlotinib 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 Superior PFS (primary endpoint)
Median PFS: 8.4 vs 5.6 mo
(HR 0.66, 95% CI 0.51-0.85)
Wu et al. 2017 (ARCHER 1050) 2013-2015 Phase 3 (C) Dacomitinib Seems to have 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
Zhao et al. 2021 (CTONG1706) 2017-08 to 2018-12 Phase 3 (C) Apatinib & Gefitinib Inferior PFS
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
Cho et al. 2023 (LASER301) 2020-02 to 2021-09 Phase 3 (C) Lazertinib 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

Continued indefinitely

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. 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
  14. AENEAS: Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, Chen S, Lv D, Zhang G, Liu C, Li J, Yu X, Lin Z, Yu Z, Wang Z, Cui J, Xu X, Fang J, Feng J, Xu Z, Ma R, Hu J, Yang N, Zhou X, Wu X, Hu C, Zhang Z, Lu Y, Hu Y, Jiang L, Wang Q, Guo R, Zhou J, Li B, Hu C, Tong W, Zhang H, Ma L, Chen Y, Jie Z, Yao Y, Zhang L, Jie W, Li W, Xiong J, Ye X, Duan J, Yang H, Sun M, Sun C, Wei H, Li C, Ali SM, Miller VA, Wu Q. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022 Sep 20;40(27):3162-3171. Epub 2022 May 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT03849768
  15. 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
  16. LASER301: Cho BC, Ahn MJ, Kang JH, Soo RA, Reungwetwattana T, Yang JC, Cicin I, Kim DW, Wu YL, Lu S, Lee KH, Pang YK, Zimina A, Fong CH, Poddubskaya E, Sezer A, How SH, Danchaivijitr P, Kim Y, Lim Y, An T, Lee H, Byun HM, Zaric B. Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301. J Clin Oncol. 2023 Sep 10;41(26):4208-4217. Epub 2023 Jun 28. link to original article contains dosing details in abstract PubMed NCT04248829

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 (primary endpoint)

Targeted therapy

Chemotherapy

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 (primary endpoint)
Median PFS: 11.2 vs 7.9 mo
(HR 0.61, 95% CI 0.43-0.87)
Lu et al. 2023 2019-12-24 to 2020-12-18 Phase 3 (C) Befotertinib Inferior PFS

Note: this drug is only approved in China; eligible patients in CONVINCE had stage IIIB/IV lung adenocarcinoma.

Biomarker eligibility criteria

  • CONVINCE: EGFR exon 19 or 21 mutations
  • Lu et al. 2023: EGFR exon 19 deletions or exon 21 Leu858Arg mutation

Targeted therapy

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
  2. Lu S, Zhou J, Jian H, Wu L, Cheng Y, Fan Y, Fang J, Chen G, Zhang Z, Lv D, Jiang L, Wu R, Jin X, Zhang X, Zhang J, Xie C, Sun G, Huang D, Cui J, Guo R, Han Z, Chen Z, Liang J, Zhuang W, Hu X, Zang A, Zhang Y, Cang S, Lan Y, Chen X, Liu L, Li X, Chen J, Ma R, Guo Y, Sun P, Tian P, Pan Y, Liu Z, Cao P, Ding L, Wang Y, Yuan X, Wu P. Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study. Lancet Respir Med. 2023 Oct;11(10):905-915. Epub 2023 May 24. link to original article PubMed NCT04206072

Lazertinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cho et al. 2023 (LASER301) 2020-02 to 2021-09 Phase 3 (E-switch-ic) Gefitinib Superior PFS (primary endpoint)
Median PFS: 20.6 vs 9.7 mo
(HR 0.45, 95% CI 0.34-0.58)

Targeted therapy

Continued indefinitely

References

  1. LASER301: Cho BC, Ahn MJ, Kang JH, Soo RA, Reungwetwattana T, Yang JC, Cicin I, Kim DW, Wu YL, Lu S, Lee KH, Pang YK, Zimina A, Fong CH, Poddubskaya E, Sezer A, How SH, Danchaivijitr P, Kim Y, Lim Y, An T, Lee H, Byun HM, Zaric B. Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301. J Clin Oncol. 2023 Sep 10;41(26):4208-4217. Epub 2023 Jun 28. link to original article contains dosing details in abstract PubMed NCT04248829

Osimertinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Soria et al. 2017 (FLAURA) 2014-2016 Phase 3 (E-RT-switch-ic) 1a. Erlotinib
1b. Gefitinib
Superior PFS (primary endpoint)
Median PFS: 18.9 vs 10.2 mo
(HR 0.46, 95% CI 0.37-0.57)

Seems to have superior OS1 (secondary endpoint)
Median OS: 38.6 vs 31.8 mo
(HR 0.80, 95% CI 0.64-1.00)
Planchard et al. 2023 (FLAURA2) 2020-06-01 to 2021-12-22 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Osimertinib
1b. Cisplatin, Pemetrexed, Osimertinib
Inferior PFS

1Reported efficacy for FLAURA is based on the 2019 update.

