Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis
© The Author(s). 2018
Received: 15 January 2018
Accepted: 14 March 2018
Published: 4 April 2018
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.
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.
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.
PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) inhibitors had comparable efficacy in adults younger vs ≥ 65 years.
The advent of Immune Checkpoint Inhibitors (ICIs) changed the landscape of cancer treatment. Efficacy of PD-1 and PD-L1 antibodies has been established in a wide spectrum of solid and hematological malignancies. [1–10] However, although cancer is predominantly a disease of older adults, the clinical efficacy of ICIs in this population has not been specifically assessed. [11, 12] Published literature suggests that aging-associated immune changes may have an impact on the activity of checkpoint inhibitors, including PD-1 and PD-L1 inhibitors.  Cytotoxic CD8+ T cells in older adults were found to have decreased TCR (T cell receptor) diversity, reduced proliferative capacity, and increased sensitivity to apoptotic signals compared to younger adults [14–16] In some studies, aging was associated with decreased expression of CD28 on the surface of CD8+ T cells which leads to decreased immune activation. [17–19] Expression of CD57, a marker of senescence, was found to be increased on the surface of cytotoxic T cells of older adults contributing to a diminished anti-tumoral immunogenic response. [20, 21] In addition, the levels of perforin and granzyme, both essential for T cell’s cytotoxic activity, were lower in older adults compared to younger individuals.  Interestingly, expression of PD-1 was found to be increased on T cells of older adults and its blockade did not restore T cell activity to the same extent as in younger adults [22–24] Our understanding of the efficacy of PD-1 and PD-L1 antibodies in older adults is limited due to underrepresentation of this patient population in prospective clinical trials due to concerns about the safety profile of the investigated agents.  Consequently, 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.
Search strategy and selection criteria
Data extracted from eligible studies included: (1) Study characteristics (first author, year of publication, study name, design, phase, arms, National Clinical Trial (NCT) number (2) Study population (total number of randomized patients, total number in each arm, total number of patients younger than 65 years, total number of patients ≥65 years, number of patients younger than 65 years in each arm, number of patients ≥65 in each arm, median age, age range, mean age (3) HR for OS and for PFS (4) HR for OS and for PFS based on age subgroups (younger vs ≥ 65 years). In the case of trials that did not include survival subgroup analysis by age, we reviewed each published trial’s supplement and the FDA medical and statistical review available on the “Drugs @FDA” database.
Aggregated estimates of OS and progression-free survival (PFS) are based on random/mixed effects (RE) models to allow for possible heterogeneity between the studies. Forest plots were used to summarize and visualize the HR with 95% confidence intervals (CI) for each study and for the aggregated estimates from the RE models. For studies reporting separate HR estimates for 65–75 and > 75 years, a combined estimate (≥ 65 years) was created using random effects modeling, and the combined estimate was used in the meta-analysis for that study. Chi-squared p-values from Cochran’s Q statistic assessed study heterogeneity. Analyses were conducted using the “Metafor” package in R software (Version 3.2.3, The R Foundation for Statistical Computing). Statistical significance is defined as P < 0.05; there were no corrections for multiple comparisons.
