Non-small cell lung cancer - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main NSCLC page for current regimens.

24 regimens on this page
25 variants on this page

Contents


Neoadjuvant therapy

MIC

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MIC: Mitomycin, Ifosfamide, Cisplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Rosell et al. 1994 Phase III (E) No preoperative therapy Superior OS
Depierre et al. 2002 Phase III (E) No preoperative therapy Seems not superior

Chemotherapy

Subsequent treatment

References

  1. Rosell R, Gómez-Codina J, Camps C, Maestre J, Padille J, Cantó A, Mate JL, Li S, Roig J, Olazábal A, Canela M, Ariza A, Skacel Z, Morera-Prat J, Abad A. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994 Jan 20;330(3):153-8. link to original article PubMed
  2. Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, Braun D, Breton JL, Lemarié E, Gouva S, Paillot N, Bréchot JM, Janicot H, Lebas FX, Terrioux P, Clavier J, Foucher P, Monchâtre M, Coëtmeur D, Level MC, Leclerc P, Blanchon F, Rodier JM, Thiberville L, Villeneuve A, Westeel V, Chastang C; French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002 Jan 1;20(1):247-53. link to original article PubMed

Adjuvant therapy

Radiation therapy

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Keller et al. 2000 (ECOG E3590) Phase III (C) Cisplatin, Etoposide, RT Seems not superior

Preceding treatment

Radiotherapy

5-week course

References

  1. ECOG E3590: Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH; Eastern Cooperative Oncology Group. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med. 2000 Oct 26;343(17):1217-22. link to original article contains protocol PubMed

Induction therapy for locally advanced disease

MIC

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MIC: Mitomycin, Ifosfamide, Cisplatin
MIP: Mitomycin, Ifosfamide, Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Sculier et al. 1999 Non-randomized portion of RCT
Sculier et al. 2004 Phase III (C) SuperMIP Seems not superior

Chemotherapy

Subsequent treatment

  • Sculier et al. 1999: MIP x 3 versus RT
  • Sculier et al. 2004: RT

References

  1. Sculier JP, Paesmans M, Lafitte JJ, Baumöhl J, Thiriaux J, van Cutsem O, Recloux P, Bureau G, Berchier MC, Zacharias C, Mommen P, Bosschaerts T, Berghmans T, van Houtte P, Ninane V, Klastersky J; European Lung Cancer Working Party. A randomised phase III trial comparing consolidation treatment with further chemotherapy to chest irradiation in patients with initially unresectable locoregional non-small-cell lung cancer responding to induction chemotherapy. Ann Oncol. 1999 Mar;10(3):295-303. link to original article PubMed
  2. Sculier JP, Lafitte JJ, Berghmans T, Van Houtte P, Lecomte J, Thiriaux J, Efremidis A, Koumakis G, Giner V, Richez M, Corhay JL, Wackenier P, Lothaire P, Paesmans M, Mommen P, Ninane V; European Lung Cancer Working Party. A phase III randomised study comparing two different dose-intensity regimens as induction chemotherapy followed by thoracic irradiation in patients with advanced locoregional non-small-cell lung cancer. Ann Oncol. 2004 Mar;15(3):399-409. link to original article PubMed

PEV

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PEV: Platinol (Cisplatin), Etoposide, Vinblastine

Regimen

Study Evidence Comparator Comparative Efficacy
Kim et al. 2002 Phase III (E) No induction Seems not superior

Chemotherapy

Subsequent treatment

References

  1. Kim TY, Yang SH, Lee SH, Park YS, Im YH, Kang WK, Ha SH, Park CI, Heo DS, Bang YJ, Kim NK. A phase III randomized trial of combined chemoradiotherapy versus radiotherapy alone in locally advanced non-small-cell lung cancer. Am J Clin Oncol. 2002 Jun;25(3):238-43. link to original article PubMed

Definitive therapy for locally advanced disease

MVP & RT

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MVP & RT: Mitomycin, Vindesine, Platinol (Cisplatin), Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Furuse et al. 1999 (JCOG9202) Phase III (E) MVP, then RT Seems to have superior OS

Chemotherapy

Radiotherapy

References

  1. JCOG9202: Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, Katagami N, Ariyoshi Y. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999 Sep;17(9):2692-9. link to original article PubMed

Consolidation or maintenance after definitive therapy for inoperable disease

Bacillus Calmette-Guérin (BCG) monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Pines 1976 Randomized (C) Observation Seems to have superior OS

