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Результаты открытого рандомизированного контролируемого исследования III фазы LUX-Lung 8: сравнение эффективности афатиниба и эрлотиниба в терапии второй линии больных распространенным плоскоклеточным раком легкого*
Результаты открытого рандомизированного контролируемого исследования III фазы LUX-Lung 8: сравнение эффективности афатиниба и эрлотиниба в терапии второй линии больных распространенным плоскоклеточным раком легкого*
Soria J-C, Felip E, Cobo M и др. Результаты открытого рандомизированного контролируемого исследования III фазы LUX-Lung 8: сравнение эффективности афатиниба и эрлотиниба в терапии второй линии больных распространенным плоскоклеточным раком легкого. Современная онкология. 2015; 17 (3): 42–52.
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Аннотация
Обоснование. Возможности лечения плоскоклеточного рака легкого на сегодняшний день ограниченны, поэтому назрела потребность в поиске новых эффективных методов лечения этого заболевания. В исследовании LUX-Lung 8 проводилось сравнение афатиниба (необратимого ингибитора рецепторов семейства ErbB) и эрлотиниба (обратимого ингибитора тирозинкиназы рецептора эпидермального фактора роста – EGFR) в терапии 2-й линии распространенного плоскоклеточного рака легкого.
Методы. Представленное открытое рандомизированное контролируемое исследование III фазы было проведено в 183 онкологических центрах в 23 странах мира. Включали взрослых пациентов с III и IV стадией плоскоклеточного рака легкого, у которых регистрировалось прогрессирование заболевания после по крайней мере 4 циклов платиносодержащей химиотерапии. Включенные пациенты были рандомизированы в 2 группы (1:1): 1-я группа получала афатиниб (40 мг в день), 2-я – эрлотиниб (150 мг в день) до момента прогрессирования заболевания. Рандомизация осуществлялась централизованно с использованием интерактивных систем голосового ответа или интерактивных систем веб-ответа, и проводилась стратификация по этническому происхождению (из Восточной Азии и других регионов Азии). Результаты распределения не маскировались для клиницистов и пациентов. Первичной конечной точкой в исследовании была выживаемость без прогрессирования (ВБП), которая оценивалась при независимой центральной проверке. Ключевая вторичная конечная точка – общая выживаемость (ОВ). Данное исследование зарегистрировано на портале CinicalTrials.gov, NCT01523587.
Результаты. Были оценены результаты лечения 795 включенных пациентов (398 в группе афатиниба, 397 в группе эрлотиниба). Медиана периода наблюдения к моменту первичной оценки ВБП составила 6,7 мес (3,1–10,2), к этому моменту набор пациентов не был закончен. Первичный анализ ВБП показал, что лечение афатинибом привело к достоверному увеличению ВБП по сравнению с эрлотинибом [медиана ВБП 2,4 мес (95% доверительный интервал – ДИ 1,9–2,9) vs 1,9 мес (1,9–2,2), отношение рисков – HR 0,82 (95% ДИ 0,68–1,00); p=0,0427]. К моменту первичного анализа ОВ [медиана периода наблюдения составила 18,4 мес (13,8–22,4)] ОВ в группе афатиниба достоверно увеличилась по сравнению с группой эрлотиниба [медиана ОВ 7,9 мес (95% ДИ 7,2–8,7) vs 6,8 мес (95% ДИ 5,9–7,8); HR 0,81 (95% ДИ 0,69–0,95)]; p=0,0077. Аналогичные результаты были получены и в отношении ВБП [медиана ВБП 2,6 мес (95% ДИ 2,0–2,9) и 1,9 мес (1,9–2,1); HR 0,81 (95% ДИ 0,69–0,96), p=0,0103]; а также в отношении доли пациентов с контролем заболевания [201 (51%) из 398 vs 157 (40%) из 397; p=0,0020]. Не было выявлено достоверных различий доли пациентов с объективным ответом между группами [22 (6%) vs 11 (3%); p=0,0551]. Объем опухоли уменьшился у 103 (26%) из 398 пациентов, получавших афатиниб, и у 90 (23%) из 397 пациентов, получавших эрлотиниб. По спектру побочных эффектов не было выявлено различий между группами: у 224 (57%) из 392 пациентов группы афатиниба и у 227 (57%) из 395 пациентов группы эрлотиниба наблюдались нежелательные явления 3-й степени тяжести и более. В группе афатиниба чаще встречались связанные с приемом препарата диарея 3-й степени тяжести – 39 (10%) vs 9 (2%), стоматит 3-й степени тяжести – 16 (4%) vs 0, в группе эрлотиниба чаще встречалась сыпь или акне 3-й степени тяжести – 23 (6%) vs 41 (10%).
