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Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis

Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis Background: Immune checkpoint inhibitors targeting PD-1/PD-L1 pathway demonstrated promising activities in variety of malignancies, however little is known regarding their efficacy in adults aged ≥65 years. Methods: We conducted a systematic review and a study-level meta-analysis to explore efficacy of ICIs based on age, younger vs older than 65 years. We included in this analysis randomized controlled phase II or III studies in patients with metastatic solid tumors that compared efficacy of PD-1 or PD-L1 inhibitors to a non-PD-1/PD-L1 inhibitor. Aggregated estimates of overall survival (OS) and progression-free survival (PFS) are based on random/ mixed effects (RE) models to allow for heterogeneity between the studies. Results: Initial search identified 53 articles, 17 were randomized controlled trials that compared nivolumab, pembrolizumab or atezolizumab to chemotherapy or targeted therapy. Only 9 trials reported hazard ratiios (HR) for OS based on age and were included in this meta-analysis. Out of those studies seven reported HR for PFS but only 4 studies included subgroup-analysis based on age for PFS. The overall estimated random-effects HR for death was 0.64 with 95% CI of 0.54–0.76 in patients ≥65 years vs. 0.68 with 95% CI of 0.61–0.75 in patients < 65 years. The overall estimated random-effects for HR for progression was 0.74 with 95% CI of 0.60–0.92 in patients ≥65 years vs. 0.73 with 95% CI of 0.61–0.88 in patients < 65 years. Conclusions: PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) inhibitors had comparable efficacy in adults younger vs ≥ 65 years. Background In some studies, aging was associated with decreased ex- The advent of Immune Checkpoint Inhibitors (ICIs) pression of CD28 on the surface of CD8+ T cells which changed the landscape of cancer treatment. Efficacy of leads to decreased immune activation. [17–19] Expres- PD-1 and PD-L1 antibodies has been established in a sion of CD57, a marker of senescence, was found to be wide spectrum of solid and hematological malignancies. increased on the surface of cytotoxic T cells of older [1–10] However, although cancer is predominantly a dis- adults contributing to a diminished anti-tumoral im- ease of older adults, the clinical efficacy of ICIs in this munogenic response. [20, 21] In addition, the levels of population has not been specifically assessed. [11, 12] perforin and granzyme, both essential for T cell’s cyto- Published literature suggests that aging-associated im- toxic activity, were lower in older adults compared to mune changes may have an impact on the activity of younger individuals. [22] Interestingly, expression of PD- checkpoint inhibitors, including PD-1 and PD-L1 inhibi- 1 was found to be increased on T cells of older adults tors. [13] Cytotoxic CD8+ T cells in older adults were and its blockade did not restore T cell activity to the found to have decreased TCR (T cell receptor) diversity, same extent as in younger adults [22–24] Our under- reduced proliferative capacity, and increased sensitivity standing of the efficacy of PD-1 and PD-L1 antibodies in to apoptotic signals compared to younger adults [14–16] older adults is limited due to underrepresentation of this patient population in prospective clinical trials due to * Correspondence: osamae_rahma@dfci.harvard.edu concerns about the safety profile of the investigated Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard agents. [25] Consequently, we conducted a systematic Medical School, Boston, MA, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 2 of 8 review and a study-level meta-analysis to explore efficacy of patients ≥65 years, number of patients younger than of ICIs based on age, younger vs older than 65 years. 65 years in each arm, number of patients ≥65 in each arm, median age, age range, mean age (3) HR for OS Methods and for PFS (4) HR for OS and for PFS based on age Search strategy and selection criteria subgroups (younger vs ≥ 65 years). In the case of trials We performed a Pubmed database search from January that did not include survival subgroup analysis by age, 2009 to December 2016 using the medical subject head- we reviewed each published trial’s supplement and the ings (MeSH) terms “pembrolizumab”, “nivolumab”, and FDA medical and statistical review available on the “atezolizumab”, the only Food and Drug Administration “Drugs @FDA” database. (FDA) PD-1/PD-L1 ICIs approved at the time this review was conducted. Search was done using the filter Statistical methods “clinical trial”. The language was restricted to English. Aggregated estimates of OS and progression-free sur- We then performed additional searches of Web of vival (PFS) are based on random/mixed effects (RE) Science, ASCO meeting database, and ESMO meeting models to allow for possible heterogeneity between the database using the same terms. We reviewed the studies. Forest plots were used to summarize and “Drugs @FDA” database for randomized studies that visualize the HR with 95% confidence intervals (CI) for did not report number of patients aged ≥65 years en- each study and for the aggregated estimates from the RE rolled on the trial or subgroup analysis for overall models. For studies reporting separate HR estimates for survival (OS) by age (younger vs ≥ 65 years). Studies 65–75 and > 75 years, a combined estimate (≥ 65 years) meeting all of the following criteria were included: (1) was created using random effects modeling, and the Randomized controlled phase II or III studies in combined estimate was used in the meta-analysis patients with metastatic solid cancer (2) Studies com- for that study. Chi-squared p-values from Cochran’s paring efficacy of PD-1 or PD-L1 inhibitors to a non- Q statistic assessed study heterogeneity. Analyses were PD-1/PD-L1 inhibitor (3) Subgroup analysis for conducted using the “Metafor” package in R software survival using a hazard ratio (HR) based on age per- (Version 3.2.3, The R Foundation for Statistical Comput- formed in study or available in FDA label review. The ing). Statistical significance is defined as P < 0.05; there selection process is shown in Fig. 1. Studies involving were no corrections for multiple comparisons. use of ICIs in hematologic malignancies were ex- cluded from this meta-analysis. Results Search results