Preceding treatment

  • RT

Immunotherapy

References

  1. Pines A. A 5-year controlled study of BCG and radiotherapy inoperable lung cancer. Lancet. 1976 Feb 21;1(7956):380-1. link to original article PubMed

Advanced or metastatic disease, first-line

Best supportive care

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Regimen

Study Evidence Comparator Comparative Efficacy
Durrant et al. 1971 Phase III (C) 1. RT
2. Mechlorethamine
3. Mechlorethamine & RT
Seems not superior
Laing et al. 1975 Phase III (C) 1. Procarbazine
2. MVPP
Seems to have superior OS
Rapp et al. 1988 Phase III (C) Cisplatin & Vindesine Inferior OS
Cartei et al. 1993 Phase III (C) Cisplatin, Cyclophosphamide, Mitomycin Inferior OS
Cullen et al. 1999 (MIC2) Phase III (C) MIC Seems to have inferior OS
Ranson et al. 2000 Phase III (C) Paclitaxel Seems to have inferior OS

No active antineoplastic treatment.

References

  1. Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet. 1971 Apr 10;1(7702):715-9. link to SD article PubMed
  2. Laing AH, Berry RJ, Newman CR, Peto J. Treatment of inoperable carcinoma of bronchus. Lancet. 1975 Dec 13;2(7946):1161-4. link to SD article PubMed
  3. Rapp E, Pater JL, Willan A, Cormier Y, Murray N, Evans WK, Hodson DI, Clark DA, Feld R, Arnold AM, Ayoub JI, Wilson KS, Latreille J, Wierzbicki RF, Hill DP. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin Oncol. 1988 Apr;6(4):633-41. link to original article PubMed
  4. Cartei G, Cartei F, Cantone A, Causarano D, Genco G, Tobaldin A, Interlandi G, Giraldi T. Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer. J Natl Cancer Inst. 1993 May 19;85(10):794-800. link to original article PubMed
  5. Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, Ferry DR, Rudd RM, Spiro SG, Cook JE, Trask C, Bessell E, Connolly CK, Tobias J, Souhami RL. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol. 1999 Oct;17(10):3188-94. link to original article PubMed
  6. Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, Anderson H, Gustafson N, Jeynes A, Gallant G, Washington T, Thatcher N. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2000 Jul 5;92(13):1074-80. link to original article PubMed

CAMP

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CAMP: Cyclophosphamide, Adriamycin (Doxorubicin), Methotrexate, Procarbazine

Regimen

Study Evidence
Bitran et al. 1978 Non-randomized

Chemotherapy

References

  1. Bitran JD, Desser RK, DeMeester T, Golomb HM. Metastatic non-oat-cell bronchogenic carcinoma: therapy with cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP). JAMA. 1978 Dec 15;240(25):2743-6. link to original article PubMed

CAP (Platinol)

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CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Miller et al. 1986 (SWOG S8012) Phase III (C) 1. FOMi
2. FOMi/CAP
Seems to have inferior OS

Chemotherapy

References

  1. SWOG S8012: Miller TP, Chen TT, Coltman CA Jr, O'Bryan RM, Vance RB, Weiss GB, Fletcher WS, Stephens RL, Livingston RB. Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung: a Southwest Oncology Group Study. J Clin Oncol. 1986 Apr;4(4):502-8. link to original article PubMed

Carboplatin & Cisplatin

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CC: Cisplatin & Carboplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Sculier et al. 1998 Phase III (C) CCI Inferior ORR

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

Chemotherapy

References

  1. Sculier JP, Paesmans M, Thiriaux J, Lecomte J, Bureau G, Giner V, Efremidis A, Lafitte JJ, Berchier MC, Alexopoulos CG, Zacharias C, Mommen P, Ninane V, Klastersky J; European Lung Cancer Working Party. Phase III randomized trial comparing cisplatin and carboplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer. J Clin Oncol. 1998 Apr;16(4):1388-96. link to original article PubMed

Cisplatin monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Gandara et al. 1993 Phase III (C) 1. HDCP
2. HDCP-M
Seems not superior
von Pawel et al. 2000 (CATAPULT I) Phase III (C) Cisplatin & Tirapazamine Inferior OS
Gatzemeier et al. 2000 Phase III (C) Cisplatin & Paclitaxel Seems to have inferior TTP