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R mutation

Targeted therapy

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. FLAURA2: Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Epub 2023 Nov 8. link to original article contains dosing details in manuscript PubMed NCT04035486
  3. ECOG-ACRIN EA5182: NCT04181060
  4. 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

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

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

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

Carboplatin & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2) 2021-12 to 2023-04 Phase 3 (C) 1. Carboplatin, Pemetrexed, Amivantamab
2. Carboplatin, Lazertinib, Pemetrexed, Amivantamab
Inferior PFS
Awaiting publication (HERTHENA-Lung02) 2022-ongoing Phase 3 (C) Patritumab-DXd TBD if different primary endpoint of PFS

Prior treatment criteria

  • MARIPOSA-2: Progression after osimertinib
  • HERTHENA-Lung02: Progression after first-line EGFR TKI therapy

Chemotherapy

21-day cycles

References

  1. MARIPOSA-2: Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, Wang J, Azuma K, Juan-Vidal O, Cobo M, Felip E, Girard N, Cortot AB, Califano R, Cappuzzo F, Owen S, Popat S, Tan JL, Salinas J, Tomasini P, Gentzler RD, William WN Jr, Reckamp KL, Takahashi T, Ganguly S, Kowalski DM, Bearz A, MacKean M, Barala P, Bourla AB, Girvin A, Greger J, Millington D, Withelder M, Xie J, Sun T, Shah S, Diorio B, Knoblauch RE, Bauml JM, Campelo RG, Cho BC; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. Epub 2023 Oct 23. link to original article contains dosing details in manuscript PubMed NCT04988295
  2. HERTHENA-Lung02: NCT05338970

Carboplatin, Pemetrexed, Amivantamab

Regimen variant #1, lower-dose amivantamab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2) 2021-12 to 2023-04 Phase 3 (E-esc) 1. Carboplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.48, 95% CI 0.36-0.64)
2. Carboplatin, Lazertinib, Pemetrexed, Amivantamab Not formally compared

Note: This amivantamab dosage was for patients weighing less than 80 kg.

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R

Chemotherapy

Targeted therapy

  • Amivantamab (Rybrevant) as follows:
    • Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8 & 15
    • Cycle 2: 1400 mg IV once on day 1
    • Cycle 3 onwards: 1750 mg IV once on day 1

21-day cycles


Regimen variant #2, higher-dose amivantamab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2) 2021-12 to 2023-04 Phase 3 (E-esc) 1. Carboplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.48, 95% CI 0.36-0.64)
2. Carboplatin, Lazertinib, Pemetrexed, Amivantamab Not formally compared

Note: This amivantamab dosage was for patients weighing 80 kg or more.

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R

Chemotherapy

Targeted therapy

  • Amivantamab (Rybrevant) as follows:
    • Cycle 1: 350 mg IV once on day 1, then 1400 mg IV once on day 2, then 1750 mg IV once per day on days 8 & 15
    • Cycle 2: 1750 mg IV once on day 1
    • Cycle 3 onwards: 2100 mg IV once on day 1

21-day cycles

References

  1. MARIPOSA-2: Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, Wang J, Azuma K, Juan-Vidal O, Cobo M, Felip E, Girard N, Cortot AB, Califano R, Cappuzzo F, Owen S, Popat S, Tan JL, Salinas J, Tomasini P, Gentzler RD, William WN Jr, Reckamp KL, Takahashi T, Ganguly S, Kowalski DM, Bearz A, MacKean M, Barala P, Bourla AB, Girvin A, Greger J, Millington D, Withelder M, Xie J, Sun T, Shah S, Diorio B, Knoblauch RE, Bauml JM, Campelo RG, Cho BC; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. Epub 2023 Oct 23. link to original article contains dosing details in manuscript PubMed NCT04988295

Carboplatin, Lazertinib, Pemetrexed, Amivantamab

Regimen variant #1, lower-dose amivantamab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2) 2021-12 to 2023-04 Phase 3 (E-esc) 1. Carboplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 8.3 vs 4.2 mo
(HR 0.44, 95% CI 0.35-0.56)
2. Carboplatin, Pemetrexed, Amivantamab Not formally compared

Note: This amivantamab dosage was for patients weighing less than 80 kg. Due to excess toxicity in this arm, the lazertinib was not started until cycle 5, after a protocol modification.