and patient characteristics Data extraction We identified 53 studies that matched our basic Data extracted from eligible studies included: (1) Study selection criteria of clinical trial involving one of the characteristics (first author, year of publication, study FDA-approved PD-1 and PD-L1 agents. Thirty-six non-- name, design, phase, arms, National Clinical Trial randomized studies were excluded. Seventeen studies (NCT) number (2) Study population (total number of were reviewed, 8 out of those 17 studies were excluded randomized patients, total number in each arm, total as they did not contain OS subgroup analysis by age. number of patients younger than 65 years, total number Final analysis included 9 studies: (6 phase 3 studies, 2 Fig. 1 Flow diagram of study inclusion Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 3 of 8 Table 1 Characteristics of included studies. Abbreviations: NSCLC (non-small lung cancer); S-NSCLC (squamous non-small lung cancer); NS-NSCLC (non-squamous non-small lung cancer); RCC (renal cell cancer); H&N (head & neck); NR (not reported); Q (every); W (weeks) Study Name Drug Phase Malignancy First line Arm 1 Arm 2 Arm 3 Patient’ number Age median Age range Age mean n (%) < 65 y n (%) ≥ 65 y Rittmeyer OAK Atezolizumab 3 NSCLC N Atezolizumab Docetaxel 850 64 33–85 63 453 (53) 397 (47) 2016 [33] 1200 mg Q 3 W 75 mg/m Q3W Fehrenbacher POPLAR Atezolizumab 2 NSCLC N Atezolizumab Docetaxel 287 62 36–84 61.5 174 (61) 113 (39) 2016 [26, 34] 1200 mg Q 3 W 75 mg/m Q3W Brahmer Checkmate- Nivolumab 3 S-NSCLC N Nivolumab Docetaxel 272 63 39–85 63 152 (56) 120 (44) 2015 [5] 017 3 mg/kg Q 2 W 75 mg/m Q3W Borghaei Checkmate- Nivolumab 3 NS-NSCLC N Nivolumab Docetaxel 582 62 21–85 NR 339 (58) 243 (42) 2015 [6] 057 3 mg/kg Q 2 W 75 mg/m Q3W Motzer Checkmate- Nivolumab 3 RCC N Nivolumab Everolimus 10 mg daily 821 62 18–88 61.3 497 (61) 324 (39) 2015 [4] 025 3 mg/kg Q 2 W Robert 01– Checkmate- Nivolumab 3 Melanoma Y Nivolumab Dacarbazine 418 65 18–87 62.7 200 (48) 218 (52) 2015 [29] 066 3 mg/kg Q 2 W 1000 mg/m Q3W Ferris Checkmate- Nivolumab 3 H&N N Nivolumab Chemotherapy 361 60 28–83 59.1 248 (69) 113 (31) 2016 [2] 141 3 mg/kg Q 2 W Herbst Keynote- Pembrolizumab 2/3 NSCLC N Pembrolizmab Pembrolizumab Docetaxel 1033 NR NR 62 604 (58) 429 (42) 2016 [8] 010 2 mg/kg Q 3 W 10 mg/kg Q 3 W 75 mg/m Q3 W Robert 06– Keynote- Pembrolizumab 3 Melanoma N Pembrolizumab Pembrolizumab Ipilimumab 834 NR NR 60.3 467 (56) 367 (44) 2015 [9] 006 10 mg/kg Q 2 W 10 mg/kg Q 3 W 3 mg/kg Q3 W Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 4 of 8 phase 2 studies, and one phase 2/3 study). Among the 9 89 years, and 2324 (42.57%) patients were older than studies included in the analysis, 5 investigated nivolu- 65 years. The random-effects estimate of the HR of mab, 2 investigated pembrolizumab, and 2 investigated PD1/PDL1 agents compared to control therapy in atezolizumab. Tumor types included metastatic non- patients under age 65 is 0.68 (95% CI 0.61 to 0.75) small cell lung cancer (NSCLC) in 5 trials, melanoma in (Fig. 3a). For this subset, there was no evidence of 2, renal cell cancer in 1, and head and neck cancer in differences between the individual studies (chi-squared one trial. Characteristics of each trial are presented in P = 0.45) in the analysis. The random-effects estimate Table 1. All studies reported a subgroup analysis based of the HR for age 65 or older is 0.64 (95% CI 0.54 to on age except for the POPLAR study [26] for which HR 0.76) (Fig. 3b). For this subset, there was evidence of were obtained from the FDA medical review of atezoli- differences in the HR between the individual studies zumab (Biologic License Application (BLA) 761,041). (chi-squared P = 0.03), suggesting considerable vari- ability in the reported results among the studies. The Overall survival comparable hazard ratios for patients 65 and older Overall comparison compared with those under 65 (0.64 vs. 0.68) as well The endpoint of interest is overall survival in studies as the substantial overlap of the confidence intervals comparing PD1/PDL1 therapy with chemotherapy/tar- of the two estimates would indicate that the effects of geted agents. The HR of the individual studies and the therapy on survival did not vary for older or younger combined results based on the random-effects models adults (Table 2). are summarized in Fig. 2. The ratios presented compare anti-PD1/PDL1 agents against chemo/targeted therapy Progression-free survival in the total population. The overall estimated, random- Overall progression-free survival effects HR is 0.69 with 95% CI of 0.63 to 0.74 (P <0. The endpoint of interest is progression-free survival in 0001). Based on the selected trials, there is evidence of a studies comparing PD1/PDL1 therapy with chemother- statistically significant, 31% reduction in the hazard of apy/targeted agents. Among studies included in this ana- death with PD1/PDL1 therapy compared with chemo/ lysis, seven had HR for overall PFS including four that targeted agents. The chi-squared test for heterogeneity reported HR for PFS according to age group. The HR of studies was not significant (P = 0.52) suggesting that for PFS of the individual studies and the combined re- the reported results of the individual trials are not sub- sults based on the random-effects models are summa- stantially different from one another. rized in Fig. 4. The overall estimated, random-effects HR is 0.74 with 95% CI of 0.60 to 0.92 (P = 0.006). Based on the selected trials, there is evidence of a statistically sig- Survival according to age The studies selected for this meta-analysis included a nificant, 26% reduction in the hazard of a PFS event with total of 5458 patients. Age range of participants was 18– PD1/PDL1 compared with chemo/targeted agents. The Fig. 2 Forest plot for OS. Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation. The HR from the Robert 01–2015 trial is lower than the others, but the weight of the trial is small and does not have great influence Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 5 of 8 Fig. 3 Forest plot for OS for patients less than 65 years (A) and ≥ 65 years (B). Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation chi-squared test for heterogeneity of studies was highly for patients age 65 or over the HR estimate is 0.74 (95% significant (P < 0.0001) suggesting that the reported HRs CI 0.60 to 0.92) (Fig. 5b) For each subset of younger and of the individual trials are substantially different. older patients, there was evidence of heterogeneity be- tween the studies (chi-squared P = 0.03 and p = 0.05, re- Progression-free survival according to age spectively), suggesting t there is considerable variability The random-effects estimate of the HR of PD1/PDL1 in the reported results among the studies within each compared with chemo/targeted therapy in patients subset. The equivalent HR estimates for the two age co- under age 65 is 0.73 (95% CI 0.61 to 0.88) (Fig. 5a), and horts along with the substantial overlap of the confi- dence intervals of the two estimates, would indicate that the effects of therapy upon PFS did not vary for older or younger adults (Table 3). Table 2 Summary of HR for OS by Age Age HR (95% CI) Discussion Age < 65 years 0.68 (0.61 to 0.75) Increased age is associated with changes in the host im- Age ≥ 65 years 0.64 (0.54 to 0.76) munity that could impact effectiveness of ICIs therefore Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 6 of 8 Fig. 4 Forest plot for PFS. Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation we aimed through this meta-analysis to evaluate the effi- important to note the age cutoff was non-uniform cacy of PD-1 and PD-L1 inhibitors in adults ≥65 years across selected studies (65–70 years). In addition, au- with advanced solid tumors compared to those < thors did not show a statistically significant benefit in 65 years. This meta-analysis suggests that the impact of terms of PFS for ICIs in adults ≥65 years (HR 0.77, PD-1/PD-L1 inhibitors is comparable between adults 95% CI 0.58–1.01) vs. a significantly favorable HR in younger vs. older than 65 years for OS [HR 0.68 (CI patients < 65 years (HR 0.58, 95% CI 0.40–0.84). Betof 0.61–0.75) vs. 0.64 (CI 0.54–0.76)] and PFS [HR 0.73 et al showed no significant difference in survival (CI 0.61–0.88) vs. 0.74 (CI 0.60–0.92)]. The data were benefit with PD1/PDL1 inhibitors according to age in not sufficient to draw any conclusions specific to pa- a retrospective analysis of patients treated in two tients ≥75 years. The number of patients older than academic medical centers. [31]However,this analysis 65 years enrolled in PD-1/PD-L1 studies is increased included only patients with metastatic melanoma and compared to what is usually seen in oncology trials 92.5% were treated with an anti-PD1 agent. but older adults remain under-represented in cancer Although it was done at a study-level, our paper clinical trials. [25, 27, 28] This is particularly true for constitutes the best level of evidence showing individuals older than 75 years who constitute more comparable efficacy for checkpoint inhibitors targeting than 25% of newly diagnosed cases of cancer every checkpoint inhibitors in adults > 65 years compared year. [11] Four of the trials included in this review to younger patients. Studies included in this meta- contained HR OS for patients ≥75 years. [4–6, 29] analysis, consistent with the majority of clinical trials However, out of 2093 individuals included in the ana- in oncology, used a numerical age cutoff. An arbitrary lyzed trials only 10% (213) were ≥ 75 year. Accord- age cutoff is not sufficient to characterize “older” ingly, data was not sufficient to draw any conclusions adults as aging is a highly variable physiological specific to adults ≥75 years. process. Older individuals are not a homogenous Few papers attempted to review this topic but only population, therefore measuring variables like func- one was performed at a meta-analysis level. [30]The tional status and comorbidity is essential to determine analysis performed by Nishijima et al..... was based on the physiologic “age” of an older adult [32]. In 9 studies, however among the trials included 4 were addition, older individuals enrolled in clinical trials with an anti-CTLA4 agents, therefore mixing two tend to be adults aged 70–75 years, with good per- classes of ICIs with different mode of action and effi- formance status, and a low number of comorbid cacy profile. Authors showed a comparable OS benefit medical conditions which does not represent the real- for ICIs in younger (HR 0.75, 95% CI 0.68 to 0.82) life population of older adults with cancer who often and older adults (HR 0.73, 95% CI 0.62–0.78). It is have functional limitations and multiple illnesses. Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 7 of 8 Fig. 5 Forest plot for PFS for patients less than 65 years (A) and ≥ 65 years (B). Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation Another limitation to our review is that data were ob- tolerance and toxicity of ICIs in older adults overall. tained partially from FDA BLA review of a particular Further study is needed including comprehensive as- drug and not directly from the study itself as in the sessment of outcomes of significant to older adults, case of POPLAR study. [26] such as functional status and preservation throughout In conclusion, our meta-analysis showed that therapy. Geriatric assessment and biomarkers of aging improvement in survival associated with the use of and immune senesce will help to fully understand the PD-1/PD-L1 inhibitors is consistent across age cut-off impact of ICIs in this growing subset of adults diag- of 65 years. More data are needed to understand nosed with cancer. efficacy among those aged ≥75 years as well as Acknowledgments Not applicable Funding Table 3 Summary of HR for PFS by Age no funding to declare. Age HR (95% CI) Age < 65 years 0.73 (0.61 to 0.88) Availability of data and materials All data generated or analyzed during this study are included in this Age ≥ 65 years 0.74 (0.60 to 0.92) published article. Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 8 of 8 Authors’ contributions 13. Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: RE and OR conceived and designed research. Data collection and extraction immune aging & checkpoint inhibitors. J Geriatr Oncol. 2017;8:229–35. was performed by RE and verified by OR. Statistical analysis was performed 14. Gupta S, Gollapudi S. CD95-mediated apoptosis in naive, central and by AG-H. SH, PO, and NJMC participated in drafting article. All authors gave effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp final approval to the version submitted. Gerontol. 2008;43:266–74. 15. Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec G. Ethics approval and consent to participate Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in Not applicable young and old people. Immun Ageing. 