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

Chemotherapy

References

  1. Gandara DR, Crowley J, Livingston RB, Perez EA, Taylor CW, Weiss G, Neefe JR, Hutchins LF, Roach RW, Grunberg SM, Braun TJ, Natale RB, Balcerzak SP. Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: a phase III study of the Southwest Oncology Group. J Clin Oncol. 1993 May;11(5):873-8. link to original article PubMed
  2. CATAPULT I: von Pawel J, von Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, Talbot D, Rey A, Butler TW, Hirsh V, Olver I, Bergman B, Ayoub J, Richardson G, Dunlop D, Arcenas A, Vescio R, Viallet J, Treat J. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: A report of the international CATAPULT I study group: cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors. J Clin Oncol. 2000 Mar;18(6):1351-9. link to original article contains protocol PubMed
  3. Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, de Marinis F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallant G. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Oct 1;18(19):3390-9. link to original article contains protocol PubMed

Cisplatin & Pemetrexed

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

Regimen

Study Evidence Comparator Comparative Efficacy
Scagliotti et al. 2008 (JMDB) Phase III (E-RT) Cisplatin & Gemcitabine Seems non-inferior

Note: although this regimen is still current for nonsquamous NSCLC, the JMDB trial was unselected by histology.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

References

  1. JMDB: Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed

Cisplatin & Vinblastine

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Regimen

Study Evidence Comparator Comparative Efficacy
Kosty et al. 1994 Phase III (C) Cisplatin, Vinblastine, Hydrazine Seems not superior

Chemotherapy

References

  1. Kosty MP, Fleishman SB, Herndon JE 2nd, Coughlin K, Kornblith AB, Scalzo A, Morris JC, Mortimer J, Green MR. Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol. 1994 Jun;12(6):1113-20. link to original article PubMed

Cisplatin & Vindesine

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VP: Vindesine & Platinol (Cisplatin)
VdsC: Vindesine & Cisplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Ruckdeschel et al. 1986 (ECOG E1581) Phase III (E) 1. CAMP
2. EC
3. MVP
Seems not superior
Rapp et al. 1988 Phase III (E) Best supportive care Superior OS
Masutani et al. 1999 Phase III (C) 1. PVI
2. PVM
Seems not superior
Vansteenkiste et al. 2001 Phase III (C) Gemcitabine Seems to have inferior clinical benefit
Kodani et al. 2002 Phase III (C) VIP (Vindesine) Seems not superior
Negoro et al. 2003 Phase III (C) Cisplatin & Irinotecan Seems not superior
Kubota et al. 2004 Phase III (E) Cisplatin & Docetaxel Seems to have inferior OS

Chemotherapy

References

  1. ECOG E1581: Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. link to original article PubMed
  2. Rapp E, Pater JL, Willan A, Cormier Y, Murray N, Evans WK, Hodson DI, Clark DA, Feld R, Arnold AM, Ayoub JI, Wilson KS, Latreille J, Wierzbicki RF, Hill DP. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin Oncol. 1988 Apr;6(4):633-41. link to original article PubMed
  3. Masutani M, Akusawa H, Kadota A, Ohchi Y, Takahashi N, Tanigawa S, Koya Y, Horie T. A phase III randomized trial of cisplatin plus vindesine versus cisplatin plus vindesine plus mitomycin C versus cisplatin plus vindesine plus ifosfamide for advanced non-small-cell lung cancer. Respirology. 1996 Mar;1(1):49-54. link to original article PubMed
  4. Vansteenkiste JF, Vandebroek JE, Nackaerts KL, Weynants P, Valcke YJ, Verresen DA, Devogelaere RC, Marien SA, Humblet YP, Dams NL; Leuven Lung Cancer Group. Clinical-benefit response in advanced non-small-cell lung cancer: a multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol. 2001 Sep;12(9):1221-30. link to original article PubMed
  5. Kodani T, Ueoka H, Kiura K, Tabata M, Takigawa N, Segawa Y, Moritaka T, Hiraki S, Harada M, Tanimoto M. A phase III randomized trial comparing vindesine and cisplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer: long-term follow-up results and analysis of prognostic factors. Lung Cancer. 2002 Jun;36(3):313-9. link to original article PubMed
  6. Negoro S, Masuda N, Takada Y, Sugiura T, Kudoh S, Katakami N, Ariyoshi Y, Ohashi Y, Niitani H, Fukuoka M; CPT-11 Lung Cancer Study Group West. Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer. Br J Cancer. 2003 Feb 10;88(3):335-41. link to original article link to PMC article contains verified protocol PubMed
  7. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004 Jan 15;22(2):254-61. link to original article PubMed

