Original Article Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer Julie Brahmer, M.D., Karen L. Reckamp, M.D., Paul Baas, M.D., Lucio Crinò, M.D., Wilfried E.E. Eberhardt, M.D., Elena Poddubskaya, M.D., Scott Antonia, M.D., Ph.D., Adam Pluzanski, M.D., Ph.D., Everett E. Vokes, M.D., Esther Holgado, M.D., Ph.D., David Waterhouse, M.D., Neal Ready, M.D., Justin Gainor, M.D., Osvaldo Arén Frontera, M.D., Libor Havel, M.D., Martin Steins, M.D., Marina C. Garassino, M.D., Joachim G. Aerts, M.D., Manuel Domine, M.D., Luis Paz-Ares, M.D., Martin Reck, M.D., Christine Baudelet, Ph.D., Christopher T. Harbison, Ph.D., Brian Lestini, M.D., Ph.D., and David R. Spigel, M.D. N Engl J Med Volume 373(2):123-135 July 9, 2015 R1유승화 / pf. 이승현

Background - Squamous cell carcinoma: 30% of NSCLC - 2nd line treatment: Docetaxel, 1999. - Nivolumab: IgG4 PD-1 immune-checkpoint-inhibitor Ab Immune escape - PD-1 receptor on activated T cell - PD-L1, PD-L2 expressed by tumor cells inhibit T cell activation - Nivolumab disrupts PD-1-mediated signalling and restore anti-tumor immunity Anti tumor immunity를 되살립니다

Study Overview In a randomized study of second-line therapy, treatment with nivolumab, an anti–PD-1 antibody, resulted in responses in more people and in better overall survival than did docetaxel. - Nivolumab monotherapy v. Docetaxel monotherapy - Randomized, open-label, international - SCC NSCLC IIIB or IV, PD after one prior platinum-containg regemen - ECOG 0 or 1 - 18yr and older

Study Overview Study design - 2012.10~2013.12 - 260 patients(randomized)/272 - 131 with nivolumab (3mg/kg iv q 2w) - 129 with docetaxel (75mg/m2 iv q 3w) End point - Primary: overall survival - Secondary: rate of objective response, progression-free survival, efficacy according to PD-L1 expression, and safety

Baseline Characteristics, Stratification Factors, and Prior Therapy. Table 1 Baseline Characteristics, Stratification Factors, and Prior Therapy. Brahmer J et al. N Engl J Med 2015;373:123-135

Kaplan–Meier Curves for Overall Survival. Figure 1 Kaplan–Meier Curves for Overall Survival. The analysis included all the patients who underwent randomization. Symbols indicate censored observations, and horizontal lines the rates of overall survival at 1 year. Brahmer J et al. N Engl J Med 2015;373:123-135

Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Figure 2 Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Panel A shows the characteristics of response and disease progression as assessed by the investigator, according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Bars indicate the duration of response. Arrows indicate ongoing response at the time of data censoring. Panel B shows the Kaplan–Meier curves for progression-free survival, defined as the time from randomization to the date of the first documented event of tumor progression, death, or last tumor assessment that could be evaluated (data-censoring date). The analysis included all the patients who underwent randomization. Symbols indicate censored observations, and the horizontal lines the rates of progression-free survival at 1 year. Panel C shows the plot of hazard ratios for death (in the analysis of overall survival) and death or disease progression (in the analysis of progression-free survival), according to the level of expression of the ligand for programmed death 1 (PD-L1) at baseline. The prespecified expression levels for the PD-L1 biomarker analysis were 1%, 5%, and 10% of cells in a section with at least 100 tumor cells that could be evaluated. Characteristics of response and disease progression as assessed by the investigator, according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Bars indicate the duration of response. Arrows indicate ongoing response at the time of data censoring. Brahmer J et al. N Engl J Med 2015;373:123-135

Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Figure 2 Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Panel A shows the characteristics of response and disease progression as assessed by the investigator, according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Bars indicate the duration of response. Arrows indicate ongoing response at the time of data censoring. Panel B shows the Kaplan–Meier curves for progression-free survival, defined as the time from randomization to the date of the first documented event of tumor progression, death, or last tumor assessment that could be evaluated (data-censoring date). The analysis included all the patients who underwent randomization. Symbols indicate censored observations, and the horizontal lines the rates of progression-free survival at 1 year. Panel C shows the plot of hazard ratios for death (in the analysis of overall survival) and death or disease progression (in the analysis of progression-free survival), according to the level of expression of the ligand for programmed death 1 (PD-L1) at baseline. The prespecified expression levels for the PD-L1 biomarker analysis were 1%, 5%, and 10% of cells in a section with at least 100 tumor cells that could be evaluated. Kaplan–Meier curves for progression-free survival, defined as the time from randomization to the date of the first documented event of tumor progression, death, or last tumor assessment that could be evaluated (data-censoring date). Brahmer J et al. N Engl J Med 2015;373:123-135

Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Figure 2 Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Panel A shows the characteristics of response and disease progression as assessed by the investigator, according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Bars indicate the duration of response. Arrows indicate ongoing response at the time of data censoring. Panel B shows the Kaplan–Meier curves for progression-free survival, defined as the time from randomization to the date of the first documented event of tumor progression, death, or last tumor assessment that could be evaluated (data-censoring date). The analysis included all the patients who underwent randomization. Symbols indicate censored observations, and the horizontal lines the rates of progression-free survival at 1 year. Panel C shows the plot of hazard ratios for death (in the analysis of overall survival) and death or disease progression (in the analysis of progression-free survival), according to the level of expression of the ligand for programmed death 1 (PD-L1) at baseline. The prespecified expression levels for the PD-L1 biomarker analysis were 1%, 5%, and 10% of cells in a section with at least 100 tumor cells that could be evaluated. Hazard ratios for death (in the analysis of overall survival) and death or disease progression (in the analysis of progression-free survival), according to the level of expression of the ligand for programmed death 1 (PD-L1) at baseline. ahmer J et al. N Engl J Med 2015;373:123-135

Clinical Activity of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Table 2 Clinical Activity of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer. Brahmer J et al. N Engl J Med 2015;373:123-135

Treatment-Related Adverse Events Reported in at Least 5% of Patients. Table 3 Treatment-Related Adverse Events Reported in at Least 5% of Patients. Brahmer J et al. N Engl J Med 2015;373:123-135

Conclusions Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. survival benefit, safety profile에서 더 우월하고 benefit은 PD-L1 expression level과 관계없다 어떤 환자가 benefit을 받을지 알려줄 biomarker찾는 연구를 해야됨