Prognostic model of survival outcomes in non-small cell lung cancer patients initiated on afatinib: pooled analysis of clinical trial data
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摘要
Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afatinib have not been evaluated.Methods: A prognostic tool for overall survival(OS)/progression free survival(PFS) based on pre-treatment clinicopathological factors was developed for EGFR-positive advanced NSCLC patients treated with first-line afatinib using penalised regression of individual-participant data from LUX-Lung 3 and 6(n = 468). Favourable, intermediate and poor risk groups were identified and externally validated using LUX-Lung 1(n = 390) and LUX-Lung 2(n = 129) trials that initiated afatinib following previous chemotherapy or EGFR inhibitor treatment.Results: Discriminative performance was good in the development and validation cohorts. For patients treated with first-line afatinib, the median OS for the favourable, intermediate and poor risk groups were > 47.7, 29.3 and 16.4 months, respectively, and the median PFS were 17.3, 13.2 and 8.3 months, respectively. The improvement in median OS with afatinib use compared to chemotherapy was > 12.4 months for the favourable risk group, whereas no OS benefit was apparent for the poor risk group. The improvement in median PFS with afatinib use compared to chemotherapy was 10.2 months for the favourable risk group and 3.2 months for the poor risk group.Conclusions: A prognostic tool was developed and validated to identify favourable, intermediate and poor risk groups for OS/PFS in EGFR-positive advanced NSCLC patients treated with afatinib. The prognostic groups can inform the likely absolute OS/PFS benefit expected from afatinib compared to chemotherapy in first-line treatment.
Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afatinib have not been evaluated.Methods: A prognostic tool for overall survival(OS)/progression free survival(PFS) based on pre-treatment clinicopathological factors was developed for EGFR-positive advanced NSCLC patients treated with first-line afatinib using penalised regression of individual-participant data from LUX-Lung 3 and 6(n = 468). Favourable, intermediate and poor risk groups were identified and externally validated using LUX-Lung 1(n = 390) and LUX-Lung 2(n = 129) trials that initiated afatinib following previous chemotherapy or EGFR inhibitor treatment.Results: Discriminative performance was good in the development and validation cohorts. For patients treated with first-line afatinib, the median OS for the favourable, intermediate and poor risk groups were > 47.7, 29.3 and 16.4 months, respectively, and the median PFS were 17.3, 13.2 and 8.3 months, respectively. The improvement in median OS with afatinib use compared to chemotherapy was > 12.4 months for the favourable risk group, whereas no OS benefit was apparent for the poor risk group. The improvement in median PFS with afatinib use compared to chemotherapy was 10.2 months for the favourable risk group and 3.2 months for the poor risk group.Conclusions: A prognostic tool was developed and validated to identify favourable, intermediate and poor risk groups for OS/PFS in EGFR-positive advanced NSCLC patients treated with afatinib. The prognostic groups can inform the likely absolute OS/PFS benefit expected from afatinib compared to chemotherapy in first-line treatment.
Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afatinib have not been evaluated.Methods: A prognostic tool for overall survival(OS)/progression free survival(PFS) based on pre-treatment clinicopathological factors was developed for EGFR-positive advanced NSCLC patients treated with first-line afatinib using penalised regression of individual-participant data from LUX-Lung 3 and 6(n = 468). Favourable, intermediate and poor risk groups were identified and externally validated using LUX-Lung 1(n = 390) and LUX-Lung 2(n = 129) trials that initiated afatinib following previous chemotherapy or EGFR inhibitor treatment.Results: Discriminative performance was good in the development and validation cohorts. For patients treated with first-line afatinib, the median OS for the favourable, intermediate and poor risk groups were > 47.7, 29.3 and 16.4 months, respectively, and the median PFS were 17.3, 13.2 and 8.3 months, respectively. The improvement in median OS with afatinib use compared to chemotherapy was > 12.4 months for the favourable risk group, whereas no OS benefit was apparent for the poor risk group. The improvement in median PFS with afatinib use compared to chemotherapy was 10.2 months for the favourable risk group and 3.2 months for the poor risk group.Conclusions: A prognostic tool was developed and validated to identify favourable, intermediate and poor risk groups for OS/PFS in EGFR-positive advanced NSCLC patients treated with afatinib. The prognostic groups can inform the likely absolute OS/PFS benefit expected from afatinib compared to chemotherapy in first-line treatment.