Docetaxel monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Roszkowski et al. 2000 Phase III (E) Best supportive care Seems to have superior OS
Georgoulias et al. 2007 Phase III (C) DG Seems to have inferior OS

Chemotherapy

References

  1. Roszkowski K, Pluzanska A, Krzakowski M, Smith AP, Saigi E, Aasebo U, Parisi A, Pham Tran N, Olivares R, Berille J. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer. 2000 Mar;27(3):145-57. link to original article PubMed
  2. Georgoulias V, Androulakis N, Kotsakis A, Hatzidaki D, Syrigos K, Polyzos A, Agelidou A, Varthalitis I, Ziras N, Agelidou M, Chandrinos V, Boukovinas I, Geroyianni A, Vamvakas L, Mavroudis D. Docetaxel versus docetaxel plus gemcitabine as front-line treatment of patients with advanced non-small cell lung cancer: a randomized, multicenter phase III trial. Lung Cancer. 2008 Jan;59(1):57-63. Epub 2007 Aug 31. link to original article PubMed

Docetaxel & Gemcitabine

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DG: Docetaxel & Gemcitabine

Regimen

Study Evidence Comparator Comparative Efficacy
Georgoulias et al. 2007 Phase III (E) Docetaxel Seems to have superior OS

Note: while this is a superior arm of a phase III RCT, the comparator (single-agent docetaxel) is not usually used in the first-line treatment and this regimen is not currently recommended by ESMO guidelines.

Chemotherapy

References

  1. Georgoulias V, Androulakis N, Kotsakis A, Hatzidaki D, Syrigos K, Polyzos A, Agelidou A, Varthalitis I, Ziras N, Agelidou M, Chandrinos V, Boukovinas I, Geroyianni A, Vamvakas L, Mavroudis D. Docetaxel versus docetaxel plus gemcitabine as front-line treatment of patients with advanced non-small cell lung cancer: a randomized, multicenter phase III trial. Lung Cancer. 2008 Jan;59(1):57-63. Epub 2007 Aug 31. link to original article PubMed

Ifosfamide & Gemcitabine

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IG: Ifosfamide & Gemcitabine

Regimen

Study Evidence Comparator Comparative Efficacy
Sculier et al. 2002 Phase III (E) 1. CCI
2. CCG
Seems not superior
Berghmans et al. 2013 (ELCWP-01041) Phase III (C) 1. GIP
2. DP
Seems not superior

Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

References

  1. Sculier JP, Lafitte JJ, Lecomte J, Berghmans T, Thiriaux J, Florin MC, Efremidis A, Alexopoulos CG, Recloux P, Ninane V, Mommen P, Paesmans M, Klastersky J; European Lung Cancer Working Party. A three-arm phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small-cell lung cancer. Ann Oncol. 2002 Jun;13(6):874-82. link to original article PubMed
  2. ELCWP-01041: Berghmans T, Lafitte JJ, Scherpereel A, Paesmans M, Lecomte J, Marco VG, Meert AP, Leclercq N, Sculier JP; European Lung Cancer Working Party. An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC. Anticancer Res. 2013 Dec;33(12):5477-82. link to original article PubMed

Gemcitabine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Vansteenkiste et al. 2001 Phase III (E) Cisplatin & Vindesine Seems to have superior clinical benefit
Sederholm et al. 2005 Phase III (C) Carboplatin & Gemcitabine Seems to have inferior OS

Note: this regimen is considered current in elderly patients or those with poor PS; these trials were unselected by these parameters.

Chemotherapy

References

  1. Vansteenkiste JF, Vandebroek JE, Nackaerts KL, Weynants P, Valcke YJ, Verresen DA, Devogelaere RC, Marien SA, Humblet YP, Dams NL; Leuven Lung Cancer Group. Clinical-benefit response in advanced non-small-cell lung cancer: a multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol. 2001 Sep;12(9):1221-30. link to original article PubMed
  2. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. link to original article PubMed

GIP

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GIP: Gemcitabine, Ifosfamide, Platinol (Cisplatin)

Regimen

Study Evidence
Sculier et al. 2007 Non-randomized portion of RCT

Chemotherapy

References

  1. Sculier JP, Lafitte JJ, Lecomte J, Alexopoulos CG, Van Cutsem O, Giner V, Efremidis A, Berchier MC, Collon T, Meert AP, Scherpereel A, Ninane V, Paesmans M, Berghmans T; European Lung Cancer Working Party. A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer. Ann Oncol. 2007 Jun;18(6):1037-42. Epub 2007 Apr 2. link to original article PubMed