2008;5:6. 16. Johnstone J, Millar J, Lelic A, Verschoor CP, Walter SD, Devereaux PJ, Consent for publication Bramson J, Loeb M. Immunosenescence in the nursing home elderly. BMC Not applicable Geriatr. 2014;14:50. 17. Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Competing interests Ouslander JG, Weyand CM, Goronzy JJ. T cell subset-specific susceptibility to The authors declare that they have no competing interests. aging. Clin Immunol. 2008;127:107–18. 18. Weng NP, Akbar AN, Goronzy J. CD28(−) T cells: their role in the age- associated decline of immune function. Trends Immunol. 2009;30:306–12. Publisher’sNote 19. Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M, Brenci S, Springer Nature remains neutral with regard to jurisdictional claims in Contini P, Olive D, Ghio M, et al. Nonantigen specific CD8+ T suppressor published maps and institutional affiliations. lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol. 2004;65:142–56. Author details 20. Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza Sections of Hematology Oncology and geriatrics, Boston University School JP, Kuruppu J, Migueles SA, Connors M, et al. Expression of CD57 defines of Medicine, Boston, MA, USA. Department of Biostatistics & Computational replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Blood. 2003;101:2711–20. Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 21. Bigley AB, Spielmann G, LaVoy EC, Simpson RJ. Can exercise-related Boston, MA, USA. improvements in immunity influence cancer prevention and prognosis in the elderly? Maturitas. 2013;76:51–6. Received: 15 January 2018 Accepted: 14 March 2018 22. Henson SM, Macaulay R, Riddell NE, Nunn CJ, Akbar AN. Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol. 2015;45:1441–51. References 23. Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C. Partial 1. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival PD-L1 pathway. Aging Cell. 2010;9:785–98. with ipilimumab in patients with metastatic melanoma. N Engl J Med. 24. Vukmanovic-Stejic M, Sandhu D, Seidel JA, Patel N, Sobande TO, Agius E, 2010;363:711–23. Jackson SE, Fuentes-Duculan J, Suarez-Farinas M, Mabbott NA, et al. The 2. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington characterization of varicella zoster virus-specific T cells in skin and blood K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell during aging. J Invest Dermatol. 2015;135:1752–62. carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67. 25. Hurria A, Levit LA, Dale W, Mohile SG, Muss HB, Fehrenbacher L, Magnuson 3. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, A, Lichtman SM, Bruinooge SS, Soto-Perez-de-Celis E, et al. Improving the Khushalani NI, Miller WH Jr, Lao CD, et al. Nivolumab versus chemotherapy in evidence base for treating older adults with Cancer: American Society of patients with advanced melanoma who progressed after anti-CTLA-4 treatment Clinical Oncology statement. J Clin Oncol. 2015;33:3826–33. (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet 26. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres Oncol. 2015;16:375–84. J, Park K, Smith D, Artal-Cortes A, Lewanski C, et al. Atezolizumab versus 4. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, docetaxel for patients with previously treated non-small-cell lung cancer Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al. Nivolumab versus (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. Lancet. 2016;387:1837–46. 5. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, 27. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus for cancer drug registration: a 7-year experience by the US Food and Drug docetaxel in advanced squamous-cell non-small-cell lung Cancer. N Engl J Administration. J Clin Oncol. 2004;22:4626–31. Med. 2015;373:123–35. 28. Singh H, Kanapuru B, Smith C, Fashoyin-Aje LA, Myers A, Kim G, Pazdur R. 6. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, FDA analysis of enrollment of older adults in clinical trials for cancer drug Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced registration: a 10-year experience by the U.S. Food and Drug Administration. nonsquamous non-small-cell lung Cancer. N Engl J Med. 2015;373:1627–39. J Clin Oncol. 2017;35 abstr 10009 7. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, 29. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD- P, McNeil C, Kalinka-Warzocha E, et al. Nivolumab in previously untreated L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375:1823–33. melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30. 8. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, 30. Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously immune checkpoint inhibitors (ICIs) between younger and older patients: a treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. a randomised controlled trial. Lancet. 2016;387:1540–50. 31. Betof AS, Nipp RD, Giobbie-Hurder A, Johnpulle RAN, Rubin K, Rubinstein SM, 9. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Flaherty KT, Lawrence DP, Johnson DB, Sullivan RJ. Impact of age on outcomes Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus Ipilimumab in with immunotherapy for patients with melanoma. Oncologist. 2017;22:963–71. Advanced Melanoma. N Engl J Med. 2015;372:2521–32. 32. Extermann M, Hurria A. Comprehensive geriatric assessment for older 10. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, patients with cancer. J Clin Oncol. 2007;25:1824–31. Schachter J, Pavlick AC, Lewis KD, et al. Pembrolizumab versus investigator- 33. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18. docetaxel in patients with previously treated non-small-cell lung cancer 11. Browse the SEER Cancer Statistics Review 1975-2012 [https://seer.cancer. (OAK): a phase 3, open-label, multicentre randomised controlled trial. gov/archive/csr/1975_2012/browse_csr.php?sectionSEL=2&pageSEL=sect_ Lancet. 2016;389:255–65. 02_table.07.html]. 34. Atezolizumab BLA 761041 Medical Review [https://www.accessdata.fda.gov/ 12. Elias R, Morales J, Rehman Y, Khurshid H. Immune checkpoint inhibitors in drugsatfda_docs/nda/2016/761041Orig1s000MedR.pdf]. older adults. Curr Oncol Rep. 2016;18:47. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis

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Springer Journals
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
DOI
10.1186/s40425-018-0336-8