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R

Chemotherapy

Targeted therapy

  • Amivantamab (Rybrevant) as follows:
    • Cycle 1: 350 mg IV once on day 1, then 1050 mg IV once on day 2, then 1400 mg IV once per day on days 8 & 15
    • Cycle 2: 1400 mg IV once on day 1
    • Cycle 3 onwards: 1750 mg IV once on day 1
  • Lazertinib (Leclaza) as follows:
    • Cycle 5 onwards: 240 mg PO once per day on days 1 to 21

21-day cycles


Regimen variant #2, higher-dose amivantamab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Passaro et al. 2023 (MARIPOSA-2) 2021-12 to 2023-04 Phase 3 (E-esc) 1. Carboplatin & Pemetrexed Superior PFS (primary endpoint)
Median PFS: 8.3 vs 4.2 mo
(HR 0.44, 95% CI 0.35-0.56)
2. Carboplatin, Pemetrexed, Amivantamab Not formally compared

Note: This amivantamab dosage was for patients weighing 80 kg or more. Due to excess toxicity in this arm, the lazertinib was not started until cycle 5, after a protocol modification.

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R

Chemotherapy

Targeted therapy

  • Amivantamab (Rybrevant) as follows:
    • Cycle 1: 350 mg IV once on day 1, then 1400 mg IV once on day 2, then 1750 mg IV once per day on days 8 & 15
    • Cycle 2: 1750 mg IV once on day 1
    • Cycle 3 onwards: 2100 mg IV once on day 1
  • Lazertinib (Leclaza) as follows:
    • Cycle 5 onwards: 240 mg PO once per day on days 1 to 21

21-day cycles

References

  1. MARIPOSA-2: Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, Wang J, Azuma K, Juan-Vidal O, Cobo M, Felip E, Girard N, Cortot AB, Califano R, Cappuzzo F, Owen S, Popat S, Tan JL, Salinas J, Tomasini P, Gentzler RD, William WN Jr, Reckamp KL, Takahashi T, Ganguly S, Kowalski DM, Bearz A, MacKean M, Barala P, Bourla AB, Girvin A, Greger J, Millington D, Withelder M, Xie J, Sun T, Shah S, Diorio B, Knoblauch RE, Bauml JM, Campelo RG, Cho BC; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. Epub 2023 Oct 23. link to original article contains dosing details in manuscript PubMed NCT04988295

Cisplatin & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Soria et al. 2015 (IMPRESS) 2012-03-29 to 2013-12-20 Phase 3 (C) Cisplatin, Pemetrexed, Gefitinib Did not meet primary endpoint of PFS

Prior treatment criteria

  • Progression after first-line gefitinib

Biomarker eligibility criteria

  • EGFR mutation positive

Chemotherapy

Supportive therapy

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
  2. HERTHENA-Lung02: NCT05338970

Advanced or metastatic disease, EGFR p.T790M mutation

Carboplatin & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2016 (AURA3) 2014-08 to 2015-09 Phase 3 (C) Osimertinib Inferior PFS

Prior treatment criteria

  • Progression after first-line EGFR TKI therapy

Biomarker eligibility criteria

  • EGFR p.T790M mutation

Chemotherapy

Supportive therapy

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

21-day cycle for 4 to 6 cycles

Subsequent treatment

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) 2014-08 to 2015-09 Phase 3 (C) Osimertinib Inferior PFS

Prior treatment criteria

  • Progression after first-line EGFR TKI therapy

Biomarker eligibility criteria

  • EGFR p.T790M mutation

Chemotherapy

Supportive therapy

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) 2015-04 to 2016-05 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

Targeted therapy

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) 2014-08 to 2015-09 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) 2015-04 to 2016-05 Phase 3 (E-switch-ooc) Docetaxel & Bevacizumab Superior PFS (primary endpoint)
Median PFS: 10.2 vs 3 mo
(HR 0.23, 95% CI 0.12-0.38)

Did not meet secondary endpoint of OS
(HR 0.79, 95% CI 0.38-1.60)

1Reported 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

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