MACC

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MACC: Methotrexate, Adriamycin (Doxorubicin), Cyclophosphamide, CCNU (Lomustine)

Regimen

Study Evidence Comparator Comparative Efficacy
Chahinian et al. 1977 Non-randomized
Cormier et al. 1982 Phase III (E) Placebo Superior OS

Chemotherapy

References

  1. Chahinian PA, Arnold DJ, Cohen JM, Purpora DP, Jaffrey IS, Teirstein AS, Kirschner PA, Holland JF. Chemotherapy for bronchogenic carcinoma: methotrexate, doxorubicin, cyclophosphamide, and lomustine. JAMA. 1977 May 30;237(22):2392-6. link to original article PubMed
  2. Cormier Y, Bergeron D, La Forge J, Lavandier M, Fournier M, Chenard J, Desmeules M. Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma. Cancer. 1982 Sep 1;50(5):845-9. link to original article PubMed

MIC

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MIC: Mitomycin, Ifosfamide, Cisplatin
MIP: Mitomycin, Ifosfamide, Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Cullen et al. 1999 (MIC2) Phase III (E) Best supportive care Seems to have superior OS
Crinò et al. 1999 Phase III (C) Cisplatin & Gemcitabine Seems to have inferior ORR
Sculier et al. 2000 Phase III (C) CarboMIP Seems not superior
Danson et al. 2003 Phase III (C) GC Seems not superior
Booton et al. 2006 (BTOG1) Phase III (C) DCb Seems not superior

Chemotherapy

References

  1. MIC2: Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, Ferry DR, Rudd RM, Spiro SG, Cook JE, Trask C, Bessell E, Connolly CK, Tobias J, Souhami RL. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol. 1999 Oct;17(10):3188-94. link to original article PubMed
  2. Crinò L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999 Nov;17(11):3522-30. link to original article contains protocol PubMed
  3. Sculier JP, Lafitte JJ, Paesmans M, Thiriaux J, Alexopoulos CG, Baumöhl J, Schmerber J, Koumakis G, Florin MC, Zacharias C, Berghmans T, Mommen P, Ninane V, Klastersky J. Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer. Br J Cancer. 2000 Nov;83(9):1128-35. link to original article link to PMC article PubMed
  4. Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. link to original article PubMed
  5. Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. link to original article PubMed

MVP (Vinblastine)

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MVP: Mitomycin, Vinblastine, Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Ruckdeschel et al. 1986 (ECOG E1581) Phase III (E) 1. CAMP
2. EC
3. VC
Seems not superior
Bonomi et al. 1989 (ECOG E1583) Phase III (C) 1. VP
2. MVP/CAMP
3. Carboplatin
4. Iproplatin
Seems not superior
Veeder et al. 1992 Phase III (C) Mitomycin Seems not superior
Smith et al. 2001 Phase III (C) MVP x 3 Seems not superior
Danson et al. 2003 Phase III (C) GC Seems not superior
Booton et al. 2006 (BTOG1) Phase III (C) DCb Seems not superior

Chemotherapy

References

  1. ECOG E1581: Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. link to original article PubMed
  2. ECOG E1583: Bonomi PD, Finkelstein DM, Ruckdeschel JC, Blum RH, Green MD, Mason B, Hahn R, Tormey DC, Harris J, Comis R, Glick J. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol. 1989 Nov;7(11):1602-13. link to original article PubMed
  3. Veeder MH, Jett JR, Su JQ, Mailliard JA, Foley JF, Dalton RJ, Etzell PS, Marschke RF Jr, Kardinal CG, Maksymiuk AW, Ebbert LP, Tazelaar HD, Witrak GA. A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer. 1992 Nov 1;70(9):2281-7. link to original article PubMed
  4. Smith IE, O'Brien ME, Talbot DC, Nicolson MC, Mansi JL, Hickish TF, Norton A, Ashley S. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol. 2001 Mar 1;19(5):1336-43. link to original article PubMed
  5. Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. link to original article PubMed
  6. BTOG1: Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. link to original article PubMed

MVP (Vindesine)

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MVP: Mitomycin, Vindesine, Platinol (Cisplatin)
PVM: Platinol (Cisplatin), Vindesine, Mitomycin

Regimen

Study Evidence Comparator Comparative Efficacy
González Barón et al. 1994 Phase III (E) MIP Seems not superior
Gridelli et al. 1996 Phase III (C) MEV Seems not superior
Boni et al. 1998 Phase III (C) MVP; CI Seems not superior
Jelić et al. 2001 Phase III (C) MVC Inferior OS