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Abstract

Background: Immune checkpoint inhibitors targeting PD-1/PD-L1 pathway demonstrated promising activities in variety of malignancies, however little is known regarding their efficacy in adults aged ≥65 years. Methods: We conducted a systematic review and a study-level meta-analysis to explore efficacy of ICIs based on age, younger vs older than 65 years. We included in this analysis randomized controlled phase II or III studies in patients with metastatic solid tumors that compared efficacy of PD-1 or PD-L1 inhibitors to a non-PD-1/PD-L1 inhibitor. Aggregated estimates of overall survival (OS) and progression-free survival (PFS) are based on random/ mixed effects (RE) models to allow for heterogeneity between the studies. Results: Initial search identified 53 articles, 17 were randomized controlled trials that compared nivolumab, pembrolizumab or atezolizumab to chemotherapy or targeted therapy. Only 9 trials reported hazard ratiios (HR) for OS based on age and were included in this meta-analysis. Out of those studies seven reported HR for PFS but only 4 studies included subgroup-analysis based on age for PFS. The overall estimated random-effects HR for death was 0.64 with 95% CI of 0.54–0.76 in patients ≥65 years vs. 0.68 with 95% CI of 0.61–0.75 in patients < 65 years. The overall estimated random-effects for HR for progression was 0.74 with 95% CI of 0.60–0.92 in patients ≥65 years vs. 0.73 with 95% CI of 0.61–0.88 in patients < 65 years. Conclusions: PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) inhibitors had comparable efficacy in adults younger vs ≥ 65 years. Background In some studies, aging was associated with decreased ex- The advent of Immune Checkpoint Inhibitors (ICIs) pression of CD28 on the surface of CD8+ T cells which changed the landscape of cancer treatment. Efficacy of leads to decreased immune activation. [17–19] Expres- PD-1 and PD-L1 antibodies has been established in a sion of CD57, a marker of senescence, was found to be wide spectrum of solid and hematological malignancies. increased on the surface of cytotoxic T cells of older [1–10] However, although cancer is predominantly a dis- adults contributing to a diminished anti-tumoral im- ease of older adults, the clinical efficacy of ICIs in this munogenic response. [20, 21] In addition, the levels of population has not been specifically assessed. [11, 12] perforin and granzyme, both essential for T cell’s cyto- Published literature suggests that aging-associated im- toxic activity, were lower in older adults compared to mune changes may have an impact on the activity of younger individuals. [22] Interestingly, expression of PD- checkpoint inhibitors, including PD-1 and PD-L1 inhibi- 1 was found to be increased on T cells of older adults tors. [13] Cytotoxic CD8+ T cells in older adults were and its blockade did not restore T cell activity to the found to have decreased TCR (T cell receptor) diversity, same extent as in younger adults [22–24] Our under- reduced proliferative capacity, and increased sensitivity standing of the efficacy of PD-1 and PD-L1 antibodies in to apoptotic signals compared to younger adults [14–16] older adults is limited due to underrepresentation of this patient population in prospective clinical trials due to * Correspondence: osamae_rahma@dfci.harvard.edu concerns about the safety profile of the investigated Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard agents. [25] Consequently, we conducted a systematic Medical School, Boston, MA, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 2 of 8 review and a study-level meta-analysis to explore efficacy of patients ≥65 years, number of patients younger than of ICIs based on age, younger vs older than 65 years. 65 years in each arm, number of patients ≥65 in each arm, median age, age range, mean age (3) HR for OS Methods and for PFS (4) HR for OS and for PFS based on age Search strategy and selection criteria subgroups (younger vs ≥ 65 years). In the case of trials We performed a Pubmed database search from January that did not include survival subgroup analysis by age, 2009 to December 2016 using the medical subject head- we reviewed each published trial’s supplement and the ings (MeSH) terms “pembrolizumab”, “nivolumab”, and FDA medical and statistical review available on the “atezolizumab”, the only Food and Drug Administration “Drugs @FDA” database. (FDA) PD-1/PD-L1 ICIs approved at the time this review was conducted. Search was done using the filter Statistical methods “clinical trial”. The language was restricted to English. Aggregated estimates of OS and progression-free sur- We then performed additional searches of Web of vival (PFS) are based on random/mixed effects (RE) Science, ASCO meeting database, and ESMO meeting models to allow for possible heterogeneity between the database using the same terms. We reviewed the studies. Forest plots were used to summarize and “Drugs @FDA” database for randomized studies that visualize the HR with 95% confidence intervals (CI) for did not report number of patients aged ≥65 years en- each study and for the aggregated estimates from the RE rolled on the trial or subgroup analysis for overall models. For studies reporting separate HR estimates for survival (OS) by age (younger vs ≥ 65 years). Studies 65–75 and > 75 years, a combined estimate (≥ 65 years) meeting all of the following criteria were included: (1) was created using random effects modeling, and the Randomized controlled phase II or III studies in combined estimate was used in the meta-analysis patients with metastatic solid cancer (2) Studies com- for that study. Chi-squared p-values from Cochran’s paring efficacy of PD-1 or PD-L1 inhibitors to a non- Q statistic assessed study heterogeneity. Analyses were PD-1/PD-L1 inhibitor (3) Subgroup analysis for conducted using the “Metafor” package in R software survival using a hazard ratio (HR) based on age per- (Version 3.2.3, The R Foundation for Statistical Comput- formed in study or available in FDA label review. The ing). Statistical significance is defined as P < 0.05; there selection process is shown in Fig. 1. Studies involving were no corrections for multiple comparisons. use of ICIs in hematologic malignancies were ex- cluded from this meta-analysis. Results Search results and patient characteristics Data extraction We identified 53 studies that matched our basic Data extracted