Выводы. Достоверное увеличение ВБП и ОВ при приеме афатиниба по сравнению с эрлотинибом наряду с управляемым профилем безопасности и удобным пероральным способом приема позволяет считать применение афатиниба дополнительной возможностью в терапии 2-й линии трудно поддающейся лечению популяции больных распространенным плоскоклеточным раком легкого.
Methods. We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov, NCT01523587.
Findings. 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6.7 months (IQR 3.1–10.2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib [median 2.4 months (95% CI 1.9–2.9) vs 1.9 months (1.9–2.2); hazard ratio (HR) 0.82 (95% CI 0.68–1.00), p=0.0427]. At the time of the primary analysis of overall survival [median follow-up 18.4 months (IQR 13.8–22.4)], overall survival was significantly greater in the afatinib group than in the erloinib group [median 7.9 months (95% CI 7.2–8.7] vs 6.8 months (5.9–7.8); HR 0.81 (95% CI 0.69–0.95), p=0.0077], as were progression-free survival [median 2.6 months (95% CI 2.0–2.9) vs 1.9 months (1.9–2.1); HR 0.81 (95% CI 0.69–0.96), p=0.0103] and disease control [201 (51%) of 398 patients vs 157 (40%) of 397; p=0.0020]. The proportion of patients with an objective response did not differ significantly between groups [22 (6%) vs 11 (3%); p=0.0551]. Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib [39 (10%) vs 9 (2%)], of grade 3 stomatitis with afatinib [16 (4%) vs none], and of grade 3 rash or acne with erlotinib [23 (6%) vs 41 (10%)].
Interpretation. The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung.
Методы. Представленное открытое рандомизированное контролируемое исследование III фазы было проведено в 183 онкологических центрах в 23 странах мира. Включали взрослых пациентов с III и IV стадией плоскоклеточного рака легкого, у которых регистрировалось прогрессирование заболевания после по крайней мере 4 циклов платиносодержащей химиотерапии. Включенные пациенты были рандомизированы в 2 группы (1:1): 1-я группа получала афатиниб (40 мг в день), 2-я – эрлотиниб (150 мг в день) до момента прогрессирования заболевания. Рандомизация осуществлялась централизованно с использованием интерактивных систем голосового ответа или интерактивных систем веб-ответа, и проводилась стратификация по этническому происхождению (из Восточной Азии и других регионов Азии). Результаты распределения не маскировались для клиницистов и пациентов. Первичной конечной точкой в исследовании была выживаемость без прогрессирования (ВБП), которая оценивалась при независимой центральной проверке. Ключевая вторичная конечная точка – общая выживаемость (ОВ). Данное исследование зарегистрировано на портале CinicalTrials.gov, NCT01523587.
Результаты. Были оценены результаты лечения 795 включенных пациентов (398 в группе афатиниба, 397 в группе эрлотиниба). Медиана периода наблюдения к моменту первичной оценки ВБП составила 6,7 мес (3,1–10,2), к этому моменту набор пациентов не был закончен. Первичный анализ ВБП показал, что лечение афатинибом привело к достоверному увеличению ВБП по сравнению с эрлотинибом [медиана ВБП 2,4 мес (95% доверительный интервал – ДИ 1,9–2,9) vs 1,9 мес (1,9–2,2), отношение рисков – HR 0,82 (95% ДИ 0,68–1,00); p=0,0427]. К моменту первичного анализа ОВ [медиана периода наблюдения составила 18,4 мес (13,8–22,4)] ОВ в группе афатиниба достоверно увеличилась по сравнению с группой эрлотиниба [медиана ОВ 7,9 мес (95% ДИ 7,2–8,7) vs 6,8 мес (95% ДИ 5,9–7,8); HR 0,81 (95% ДИ 0,69–0,95)]; p=0,0077. Аналогичные результаты были получены и в отношении ВБП [медиана ВБП 2,6 мес (95% ДИ 2,0–2,9) и 1,9 мес (1,9–2,1); HR 0,81 (95% ДИ 0,69–0,96), p=0,0103]; а также в отношении доли пациентов с контролем заболевания [201 (51%) из 398 vs 157 (40%) из 397; p=0,0020]. Не было выявлено достоверных различий доли пациентов с объективным ответом между группами [22 (6%) vs 11 (3%); p=0,0551]. Объем опухоли уменьшился у 103 (26%) из 398 пациентов, получавших афатиниб, и у 90 (23%) из 397 пациентов, получавших эрлотиниб. По спектру побочных эффектов не было выявлено различий между группами: у 224 (57%) из 392 пациентов группы афатиниба и у 227 (57%) из 395 пациентов группы эрлотиниба наблюдались нежелательные явления 3-й степени тяжести и более. В группе афатиниба чаще встречались связанные с приемом препарата диарея 3-й степени тяжести – 39 (10%) vs 9 (2%), стоматит 3-й степени тяжести – 16 (4%) vs 0, в группе эрлотиниба чаще встречалась сыпь или акне 3-й степени тяжести – 23 (6%) vs 41 (10%).