引文
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8. Florescu M,Hasan B,Seymour L,Ding K,Shepherd FA.A clinical prognostic index for patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group study BR.21.J Thorac Oncol.2008;3:590-8.
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10. Kaneda H,Tamura K,Kurata T,Uejima H,Nakagawa K,Fukuoka M.Retrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced non-small-cell lung cancer.Lung Cancer.2004;46:247-54.
11. Cha YK,Lee HY,Ahn MJ,Choi YL,Lee JH,Park K,et al.Survival outcome assessed according to tumor burden and progression patterns in patients with epidermal growth factor receptor mutant lung adenocarcinoma undergoing epidermal growth factor receptor tyrosine kinase inhibitor therapy.Clin Lung Cancer.2015; 16:228-36.
12. Wang FH,Zhang Y,Zhao HY,Chen LK,Shi YX,Zhang L.Validation of a clinical prognostic model in Chinese patients with metastatic and advanced pretreated non-small cell lung cancertreated with gefitinib.Med Oncol.2011;28:331-5.(in Chinese)
13. Chen YM,Lai CH,Chang HC,Chao TY,Tseng CC,Fang WF,et al.The impact of clinical parameters on progression-free survival of non-small cell lung cancer patients harb oring EGFR-mutations receiving first-line EGFR-tyrosine kinase inhibitors.Lung Cancer.2016;93:47-54.
14. Cioffi P,Marotta V,Fanizza C,Giglioni A,Natoli C,Petrelli F,et al.Effectiveness and response predictive factors of erlotinib in a nonsmall cell lung cancer unselected European population previously treated:a retrospective,observational,multicentric study.J Oncol Pharm Pract.2013;19:246-53.
15. Jiang T,Cheng RR,Zhang GW,Su CX,Zhao C,Li XF,et al.Characterization of liver metastasis and its effect on targeted therapy in EGFR-mutant NSCLC:a multicenter study.Clin Lung Cancer.2017;18:631-9.
16. Fukihara J,Watanabe N,Taniguchi H,Kondoh Y,Kimura T,Kataoka K,et al.Clinical predictors of response to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.Oncology.2014;86:86-93.
17. Lee JY,Lim SH,Kim M,Kim S,Jung HA,Chang WJ,et al.Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs?Cancer Chemother Pharmacol.2014;73:1063-70.
18. Yao ZH,Liao WY,Ho CC,Chen KY,Shih JY,Chen JS,et al.Realworld data on prognostic factors for overall survival in EGFR mutation-positive advanced non-small cell lung cancer patients treated with first-line gefitinib.Oncologist.2017;22:1075-83.
19. Wu KL,Tsai MJ,Yang CJ,Chang WA,Hung JY,Yen CJ,et al.Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib.Lung Cancer.2015;88:187-94.
20. Park JH,Kim TM,Keam B,Jeon YK,Lee SH,Kim DW,et al.Tumor burden is predictive of survival in patients with non-smallcell lung cancer and with activating epidermal growth factor receptor mutations who receive gefitinib.Clin Lung Cancer.2013;14:383-9.
21. Miller VA,Hirsh V,Cadranel J,Chen YM,Park K,Kim SW,et al.Afatinib versus placebo for patients with advanced,metastatic nonsmall-cell lung cancer after failure of erlotinib,gefitinib,or both,and one or two lines of chemotherapy(LUX-Lung 1):a phase 2b/3randomised trial.Lancet Oncol.2012;13:528-38.
22. Yang JCH,Shih JY,Su WC,Hsia TC,Tsai CM,Ou SHI,et al.Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations(LUX-Lung 2):a phase 2 trial.Lancet Oncol.2012;13:539-48.
23. Yang JCH,Sequist LV,Geater SL,Tsai CM,Mok TSK,Schuler M,et al.Clinical activity of afatinib in patients with advanced nonsmall-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;16:830-8.
24. Yang JCH,Wu YL,Schuler M,Sebastian M,Popat S,Yamamoto N,et al.Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma(LUX-Lung 3 and LUXLung 6):analysis of overall survival data from two randomised,phase 3 trials.Lancet Oncol.2015;16:141-51.