from eligible studies included: (1) Study selection criteria of clinical trial involving one of the characteristics (first author, year of publication, study FDA-approved PD-1 and PD-L1 agents. Thirty-six non-- name, design, phase, arms, National Clinical Trial randomized studies were excluded. Seventeen studies (NCT) number (2) Study population (total number of were reviewed, 8 out of those 17 studies were excluded randomized patients, total number in each arm, total as they did not contain OS subgroup analysis by age. number of patients younger than 65 years, total number Final analysis included 9 studies: (6 phase 3 studies, 2 Fig. 1 Flow diagram of study inclusion Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 3 of 8 Table 1 Characteristics of included studies. Abbreviations: NSCLC (non-small lung cancer); S-NSCLC (squamous non-small lung cancer); NS-NSCLC (non-squamous non-small lung cancer); RCC (renal cell cancer); H&N (head & neck); NR (not reported); Q (every); W (weeks) Study Name Drug Phase Malignancy First line Arm 1 Arm 2 Arm 3 Patient’ number Age median Age range Age mean n (%) < 65 y n (%) ≥ 65 y Rittmeyer OAK Atezolizumab 3 NSCLC N Atezolizumab Docetaxel 850 64 33–85 63 453 (53) 397 (47) 2016 [33] 1200 mg Q 3 W 75 mg/m Q3W Fehrenbacher POPLAR Atezolizumab 2 NSCLC N Atezolizumab Docetaxel 287 62 36–84 61.5 174 (61) 113 (39) 2016 [26, 34] 1200 mg Q 3 W 75 mg/m Q3W Brahmer Checkmate- Nivolumab 3 S-NSCLC N Nivolumab Docetaxel 272 63 39–85 63 152 (56) 120 (44) 2015 [5] 017 3 mg/kg Q 2 W 75 mg/m Q3W Borghaei Checkmate- Nivolumab 3 NS-NSCLC N Nivolumab Docetaxel 582 62 21–85 NR 339 (58) 243 (42) 2015 [6] 057 3 mg/kg Q 2 W 75 mg/m Q3W Motzer Checkmate- Nivolumab 3 RCC N Nivolumab Everolimus 10 mg daily 821 62 18–88 61.3 497 (61) 324 (39) 2015 [4] 025 3 mg/kg Q 2 W Robert 01– Checkmate- Nivolumab 3 Melanoma Y Nivolumab Dacarbazine 418 65 18–87 62.7 200 (48) 218 (52) 2015 [29] 066 3 mg/kg Q 2 W 1000 mg/m Q3W Ferris Checkmate- Nivolumab 3 H&N N Nivolumab Chemotherapy 361 60 28–83 59.1 248 (69) 113 (31) 2016 [2] 141 3 mg/kg Q 2 W Herbst Keynote- Pembrolizumab 2/3 NSCLC N Pembrolizmab Pembrolizumab Docetaxel 1033 NR NR 62 604 (58) 429 (42) 2016 [8] 010 2 mg/kg Q 3 W 10 mg/kg Q 3 W 75 mg/m Q3 W Robert 06– Keynote- Pembrolizumab 3 Melanoma N Pembrolizumab Pembrolizumab Ipilimumab 834 NR NR 60.3 467 (56) 367 (44) 2015 [9] 006 10 mg/kg Q 2 W 10 mg/kg Q 3 W 3 mg/kg Q3 W Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 4 of 8 phase 2 studies, and one phase 2/3 study). Among the 9 89 years, and 2324 (42.57%) patients were older than studies included in the analysis, 5 investigated nivolu- 65 years. The random-effects estimate of the HR of mab, 2 investigated pembrolizumab, and 2 investigated PD1/PDL1 agents compared to control therapy in atezolizumab. Tumor types included metastatic non- patients under age 65 is 0.68 (95% CI 0.61 to 0.75) small cell lung cancer (NSCLC) in 5 trials, melanoma in (Fig. 3a). For this subset, there was no evidence of 2, renal cell cancer in 1, and head and neck cancer in differences between the individual studies (chi-squared one trial. Characteristics of each trial are presented in P = 0.45) in the analysis. The random-effects estimate Table 1. All studies reported a subgroup analysis based of the HR for age 65 or older is 0.64 (95% CI 0.54 to on age except for the POPLAR study [26] for which HR 0.76) (Fig. 3b). For this subset, there was evidence of were obtained from the FDA medical review of atezoli- differences in the HR between the individual studies zumab (Biologic License Application (BLA) 761,041). (chi-squared P = 0.03), suggesting considerable vari- ability in the reported results among the studies. The Overall survival comparable hazard ratios for patients 65 and older Overall comparison compared with those under 65 (0.64 vs. 0.68) as well The endpoint of interest is overall survival in studies as the substantial overlap of the confidence intervals comparing PD1/PDL1 therapy with chemotherapy/tar- of the two estimates would indicate that the effects of geted agents. The HR of the individual studies and the therapy on survival did not vary for older or younger combined results based on the random-effects models adults (Table 2). are summarized in Fig. 2. The ratios presented compare anti-PD1/PDL1 agents against chemo/targeted therapy Progression-free survival in the total population. The overall estimated, random- Overall progression-free survival effects HR is 0.69 with 95% CI of 0.63 to 0.74 (P <0. The endpoint of interest is progression-free survival in 0001). Based on the selected trials, there is evidence of a studies comparing PD1/PDL1 therapy with chemother- statistically significant, 31% reduction in the hazard of apy/targeted agents. Among studies included in this ana- death with PD1/PDL1 therapy compared with chemo/ lysis, seven had HR for overall PFS including four that targeted agents. The chi-squared test for heterogeneity reported HR for PFS according to age group. The HR of studies was not significant (P = 0.52) suggesting that for PFS of the individual studies and the combined re- the reported results of the individual trials are not sub- sults based on the random-effects models are summa- stantially different from one another. rized in Fig. 4. The overall estimated, random-effects HR is 0.74 with 95% CI of 0.60 to 0.92 (P = 0.006). Based on the selected trials, there is evidence of a statistically sig- Survival according to age The studies selected for this meta-analysis included a nificant, 26% reduction in the hazard of a PFS event with total of 5458 patients. Age range of participants was 18– PD1/PDL1 compared with chemo/targeted agents. The Fig. 2 Forest plot for OS. Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation. The HR from the Robert 01–2015 trial is lower than the others, but the weight of the trial is small and does not have great influence Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 5 of 8 Fig. 3 Forest plot for OS for patients less than 65 years (A) and ≥ 65 years (B). Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation chi-squared test for heterogeneity of studies was highly for patients age 65 or over the HR estimate is 0.74 (95% significant (P < 0.0001) suggesting that the reported HRs CI 0.60 to 0.92) (Fig. 5b) For each subset of younger and of the individual trials are substantially different. older patients, there was evidence of heterogeneity be- tween the studies (chi-squared P = 0.03 and p = 0.05, re- Progression-free survival according to age spectively), suggesting t there is considerable variability The random-effects estimate of the HR of PD1/PDL1 in the reported results among the studies within each compared with chemo/targeted therapy in patients subset. The equivalent HR estimates for the two age co- under age 65 is 0.73 (95% CI 0.61 to 0.88) (Fig. 5a), and horts along with the substantial overlap of the confi- dence intervals of the two estimates, would indicate that the effects of therapy upon PFS did not vary for older or younger adults (Table 3). Table 2 Summary of HR for OS by Age Age HR (95% CI) Discussion Age < 65 years 0.68 (0.61 to 0.75) Increased age is associated with changes in the host im- Age ≥ 65 years 0.64 (0.54 to 0.76) munity that could impact effectiveness of ICIs therefore Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 6 of 8 Fig. 4 Forest plot for PFS. Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation we aimed through this meta-analysis to evaluate the effi- important to note the age cutoff was non-uniform cacy of PD-1 and PD-L1 inhibitors in adults ≥65 years across selected studies (65–70 years). In addition, au- with advanced solid tumors compared to those < thors did not show a statistically significant benefit in 65 years. This meta-analysis suggests that the impact of terms of PFS for ICIs in adults ≥65 years (HR 0.77, PD-1/PD-L1 inhibitors is comparable between adults 95% CI 0.58–1.01) vs. a significantly favorable HR in younger vs. older than 65 years for OS [HR 0.68 (CI patients < 65 years (HR 0.58, 95% CI 0.40–0.84). Betof 0.61–0.75) vs. 0.64 (CI 0.54–0.76)] and PFS [HR 0.73 et al showed no significant difference in survival (CI 0.61–0.88) vs. 0.74 (CI 0.60–0.92)]. The data were benefit with PD1/PDL1 inhibitors according to age in not sufficient to draw any conclusions specific to pa- a retrospective analysis of patients treated in two tients ≥75 years. The number of patients older than academic medical centers. [31]However,this analysis 65 years enrolled in PD-1/PD-L1 studies is increased included only patients with metastatic melanoma and compared to what is usually seen in oncology trials 92.5% were treated with an anti-PD1 agent. but older adults remain under-represented in cancer Although it was done at a study-level, our paper clinical trials. [25, 27, 28] This is particularly true for constitutes the best level of evidence showing individuals older than 75 years who constitute more comparable efficacy for checkpoint inhibitors targeting than 25% of newly diagnosed cases of cancer every checkpoint inhibitors in adults > 65 years compared year. [11] Four of the trials included in this review to younger patients. Studies included in this meta- contained HR OS for patients ≥75 years. [4–6, 29] analysis, consistent with the majority of clinical trials However, out of 2093 individuals included in the ana- in oncology, used a numerical age cutoff. An arbitrary lyzed trials only 10% (213) were ≥ 75 year. Accord- age cutoff is not sufficient to characterize “older” ingly, data was not sufficient to draw any conclusions adults as aging is a highly variable physiological specific to adults ≥75 years. process. Older individuals are not a homogenous Few papers attempted to review this topic but only population, therefore measuring variables like func- one was performed at a meta-analysis level. [30]The tional status and comorbidity is essential to determine analysis performed by Nishijima et al..... was based on the physiologic “age” of an older adult [32]. In 9 studies, however among the trials included 4 were addition, older individuals enrolled in clinical trials with an anti-CTLA4 agents, therefore mixing two tend to be adults aged 70–75 years, with good per- classes of ICIs with different mode of action and effi- formance status, and a low number of comorbid cacy profile. Authors showed a comparable OS benefit medical conditions which does not represent the real- for ICIs in younger (HR 0.75, 95% CI 0.68 to 0.82) life population of older adults with cancer who often and older adults (HR 0.73, 95% CI 0.62–0.78). It is have functional limitations and multiple illnesses. Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 7 of 8 Fig. 5 Forest plot for PFS for patients less than 65 years (A) and ≥ 65 years (B). Studies are listed on the left and HR with 95% CI are on the right. Box sizes are inversely proportional to the standard error of the study; therefore, larger boxes indicate greater weight of the trial in the meta-analysis estimation Another limitation to our review is that data were ob- tolerance and toxicity of ICIs in older adults overall. tained partially from FDA BLA review of a particular Further study is needed including comprehensive as- drug and not directly from the study itself as in the sessment of outcomes of significant to older adults, case of POPLAR study. [26] such as functional status and preservation throughout In conclusion, our meta-analysis showed that therapy. Geriatric assessment and biomarkers of aging improvement in survival associated with the use of and immune senesce will help to fully understand the PD-1/PD-L1 inhibitors is consistent across age cut-off impact of ICIs in this growing subset of adults diag- of 65 years. More data are needed to understand nosed with cancer. efficacy among those aged ≥75 years as well as Acknowledgments Not applicable Funding Table 3 Summary of HR for PFS by Age no funding to declare. Age HR (95% CI) Age < 65 years 0.73 (0.61 to 0.88) Availability of data and materials All data generated or analyzed during this study are included in this Age ≥ 65 years 0.74 (0.60 to 0.92) published article. Elias et al. Journal for ImmunoTherapy of Cancer (2018) 6:26 Page 8 of 8 Authors’ contributions 13. Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: RE and OR conceived and designed research. Data collection and extraction immune aging & checkpoint inhibitors. J Geriatr Oncol. 2017;8:229–35. was performed by RE and verified by OR. Statistical analysis was performed 14. Gupta S, Gollapudi S. CD95-mediated apoptosis in naive, central and by AG-H. SH, PO, and NJMC participated in drafting article. All authors gave effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp final approval to the version submitted. Gerontol. 2008;43:266–74. 15. Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec G. Ethics approval and consent to participate Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in Not applicable young and old people. Immun Ageing. 2008;5:6. 16. Johnstone J, Millar J, Lelic A, Verschoor CP, Walter SD, Devereaux PJ, Consent for publication Bramson J, Loeb M. Immunosenescence in the nursing home elderly. BMC Not applicable Geriatr. 2014;14:50. 17. Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Competing interests Ouslander JG, Weyand CM, Goronzy JJ. T cell subset-specific susceptibility to The authors declare that they have no competing interests. aging. Clin Immunol. 2008;127:107–18. 18. Weng NP, Akbar AN, Goronzy J. CD28(−) T cells: their role in the age- associated decline of immune function. Trends Immunol. 2009;30:306–12. Publisher’sNote 19. Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M, Brenci S, Springer Nature remains neutral with regard to jurisdictional claims in Contini P, Olive D, Ghio M, et al. Nonantigen specific CD8+ T suppressor published maps and institutional affiliations. lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol. 2004;65:142–56. Author details 20. Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza Sections of Hematology Oncology and geriatrics, Boston University School JP, Kuruppu J, Migueles SA, Connors M, et al. Expression of CD57 defines of Medicine, Boston, MA, USA. Department of Biostatistics & Computational replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Blood. 2003;101:2711–20. Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 21. Bigley AB, Spielmann G, LaVoy EC, Simpson RJ. Can exercise-related Boston, MA, USA. improvements in immunity influence cancer prevention and prognosis in the elderly? Maturitas. 2013;76:51–6. Received: 15 January 2018 Accepted: 14 March 2018 22. Henson SM, Macaulay R, Riddell NE, Nunn CJ, Akbar AN. Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol. 2015;45:1441–51. References 23. Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C. Partial 1. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival PD-L1 pathway. Aging Cell. 2010;9:785–98. with ipilimumab in patients with metastatic melanoma. N Engl J Med. 24. Vukmanovic-Stejic M, Sandhu D, Seidel JA, Patel N, Sobande TO, Agius E, 2010;363:711–23. Jackson SE, Fuentes-Duculan J, Suarez-Farinas M, Mabbott NA, et al. The 2. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington characterization of varicella zoster virus-specific T cells in skin and blood K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell during aging. J Invest Dermatol. 2015;135:1752–62. carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67. 25. Hurria A, Levit LA, Dale W, Mohile SG, Muss HB, Fehrenbacher L, Magnuson 3. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, A, Lichtman SM, Bruinooge SS, Soto-Perez-de-Celis E, et al. Improving the Khushalani NI, Miller WH Jr, Lao CD, et al. Nivolumab versus chemotherapy in evidence base for treating older adults with Cancer: American Society of patients with advanced melanoma who progressed after anti-CTLA-4 treatment Clinical Oncology statement. J Clin Oncol. 2015;33:3826–33. (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet 26. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres Oncol. 2015;16:375–84. J, Park K, Smith D, Artal-Cortes A, Lewanski C, et al. Atezolizumab versus 4. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, docetaxel for patients with previously treated non-small-cell lung cancer Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al. Nivolumab versus (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. Lancet. 2016;387:1837–46. 5. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, 27. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus for cancer drug registration: a 7-year experience by the US Food and Drug docetaxel in advanced squamous-cell non-small-cell lung Cancer. N Engl J Administration. J Clin Oncol. 2004;22:4626–31. Med. 2015;373:123–35. 28. Singh H, Kanapuru B, Smith C, Fashoyin-Aje LA, Myers A, Kim G, Pazdur R. 6. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, FDA analysis of enrollment of older adults in clinical trials for cancer drug Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced registration: a 10-year experience by the U.S. Food and Drug Administration. nonsquamous non-small-cell lung Cancer. N Engl J Med. 2015;373:1627–39. J Clin Oncol. 2017;35 abstr 10009 7. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, 29. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD- P, McNeil C, Kalinka-Warzocha E, et al. Nivolumab in previously untreated L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375:1823–33. melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30. 8. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, 30. Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously immune checkpoint inhibitors (ICIs) between younger and older patients: a treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. a randomised controlled trial. Lancet. 2016;387:1540–50. 31. Betof AS, Nipp RD, Giobbie-Hurder A, Johnpulle RAN, Rubin K, Rubinstein SM, 9. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Flaherty KT, Lawrence DP, Johnson DB, Sullivan RJ. Impact of age on outcomes Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus Ipilimumab in with immunotherapy for patients with melanoma. Oncologist. 2017;22:963–71. Advanced Melanoma. N Engl J Med. 2015;372:2521–32. 32. Extermann M, Hurria A. Comprehensive geriatric assessment for older 10. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, patients with cancer. J Clin Oncol. 2007;25:1824–31. Schachter J, Pavlick AC, Lewis KD, et al. Pembrolizumab versus investigator- 33. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18. docetaxel in patients with previously treated non-small-cell lung cancer 11. Browse the SEER Cancer Statistics Review 1975-2012 [https://seer.cancer. (OAK): a phase 3, open-label, multicentre randomised controlled trial. gov/archive/csr/1975_2012/browse_csr.php?sectionSEL=2&pageSEL=sect_ Lancet. 2016;389:255–65. 02_table.07.html]. 34. Atezolizumab BLA 761041 Medical Review [https://www.accessdata.fda.gov/ 12. Elias R, Morales J, Rehman Y, Khurshid H. Immune checkpoint inhibitors in drugsatfda_docs/nda/2016/761041Orig1s000MedR.pdf]. older adults. Curr Oncol Rep. 2016;18:47.

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Published: Apr 4, 2018

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