Search results and patient characteristics
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)
n (%) < 65 y
n (%) ≥ 65 y
Rittmeyer 2016 
Atezolizumab 1200 mg Q 3 W
75 mg/m2 Q 3 W
Atezolizumab 1200 mg Q 3 W
75 mg/m2 Q 3 W
Brahmer 2015 
Nivolumab 3 mg/kg Q 2 W
75 mg/m2 Q 3 W
Borghaei 2015 
Nivolumab 3 mg/kg Q 2 W
75 mg/m2 Q 3 W
Motzer 2015 
Nivolumab 3 mg/kg Q 2 W
Everolimus 10 mg daily
Robert 01–2015 
3 mg/kg Q 2 W
1000 mg/m2 Q 3 W
Ferris 2016 
3 mg/kg Q 2 W
Herbst 2016 
2 mg/kg Q 3 W
Pembrolizumab 10 mg/kg Q 3 W
75 mg/m2 Q 3 W
Robert 06–2015 
10 mg/kg Q 2 W
10 mg/kg Q 3 W
3 mg/kg Q 3 W
Survival according to age
Summary of HR for OS by Age
HR (95% CI)
Age < 65 years
0.68 (0.61 to 0.75)
Age ≥ 65 years
0.64 (0.54 to 0.76)
Overall progression-free survival
Progression-free survival according to age
Summary of HR for PFS by Age
HR (95% CI)
Age < 65 years
0.73 (0.61 to 0.88)
Age ≥ 65 years
0.74 (0.60 to 0.92)
Increased age is associated with changes in the host immunity that could impact effectiveness of ICIs therefore we aimed through this meta-analysis to evaluate the efficacy of PD-1 and PD-L1 inhibitors in adults ≥65 years with advanced solid tumors compared to those < 65 years. This meta-analysis suggests that the impact of PD-1/PD-L1 inhibitors is comparable between adults younger vs. older than 65 years for OS [HR 0.68 (CI 0.61–0.75) vs. 0.64 (CI 0.54–0.76)] and PFS [HR 0.73 (CI 0.61–0.88) vs. 0.74 (CI 0.60–0.92)]. The data were not sufficient to draw any conclusions specific to patients ≥75 years. The number of patients older than 65 years enrolled in PD-1/PD-L1 studies is increased compared to what is usually seen in oncology trials but older adults remain under-represented in cancer clinical trials. [25, 27, 28] This is particularly true for individuals older than 75 years who constitute more than 25% of newly diagnosed cases of cancer every year.  Four of the trials included in this review contained HR OS for patients ≥75 years. [4–6, 29] However, out of 2093 individuals included in the analyzed trials only 10% (213) were ≥ 75 year. Accordingly, data was not sufficient to draw any conclusions specific to adults ≥75 years.
Few papers attempted to review this topic but only one was performed at a meta-analysis level.  The analysis performed by Nishijima et al..... was based on 9 studies, however among the trials included 4 were with an anti-CTLA4 agents, therefore mixing two classes of ICIs with different mode of action and efficacy profile. Authors showed a comparable OS benefit for ICIs in younger (HR 0.75, 95% CI 0.68 to 0.82) and older adults (HR 0.73, 95% CI 0.62–0.78). It is important to note the age cutoff was non-uniform across selected studies (65–70 years). In addition, authors did not show a statistically significant benefit in terms of PFS for ICIs in adults ≥65 years (HR 0.77, 95% CI 0.58–1.01) vs. a significantly favorable HR in patients < 65 years (HR 0.58, 95% CI 0.40–0.84). Betof et al showed no significant difference in survival benefit with PD1/PDL1 inhibitors according to age in a retrospective analysis of patients treated in two academic medical centers.  However, this analysis included only patients with metastatic melanoma and 92.5% were treated with an anti-PD1 agent.
Although it was done at a study-level, our paper constitutes the best level of evidence showing comparable efficacy for checkpoint inhibitors targeting checkpoint inhibitors in adults > 65 years compared to younger patients. Studies included in this meta-analysis, consistent with the majority of clinical trials in oncology, used a numerical age cutoff. An arbitrary age cutoff is not sufficient to characterize “older” adults as aging is a highly variable physiological process. Older individuals are not a homogenous population, therefore measuring variables like functional status and comorbidity is essential to determine the physiologic “age” of an older adult . In addition, older individuals enrolled in clinical trials tend to be adults aged 70–75 years, with good performance status, and a low number of comorbid medical conditions which does not represent the real-life population of older adults with cancer who often have functional limitations and multiple illnesses. Another limitation to our review is that data were obtained partially from FDA BLA review of a particular drug and not directly from the study itself as in the case of POPLAR study. 
In conclusion, our meta-analysis showed that improvement in survival associated with the use of PD-1/PD-L1 inhibitors is consistent across age cut-off of 65 years. More data are needed to understand efficacy among those aged ≥75 years as well as tolerance and toxicity of ICIs in older adults overall. Further study is needed including comprehensive assessment of outcomes of significant to older adults, such as functional status and preservation throughout therapy. Geriatric assessment and biomarkers of aging and immune senesce will help to fully understand the impact of ICIs in this growing subset of adults diagnosed with cancer.
no funding to declare.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
RE and OR conceived and designed research. Data collection and extraction was performed by RE and verified by OR. Statistical analysis was performed by AG-H. SH, PO, and NJMC participated in drafting article. All authors gave final approval to the version submitted.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis 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.
- Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.View ArticlePubMedPubMed CentralGoogle Scholar
- Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67.View ArticlePubMedPubMed CentralGoogle Scholar
- Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84.View ArticlePubMedGoogle Scholar
- Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.View ArticlePubMedPubMed CentralGoogle Scholar
- Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung Cancer. N Engl J Med. 2015;373:123–35.View ArticlePubMedPubMed CentralGoogle Scholar
- Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung Cancer. N Engl J Med. 2015;373:1627–39.View ArticlePubMedPubMed CentralGoogle Scholar
- Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375:1823–33.View ArticlePubMedGoogle Scholar
- Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.View ArticlePubMedGoogle Scholar
- Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–32.View ArticlePubMedGoogle Scholar
- Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18.View ArticlePubMedGoogle Scholar
- Browse the SEER Cancer Statistics Review 1975-2012 [https://seer.cancer.gov/archive/csr/1975_2012/browse_csr.php?sectionSEL=2&pageSEL=sect_02_table.07.html].
- Elias R, Morales J, Rehman Y, Khurshid H. Immune checkpoint inhibitors in older adults. Curr Oncol Rep. 2016;18:47.View ArticlePubMedGoogle Scholar
- Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: immune aging & checkpoint inhibitors. J Geriatr Oncol. 2017;8:229–35.View ArticlePubMedGoogle Scholar
- Gupta S, Gollapudi S. CD95-mediated apoptosis in naive, central and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp Gerontol. 2008;43:266–74.View ArticlePubMedGoogle Scholar
- Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec G. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing. 2008;5:6.View ArticlePubMedPubMed CentralGoogle Scholar
- Johnstone J, Millar J, Lelic A, Verschoor CP, Walter SD, Devereaux PJ, Bramson J, Loeb M. Immunosenescence in the nursing home elderly. BMC Geriatr. 2014;14:50.View ArticlePubMedPubMed CentralGoogle Scholar
- Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ. T cell subset-specific susceptibility to aging. Clin Immunol. 2008;127:107–18.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.View ArticlePubMedPubMed CentralGoogle Scholar
- Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M, Brenci S, Contini P, Olive D, Ghio M, et al. Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol. 2004;65:142–56.View ArticlePubMedGoogle Scholar
- Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101:2711–20.View ArticlePubMedGoogle Scholar
- Bigley AB, Spielmann G, LaVoy EC, Simpson RJ. Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly? Maturitas. 2013;76:51–6.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C. Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway. Aging Cell. 2010;9:785–98.View ArticlePubMedPubMed CentralGoogle Scholar
- Vukmanovic-Stejic M, Sandhu D, Seidel JA, Patel N, Sobande TO, Agius E, Jackson SE, Fuentes-Duculan J, Suarez-Farinas M, Mabbott NA, et al. The characterization of varicella zoster virus-specific T cells in skin and blood during aging. J Invest Dermatol. 2015;135:1752–62.View ArticlePubMedPubMed CentralGoogle Scholar
- Hurria A, Levit LA, Dale W, Mohile SG, Muss HB, Fehrenbacher L, Magnuson A, Lichtman SM, Bruinooge SS, Soto-Perez-de-Celis E, et al. Improving the evidence base for treating older adults with Cancer: American Society of Clinical Oncology statement. J Clin Oncol. 2015;33:3826–33.View ArticlePubMedGoogle Scholar
- Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387:1837–46.View ArticlePubMedGoogle Scholar
- Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004;22:4626–31.View ArticlePubMedGoogle Scholar
- Singh H, Kanapuru B, Smith C, Fashoyin-Aje LA, Myers A, Kim G, Pazdur R. FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: a 10-year experience by the U.S. Food and Drug Administration. J Clin Oncol. 2017;35 abstr 10009Google Scholar
- Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.View ArticlePubMedGoogle Scholar
- Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7.View ArticlePubMedGoogle Scholar
- Betof AS, Nipp RD, Giobbie-Hurder A, Johnpulle RAN, Rubin K, Rubinstein SM, Flaherty KT, Lawrence DP, Johnson DB, Sullivan RJ. Impact of age on outcomes with immunotherapy for patients with melanoma. Oncologist. 2017;22:963–71.View ArticlePubMedGoogle Scholar
- Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol. 2007;25:1824–31.View ArticlePubMedGoogle Scholar
- Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2016;389:255–65.View ArticlePubMedGoogle Scholar
- Atezolizumab BLA 761041 Medical Review [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761041Orig1s000MedR.pdf].