Выводы. Достоверное увеличение ВБП и ОВ при приеме афатиниба по сравнению с эрлотинибом наряду с управляемым профилем безопасности и удобным пероральным способом приема позволяет считать применение афатиниба дополнительной возможностью в терапии 2-й линии трудно поддающейся лечению популяции больных распространенным плоскоклеточным раком легкого.
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Methods. We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov, NCT01523587.
Findings. 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6.7 months (IQR 3.1–10.2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib [median 2.4 months (95% CI 1.9–2.9) vs 1.9 months (1.9–2.2); hazard ratio (HR) 0.82 (95% CI 0.68–1.00), p=0.0427]. At the time of the primary analysis of overall survival [median follow-up 18.4 months (IQR 13.8–22.4)], overall survival was significantly greater in the afatinib group than in the erloinib group [median 7.9 months (95% CI 7.2–8.7] vs 6.8 months (5.9–7.8); HR 0.81 (95% CI 0.69–0.95), p=0.0077], as were progression-free survival [median 2.6 months (95% CI 2.0–2.9) vs 1.9 months (1.9–2.1); HR 0.81 (95% CI 0.69–0.96), p=0.0103] and disease control [201 (51%) of 398 patients vs 157 (40%) of 397; p=0.0020]. The proportion of patients with an objective response did not differ significantly between groups [22 (6%) vs 11 (3%); p=0.0551]. Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib [39 (10%) vs 9 (2%)], of grade 3 stomatitis with afatinib [16 (4%) vs none], and of grade 3 rash or acne with erlotinib [23 (6%) vs 41 (10%)].
Interpretation. The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung.
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2. Reck M, Popat S, Reinmuth N et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 (Suppl. 3): iii27–iii39.
3. Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 2012; 13: e418–26.
4. Scagliotti GV, Novello S, Rapetti S, Papotti M. Current state-of-theart therapy for advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book 2013; 354–8.
5. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-byhistology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64–70.
6. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–73.
7. Rizvi NA, Mazieres J, Planchard D et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16: 257–65
8. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; published online May 31. DOI: 10.1056/ NEJMoa1504627
9. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21: 3798–807.
10. Lopez-Malpartida AV, Ludena MD, Varela G, Garcia PJ. Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. Lung Cancer 2009; 65: 25–33.
11. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–44.
12. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013; 24: 2371–6.
13. Clark GM, Zborowski DM, Santabarbara P et al. Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 2006; 7: 389–94.
14. Wojtowicz-Praga S, Leon L. Comparative efficacy and safety of erlotinib in non-small cell lung cancer (NSCLC) of squamous cell and adenocarcinoma histology in the phase III NCIC CTG BR.21 and saturn (BO18192) trials. Ann Oncol 2012; 23 (Suppl. 9): ix419. abstr 1277P.
15. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33–42.
16. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–74.
17. Heinmoller P, Gross C, Beyser K et al. HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin Cancer Res 2003; 9: 5238–43.
18. Hirsch FR, Franklin WA, Veve R et al. HER2/neu expression in malignant lung tumors. Semin Oncol 2002; 29 (Suppl. 4): 51–8.
19. Ugocsai K, Mandoky L, Tiszlavicz L, Molnar J. Investigation of HER2 overexpression in non-small cell lung cancer. Anticancer Res 2005; 25: 3061–6.
20. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–25.
21. Dhanasekaran SM, Alejandro BO, Chen G et al. Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nat Commun 2014; 5: 5893.
22. Solca F, Dahl G, Zoephel A et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343: 342–50.
23. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–34.
24. Wu YL, Zhou C, Hu CP et al. 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; 15: 213–22.
25. Yang JC, Wu YL, Schuler M et al. 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; 16: 141–51.
26. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–38.