25. Wu YL,Zhou CC,Hu CP,Feng JF,Lu S,Huang YC,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 phasetrial.Lancet Oncol.2014;15:213-22.
26. Halabi S,Lin CY,Kelly WK,Fizazi KS,Moul JW,Kaplan EB,et al.Updated prognostic model for predicting overall survival in firstline chemotherapy for patients with metastatic castration-resistant prostate cancer.J Clin Oncol.2014;32:671-7.
27. Huang YQ,Liang CH,He L,Tian J,Liang CS,Chen X,et al.Development and validation of a radiomics nomogram for preoperative prediction of lymph node metastasis in colorectal cancer.J Clin Oncol.2016;34:2157-64.
28. Soria JC,Mok TS,Cappuzzo F,Janne PA.EGFR-mutated oncogene-addicted non-small cell lung cancer:current trends and future prospects.Cancer Treat Rev.2012;38:416-30.
29. Kibbelaar RE,Oortgiesen BE,van der Wal-Oost AM,Boslooper K,Coebergh JW,Veeger NJGM,et al.Bridging the gap between the randomised clinical trial world and the real wo rld by combination of population-based registry and electronic health record data:a case study in haemato-oncology.Eur J Cancer.2017;86:178-85.
2. Kent DM,Nelson J,Dahabreh IJ,Rothwell PM,Altman DG,Hayward RA.Risk and treatment effect heterogeneity:re-analysis of individual participant data from 32 large clinical trials.Int J Epidemiol.2016;45:2075-88.
3. Kent DM,Rothwell PM,Ioannidis JP,Altman DG,Hayward RA.Assessing and reporting heterogeneity in treatment effects in clinical trials:a proposal.Trials.2010; 11:85.
4. Chen G,Feng J,Zhou C,Wu YL,Liu XQ,Wang C,et al.Quality of life(QoL)analyses from OPTIMAL(CTONG-0802),a phaseⅢ,randomised,open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer(NSCLC).Ann Oncol.2013;24:1615-22.
5. Park K,Tan EH,O'Byrne K,Zhang L,Boyer M,Mok T,et al.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; 17:577-89.
6. Aydiner A,Yildiz I,Seyidova A.Clinical outcomes and prognostic factors associated with the response to erlotinib in non-small-cell lung cancer patients with unknown EGFR mutational status.Asian Pac J Cancer Prev.2013; 14:3255-61.
7. Faehling M,Eckert R,Kuom S,Kamp T,Stoiber KM,Schumann C.Benefit of erlotinib in patients with non-small-cell lung cancer is related to smoking status,gender,skin rash and radiological response but not to histology and treatment line.Oncology.2010;78:249-58.
8. Florescu M,Hasan B,Seymour L,Ding K,Shepherd FA.A clinical prognostic index for patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group study BR.21.J Thorac Oncol.2008;3:590-8.
9. Krawczyk P,Kowalski DM,Krawczyk KW,Szczyrek M,Mlak R,Rolski A,et al.Predictive and prognostic factors in second-and third-line erlotinib treatment in NSCLC patients with known status of the EGFR gene.Oncol Rep.2013;30:1463-72.
10. Kaneda H,Tamura K,Kurata T,Uejima H,Nakagawa K,Fukuoka M.Retrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced non-small-cell lung cancer.Lung Cancer.2004;46:247-54.
11. Cha YK,Lee HY,Ahn MJ,Choi YL,Lee JH,Park K,et al.Survival outcome assessed according to tumor burden and progression patterns in patients with epidermal growth factor receptor mutant lung adenocarcinoma undergoing epidermal growth factor receptor tyrosine kinase inhibitor therapy.Clin Lung Cancer.2015; 16:228-36.
12. Wang FH,Zhang Y,Zhao HY,Chen LK,Shi YX,Zhang L.Validation of a clinical prognostic model in Chinese patients with metastatic and advanced pretreated non-small cell lung cancertreated with gefitinib.Med Oncol.2011;28:331-5.(in Chinese)
13. Chen YM,Lai CH,Chang HC,Chao TY,Tseng CC,Fang WF,et al.The impact of clinical parameters on progression-free survival of non-small cell lung cancer patients harb oring EGFR-mutations receiving first-line EGFR-tyrosine kinase inhibitors.Lung Cancer.2016;93:47-54.