Chemotherapy

References

  1. González Barón M, Feliu J, Espinosa E, García Girón C, Blanco E, Garrido P, Colmenarejo A, Ordóñez A, Moyano A, de la Gándara I, Zamora P; ONCOPAZ Cooperative Group. Comparison of two chemotherapeutic regimens--mitomycin + vindesine + cisplatin (MVP) vs mitomycin + ifosfamide + cisplatin (MIP)--in advanced non-small-cell lung cancer. Ann Oncol. 1994 Apr;5(4):323-7. link to original article PubMed
  2. Gridelli C, Perrone F, Palmeri S, D'Aprile M, Cognetti F, Rossi A, Gebbia V, Pepe R, Veltri E, Airoma G, Russo A, Incoronato P, Scinto AF, Palazzolo G, Natali M, Leonardi V, Gallo C, De Placido S, Bianco AR; The Gruppo Oncologico Centro-Sud-Isole (GOSCI). Mitomycin C plus vindesine plus etoposide (MEV) versus mitomycin C plus vindesine plus cisplatin (MVP) in stage IV non-small-cell lung cancer: A phase III multicentre randomised trial. Ann Oncol. 1996 Oct;7(8):821-6. link to original article PubMed
  3. Boni C, Savoldi L, Bisagni G, Ceci G, Crinò L, De Lisi V, Di Costanzo F, Lasagni L, Manenti AL, Moretti G, Rondini E, Sassi M, Zadro A. Bolus versus 5-day continuous infusion of cisplatin with mitomycin and vindesine in the treatment of advanced non-small cell lung cancer (NSCLC): a phase III prospective randomised trial of the Italian Oncology Group for Clinical Research (GOIRC). Eur J Cancer. 1998 Nov;34(12):1974-6. link to original article PubMed
  4. Jelić S, Mitrović L, Radosavljević D, Elezar E, Babović N, Kovcin V, Tomasević Z, Kovacević S, Gavrilović D, Radulović S. Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study. Lung Cancer. 2001 Oct;34(1):1-13. link to original article PubMed

Paclitaxel monotherapy

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Variant #1, 100 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Comparative Efficacy
Comella et al. 2004 (SICOG 9909) Phase III (E) 1. Gemcitabine Not reported
2. GT
3. GV
Seems to have inferior OS

Chemotherapy

28-day cycle for up to 6 cycles

Variant #2, 200 mg/m2 q3wk

Study Evidence Comparator Comparative Efficacy
Ranson et al. 2000 Phase III (E) Best supportive care Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, Anderson H, Gustafson N, Jeynes A, Gallant G, Washington T, Thatcher N. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2000 Jul 5;92(13):1074-80. link to original article PubMed
  2. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Cormier et al. 1982 Phase III (C) MACC Inferior OS

No active antineoplastic treatment.

References

  1. Cormier Y, Bergeron D, La Forge J, Lavandier M, Fournier M, Chenard J, Desmeules M. Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma. Cancer. 1982 Sep 1;50(5):845-9. link to original article PubMed

Vindesine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Einhorn et al. 1986 Phase III (C) 1. Cisplatin & Vindesine
2. Cisplatin, Mitomycin, Vindesine
Seems not superior
Furuse et al. 1996 Phase III (C) Vinorelbine Inferior ORR

Chemotherapy

References

  1. Einhorn LH, Loehrer PJ, Williams SD, Meyers S, Gabrys T, Nattan SR, Woodburn R, Drasga R, Songer J, Fisher W, Stephens D, Hu S. Random prospective study of vindesine versus vindesine plus high-dose cisplatin versus vindesine plus cisplatin plus mitomycin C in advanced non-small-cell lung cancer. J Clin Oncol. 1986 Jul;4(7):1037-43. link to original article PubMed
  2. Furuse K, Fukuoka M, Kuba M, Yamori S, Nakai Y, Negoro S, Katagami N, Takada Y, Kinuwaki E, Kawahara M, Kubota K, Sakuma A, Niitani H; The Japan Vinorelbine Lung Cancer Cooperative Study Group. Randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small-cell lung cancer (NSCLC). Ann Oncol. 1996 Oct;7(8):815-20. link to original article PubMed

Vinorelbine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Crawford et al. 1996 Randomized (E-RT) FULV Seems to have superior OS