27. Machiels J, Haddad R, Fayette J et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; 16: 583–94.
28. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (Suppl. 15): abstr 7558.
29. Hamilton M, Wolf JL, Rusk J et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 2006; 12: 2166–71.
30. Smit EF, Gervais R, Zhou C et al. Efficacy and safety results from CurrentS, a double-blind, randomized, phase III study of secondline erlotinib (150 mg versus 300 mg) in current smokers with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2014; 32 (Suppl. 5): abstr 8046.
31. Li N, Yang L, Ou W et al. Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer. PLoS One 2014; 9: e102777.
32. Shepherd FA, Dancey J, Ramlau R et al. 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; 18: 2095–103.
33. Garassino MC, Martelli O, Broggini M et al. 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; 14: 981–8.
34. Yi ES, Harclerode D, Gondo M et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol 1997; 10: 142–48.
35. Nelson V, Ziehr J, Agulnik M, Johnson M. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013; 6: 135–43.
36. Garon EB, Balmanoukian A, Hamid O et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). J Thorac Oncol 2013; 8 (Suppl. 2): abstr MO18.02
37. Katakami N, Atagi S, Goto K et al. 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; 31: 3335–41.
2. Reck M, Popat S, Reinmuth N et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 (Suppl. 3): iii27–iii39.
3. Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 2012; 13: e418–26.
4. Scagliotti GV, Novello S, Rapetti S, Papotti M. Current state-of-theart therapy for advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book 2013; 354–8.
5. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-byhistology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64–70.
6. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–73.
7. Rizvi NA, Mazieres J, Planchard D et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16: 257–65
8. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; published online May 31. DOI: 10.1056/ NEJMoa1504627
9. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21: 3798–807.
10. Lopez-Malpartida AV, Ludena MD, Varela G, Garcia PJ. Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. Lung Cancer 2009; 65: 25–33.
11. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–44.
12. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013; 24: 2371–6.
13. Clark GM, Zborowski DM, Santabarbara P et al. Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 2006; 7: 389–94.
14. Wojtowicz-Praga S, Leon L. Comparative efficacy and safety of erlotinib in non-small cell lung cancer (NSCLC) of squamous cell and adenocarcinoma histology in the phase III NCIC CTG BR.21 and saturn (BO18192) trials. Ann Oncol 2012; 23 (Suppl. 9): ix419. abstr 1277P.
15. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33–42.
16. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–74.
17. Heinmoller P, Gross C, Beyser K et al. HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin Cancer Res 2003; 9: 5238–43.
18. Hirsch FR, Franklin WA, Veve R et al. HER2/neu expression in malignant lung tumors. Semin Oncol 2002; 29 (Suppl. 4): 51–8.
19. Ugocsai K, Mandoky L, Tiszlavicz L, Molnar J. Investigation of HER2 overexpression in non-small cell lung cancer. Anticancer Res 2005; 25: 3061–6.
20. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–25.
21. Dhanasekaran SM, Alejandro BO, Chen G et al. Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nat Commun 2014; 5: 5893.
22. Solca F, Dahl G, Zoephel A et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343: 342–50.
23. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–34.
24. Wu YL, Zhou C, Hu CP et al. 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; 15: 213–22.
25. Yang JC, Wu YL, Schuler M et al. 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; 16: 141–51.
26. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–38.
27. Machiels J, Haddad R, Fayette J et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; 16: 583–94.
28. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (Suppl. 15): abstr 7558.
29. Hamilton M, Wolf JL, Rusk J et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 2006; 12: 2166–71.
30. Smit EF, Gervais R, Zhou C et al. Efficacy and safety results from CurrentS, a double-blind, randomized, phase III study of secondline erlotinib (150 mg versus 300 mg) in current smokers with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2014; 32 (Suppl. 5): abstr 8046.
31. Li N, Yang L, Ou W et al. Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer. PLoS One 2014; 9: e102777.
32. Shepherd FA, Dancey J, Ramlau R et al. 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; 18: 2095–103.
33. Garassino MC, Martelli O, Broggini M et al. 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; 14: 981–8.
34. Yi ES, Harclerode D, Gondo M et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol 1997; 10: 142–48.
35. Nelson V, Ziehr J, Agulnik M, Johnson M. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013; 6: 135–43.
36. Garon EB, Balmanoukian A, Hamid O et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). J Thorac Oncol 2013; 8 (Suppl. 2): abstr MO18.02
37. Katakami N, Atagi S, Goto K et al. 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; 31: 3335–41.
________________________________________________
2. Reck M, Popat S, Reinmuth N et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 (Suppl. 3): iii27–iii39.
3. Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 2012; 13: e418–26.