14. Cioffi P,Marotta V,Fanizza C,Giglioni A,Natoli C,Petrelli F,et al.Effectiveness and response predictive factors of erlotinib in a nonsmall cell lung cancer unselected European population previously treated:a retrospective,observational,multicentric study.J Oncol Pharm Pract.2013;19:246-53.
15. Jiang T,Cheng RR,Zhang GW,Su CX,Zhao C,Li XF,et al.Characterization of liver metastasis and its effect on targeted therapy in EGFR-mutant NSCLC:a multicenter study.Clin Lung Cancer.2017;18:631-9.
16. Fukihara J,Watanabe N,Taniguchi H,Kondoh Y,Kimura T,Kataoka K,et al.Clinical predictors of response to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.Oncology.2014;86:86-93.
17. Lee JY,Lim SH,Kim M,Kim S,Jung HA,Chang WJ,et al.Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs?Cancer Chemother Pharmacol.2014;73:1063-70.
18. Yao ZH,Liao WY,Ho CC,Chen KY,Shih JY,Chen JS,et al.Realworld data on prognostic factors for overall survival in EGFR mutation-positive advanced non-small cell lung cancer patients treated with first-line gefitinib.Oncologist.2017;22:1075-83.
19. Wu KL,Tsai MJ,Yang CJ,Chang WA,Hung JY,Yen CJ,et al.Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib.Lung Cancer.2015;88:187-94.
20. Park JH,Kim TM,Keam B,Jeon YK,Lee SH,Kim DW,et al.Tumor burden is predictive of survival in patients with non-smallcell lung cancer and with activating epidermal growth factor receptor mutations who receive gefitinib.Clin Lung Cancer.2013;14:383-9.
21. Miller VA,Hirsh V,Cadranel J,Chen YM,Park K,Kim SW,et al.Afatinib versus placebo for patients with advanced,metastatic nonsmall-cell lung cancer after failure of erlotinib,gefitinib,or both,and one or two lines of chemotherapy(LUX-Lung 1):a phase 2b/3randomised trial.Lancet Oncol.2012;13:528-38.
22. Yang JCH,Shih JY,Su WC,Hsia TC,Tsai CM,Ou SHI,et al.Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations(LUX-Lung 2):a phase 2 trial.Lancet Oncol.2012;13:539-48.
23. Yang JCH,Sequist LV,Geater SL,Tsai CM,Mok TSK,Schuler M,et al.Clinical activity of afatinib in patients with advanced nonsmall-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;16:830-8.
24. Yang JCH,Wu YL,Schuler M,Sebastian M,Popat S,Yamamoto N,et al.Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma(LUX-Lung 3 and LUXLung 6):analysis of overall survival data from two randomised,phase 3 trials.Lancet Oncol.2015;16:141-51.
25. Wu YL,Zhou CC,Hu CP,Feng JF,Lu S,Huang YC,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 phasetrial.Lancet Oncol.2014;15:213-22.
26. Halabi S,Lin CY,Kelly WK,Fizazi KS,Moul JW,Kaplan EB,et al.Updated prognostic model for predicting overall survival in firstline chemotherapy for patients with metastatic castration-resistant prostate cancer.J Clin Oncol.2014;32:671-7.
27. Huang YQ,Liang CH,He L,Tian J,Liang CS,Chen X,et al.Development and validation of a radiomics nomogram for preoperative prediction of lymph node metastasis in colorectal cancer.J Clin Oncol.2016;34:2157-64.
28. Soria JC,Mok TS,Cappuzzo F,Janne PA.EGFR-mutated oncogene-addicted non-small cell lung cancer:current trends and future prospects.Cancer Treat Rev.2012;38:416-30.
29. Kibbelaar RE,Oortgiesen BE,van der Wal-Oost AM,Boslooper K,Coebergh JW,Veeger NJGM,et al.Bridging the gap between the randomised clinical trial world and the real wo rld by combination of population-based registry and electronic health record data:a case study in haemato-oncology.Eur J Cancer.2017;86:178-85.