Chemotherapy

References

  1. Crawford J, O'Rourke M, Schiller JH, Spiridonidis CH, Yanovich S, Ozer H, Langleben A, Hutchins L, Koletsky A, Clamon G, Burman S, White R, Hohneker J. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol. 1996 Oct;14(10):2774-84. Erratum in: J Clin Oncol 1996 Dec;14(12):3175. Spiridonitis CH [corrected to Spiridonidis CH]. link to original article PubMed

VIP

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VIP: Vinblastine, Ifosfamide, Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Kosmidis et al. 1996a Phase III (C) VIP-16 Seems not superior

Chemotherapy

References

  1. Kosmidis P, Mylonakis N, Fountzilas G, Pavlidis N, Samantas E, Karabelis A, Kattis K, Skarlos D; Hellenic Co-Operative Oncology Group. A prospective randomized phase III study in non-small-cell lung cancer comparing cisplatin, ifosfamide, vinblastine (VIP) versus cisplatin, ifosfamide and etoposide (VIP-16). Ann Oncol. 1996 Jul;7(5):517-20. link to original article PubMed

Maintenance after first-line therapy

Erlotinib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Cappuzzo et al. 2010 (SATURN) Phase III (E-RT) Placebo Superior PFS
Pérol et al. 2012 Phase III (E) 1. Gemcitabine Not reported
2. Observation Superior PFS
Cicènas et al. 2016 (IUNO) Phase III (E) See link See link

Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks. The trials included here did not require EGFR mutation as a condition for enrollment.

Preceding treatment

Chemotherapy

Continued indefinitely

References

  1. SATURN: Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010 Jun;11(6):521-9. Epub 2010 May 20. link to original article contains protocol PubMed
  2. Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original article contains verified protocol PubMed
  3. IUNO: Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. link to original article contains verified protocol PubMed

Advanced or metastatic disease, subsequent lines of therapy

Best supportive care

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Regimen

Study Evidence Comparator Comparative Efficacy
Shepherd et al. 2000 Phase III (C) Docetaxel Seems to have inferior OS

No active antineoplastic treatment.

References

  1. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. link to original article contains protocol PubMed

Erlotinib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Shepherd et al. 2005 (NCIC CTG BR.21) Phase III (E-RT) Placebo Superior OS
Natale et al. 2011 (ZEST) Phase III (C) Vandetanib Did not meet primary endpoint of PFS
Herbst et al. 2011 (BeTa) Phase III (C) Erlotinib & Bevacizumab Did not meet primary endpoint of OS
Ciuleanu et al. 2012 (TITAN) Phase III (E) Investigator's choice of:
1. Docetaxel
2. Pemetrexed
Did not meet primary endpoint of OS
Scagliotti et al. 2012 (SUN 1087) Phase III (C) Erlotinib & Sunitinib Did not meet primary endpoint of OS
Ramalingam et al. 2012 (A7471028) Randomized Phase II (C) Dacomitinib Seems to have inferior PFS
Karampeazis et al. 2013 Phase III (E) Pemetrexed Did not meet primary endpoint of TTP
Garassino et al. 2013 (TAILORNSCLC) Phase III (E) Docetaxel Seems to have inferior OS
Kawaguchi et al. 2014 (DELTANSCLC) Phase III (E) Docetaxel Might have inferior PFS
Ramalingam et al. 2014 (ARCHER 1009) Phase III (C) Dacomitinib Did not meet primary endpoint of PFS
Scagliotti et al. 2015 (ADVIGO 1018) Phase III (C) Erlotinib & Figitumumab Did not meet primary endpoint of OS
Soria et al. 2015 (LUX-Lung 8) Phase III (C) Afatinib Inferior OS
Yoshioka et al. 2015 (ATTENTION) Phase III (C) Erlotinib & Tivantinib Did not meet primary endpoint of OS
Scagliotti et al. 2015 (MARQUEE) Phase III (C) Erlotinib & Tivantinib Did not meet primary endpoint of OS
Urata et al. 2016 (WJOG 5108L) Phase III (C) Gefitinib Inconclusive whether non-inferior PFS
Smit et al. 2016 (CurrentS) Phase III (C) Erlotinib; high-dose Did not meet primary endpoint of PFS
Cicènas et al. 2016 (IUNO) Phase III (C) See link See link
Neal et al. 2016 (ECOG-ACRIN 1512) Randomized Phase II (C) 1. Cabozantinib Inferior PFS
2. Cabozantinib & Erlotinib Inferior PFS
Spigel et al. 2016 (METLung) Phase III (C) Erlotinib & Onartuzumab Might have superior OS
Wang et al. 2017a Phase III (C) Erlotinib, Bevacizumab, Panitumumab Seems to have inferior OS
Gridelli et al. 2018 (AvaALL) Phase III (C) Investigator's choice of:
1. Docetaxel & Bevacizumab
2. Erlotinib & Bevacizumab
3. Pemetrexed & Bevacizumab
Did not meet primary endpoint of OS

Note: the trials included here did not require EGFR mutation as a condition for enrollment. Given the FDA limitation on use in this setting, these regimens have been moved to the historical page. Note that there is another trial named TAILOR in colorectal cancer and another trial named DELTA in indolent lymphoma.