4. Scagliotti GV, Novello S, Rapetti S, Papotti M. Current state-of-theart therapy for advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book 2013; 354–8.
5. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-byhistology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64–70.
6. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–73.
7. Rizvi NA, Mazieres J, Planchard D et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16: 257–65
8. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; published online May 31. DOI: 10.1056/ NEJMoa1504627
9. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21: 3798–807.
10. Lopez-Malpartida AV, Ludena MD, Varela G, Garcia PJ. Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. Lung Cancer 2009; 65: 25–33.
11. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–44.
12. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013; 24: 2371–6.
13. Clark GM, Zborowski DM, Santabarbara P et al. Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 2006; 7: 389–94.
14. Wojtowicz-Praga S, Leon L. Comparative efficacy and safety of erlotinib in non-small cell lung cancer (NSCLC) of squamous cell and adenocarcinoma histology in the phase III NCIC CTG BR.21 and saturn (BO18192) trials. Ann Oncol 2012; 23 (Suppl. 9): ix419. abstr 1277P.
15. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33–42.
16. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–74.
17. Heinmoller P, Gross C, Beyser K et al. HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin Cancer Res 2003; 9: 5238–43.
18. Hirsch FR, Franklin WA, Veve R et al. HER2/neu expression in malignant lung tumors. Semin Oncol 2002; 29 (Suppl. 4): 51–8.
19. Ugocsai K, Mandoky L, Tiszlavicz L, Molnar J. Investigation of HER2 overexpression in non-small cell lung cancer. Anticancer Res 2005; 25: 3061–6.
20. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–25.
21. Dhanasekaran SM, Alejandro BO, Chen G et al. Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nat Commun 2014; 5: 5893.
22. Solca F, Dahl G, Zoephel A et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343: 342–50.
23. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–34.
24. Wu YL, Zhou C, Hu CP et al. 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; 15: 213–22.
25. Yang JC, Wu YL, Schuler M et al. 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; 16: 141–51.
26. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–38.
27. Machiels J, Haddad R, Fayette J et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; 16: 583–94.
28. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (Suppl. 15): abstr 7558.
29. Hamilton M, Wolf JL, Rusk J et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 2006; 12: 2166–71.
30. Smit EF, Gervais R, Zhou C et al. Efficacy and safety results from CurrentS, a double-blind, randomized, phase III study of secondline erlotinib (150 mg versus 300 mg) in current smokers with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2014; 32 (Suppl. 5): abstr 8046.
31. Li N, Yang L, Ou W et al. Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer. PLoS One 2014; 9: e102777.
32. Shepherd FA, Dancey J, Ramlau R et al. 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; 18: 2095–103.
33. Garassino MC, Martelli O, Broggini M et al. 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; 14: 981–8.
34. Yi ES, Harclerode D, Gondo M et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol 1997; 10: 142–48.
35. Nelson V, Ziehr J, Agulnik M, Johnson M. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013; 6: 135–43.
36. Garon EB, Balmanoukian A, Hamid O et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). J Thorac Oncol 2013; 8 (Suppl. 2): abstr MO18.02
37. Katakami N, Atagi S, Goto K et al. 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; 31: 3335–41.
Авторы
________________________________________________
1 Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France;
2 Medical Oncology Department, Vall d’ Hebron University Hospital, Vall d’ Hebron Institute of Oncology, Barcelona, Spain;
3 Hospital Carlos Haya, Malaga, Spain;
4 Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China;
5 Athens School of Medicine, Athens, Greece;
6 Chungbuk National University College of Medicine, Cheongju, South Korea;
7 Ege University Faculty of Medicine, Izmir, Turkey;
8 Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece;
9 First Hospital Affiliated to Jilin University, Jilin, China;
10 Hospital Lozano Blesa, Zaragoza, Spain;
11 Izmir Chest Diseases Research Hospital, Izmir, Turkey;
12 Istituto Nazionale Tumori “Fondazione G Pascale”-IRCCS, Naples, Italy;
13 Department of Medicine, Ulsan University Hospital, Ulsan, South Korea;
14 University Hospital, Bologna, Italy;
15 Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA;
16 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA;
17 Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada
*Jean-Charles.Soria@gustaveroussy.fr
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