Preceding treatment

Chemotherapy

Continued indefinitely

References

  1. NCIC CTG BR.21: Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article contains protocol PubMed
  2. ZEST: Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, Ferry D, Mulatero C, Whorf R, Thompson J, Barlesi F, Langmuir P, Gogov S, Rowbottom JA, Goss GD. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011 Mar 10;29(8):1059-66. Epub 2011 Jan 31. link to original article contains protocol PubMed
    1. Dataset: Project Data Sphere
  3. BeTa: Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh CH, O'Connor P, Hainsworth J. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011 May 28;377(9780):1846-54. link to original article link to PMC article contains protocol PubMed
  4. TITAN: Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. link to original article contains protocol PubMed
  5. SUN 1087: Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, Wierzbicki RF, Albert I, Thomas M, Miziara JE, Papai ZS, Karaseva N, Thongprasert S, Portulas ED, von Pawel J, Zhang K, Selaru P, Tye L, Chao RC, Govindan R. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2070-8. Epub 2012 May 7. link to original article contains protocol PubMed
  6. 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. link to original article link to PMC article PubMed
  7. Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, Agelaki S, Vamvakas L, Samonis G, Mavroudis D, Georgoulias V. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013 Aug 1;119(15):2754-64. Epub 2013 May 9. link to original article contains verified protocol PubMed
  8. TAILOR: Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. link to original article contains verified protocol PubMed
  9. DELTA: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains verified protocol PubMed
  10. ARCHER 1009: Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15.link to original article PubMed
  11. ADVIGO 1018: Scagliotti GV, Bondarenko I, Blackhall F, Barlesi F, Hsia TC, Jassem J, Milanowski J, Popat S, Sanchez-Torres JM, Novello S, Benner RJ, Green S, Molpus K, Soria JC, Shepherd FA. Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer. Ann Oncol. 2015 Mar;26(3):497-504. Epub 2014 Nov 13. link to original article PubMed
  12. LUX-Lung 8: Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains protocol PubMed
  13. ATTENTION: Yoshioka H, Azuma K, Yamamoto N, Takahashi T, Nishio M, Katakami N, Ahn MJ, Hirashima T, Maemondo M, Kim SW, Kurosaki M, Akinaga S, Park K, Tsai CM, Tamura T, Mitsudomi T, Nakagawa K. A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann Oncol. 2015 Oct;26(10):2066-72. Epub 2015 Jul 7. link to original article PubMed
  14. MARQUEE: Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, Akerley W, Orlov S, Santoro A, Spigel D, Hirsh V, Shepherd FA, Sequist LV, Sandler A, Ross JS, Wang Q, von Roemeling R, Shuster D, Schwartz B. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Aug 20;33(24):2667-74. Epub 2015 Jul 13. link to original article contains protocol PubMed
  15. 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 verified protocol PubMed
  16. CurrentS: Smit EF, Wu YL, Gervais R, Zhou C, Felip E, Feng J, Guclu SZ, Hoiczyk M, Dorokhova E, Freudensprung U, Grange S, Perez-Moreno PD, Mitchell L, Reck M. A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS). Lung Cancer. 2016 Sep;99:94-101. Epub 2016 Jun 27. link to original article PubMed
  17. IUNO: Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. link to original article contains verified protocol PubMed
  18. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN 1512 Investigators. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed
  19. METLung: Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol. 2017 Feb;35(4):412-420. Epub 2016 Dec 12. link to original article contains verified protocol PubMed
  20. Wang Y, Wang H, Jiang Y, Zhang Y, Wang X. A randomized phase III study of combining erlotinib with bevacizumab and panitumumab versus erlotinib alone as second-line therapy for Chinese patients with non-small-cell lung cancer. Biomed Pharmacother. 2017 May;89:875-879. Epub 2017 Mar 6. link to SD article PubMed
  21. AvaALL: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. link to original article link to PMC article contains verified protocol in supplement PubMed