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The use of immunotherapy in older patients with advanced non-small cell lung cancer

Open AccessPublished:April 12, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102394

      Highlights

      • Almost half of patients with newly diagnosed NSCLC are aged 70 years or older.
      • Immune checkpoint blockers as single agent appear to have similar efficacy and safety between younger and older patients.
      • No prospective studies with immunotherapy-based combinations have focused on older patients with NSCLC.
      • The comprehensive geriatric assessment may help allocating patients to anticancer treatments.
      • Immunosenescence does not appear to be age-related; strategies to revert it may have practical implications.

      Abstract

      Immune checkpoint blockers (ICBs) have a pivotal role in the management of non-small cell lung cancer (NSCLC), both as single agent and in combination strategies, providing a meaningful clinical and survival benefit.
      Older patients are underrepresented in clinical trials, including those involving immunotherapy, even though almost half of the patients with newly diagnosed NSCLC are aged 70 years or older. Moreover, due to selection biases, usually “fit” patients are preferably enrolled. This results in a lack of evidence regarding the use of ICBs in the older population, particularly when referring to chemo-immunotherapy regimens.
      Since ICBs are indeed of paramount importance in the treatment of patients with NSCLC, efforts are needed to optimize their use also in the older population. This entails furthermore taking into account additional features including the degree of fitness of the patient and the different health domains that can be affected by aging.
      This review aims to delve into the current evidences about the efficacy and toxicity of ICBs in monotherapy and in combination in older patients with advanced NSCLC, the role of the comprehensive geriatric assessment in supporting the selection of patients receiving immunotherapy, as well as the value of immunosenescence in modulating the activity of these drugs.

      Keywords

      Introduction

      Lung cancer is one of the most frequently occurring cancer worldwide and is responsible for the greatest burden in terms of cancer-related deaths [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Based on the Surveillance, Epidemiology, and End Results (SEER) database, it has been estimated that 47% of lung cancer diagnoses performed before 2003 in the U.S. occurred in patients aged 70 or above, with 14% of the cases diagnosed in patients aged 80 years and older (i.e., “oldest old” patients) [
      • Owonikoko T.K.
      • Ragin C.C.
      • Belani C.P.
      • et al.
      Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database.
      ], while as of 2018 > 35% of new lung cancer cases were done in subjects aged > 75 [

      SEER Cancer Stat Facts: Lung and Bronchus Cancer. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/lungb.html.

      ]. In the context of a remarkable aging of the population worldwide, the fastest-growing proportion is represented by people older than 65 years [
      • Owonikoko T.K.
      • Ragin C.C.
      • Belani C.P.
      • et al.
      Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database.
      ]. The treatment of lung cancer among older patients may be challenging due to several reasons. Physiological modifications related to aging may affect pharmacokinetics of the drugs as well as pharmacodynamics [
      • McLean A.J.
      • Le Couteur D.G.
      Aging biology and geriatric clinical pharmacology.
      ]. Moreover, these patients more frequently present organs’ impairment, reduced functional capability, comorbidities and lack of social support, and are exposed to a higher risk of pharmacological interactions [
      • Owonikoko T.K.
      • Ragin C.C.
      • Belani C.P.
      • et al.
      Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database.
      ,
      • Laconi E.
      • Marongiu F.
      • DeGregori J.
      Cancer as a disease of old age: changing mutational and microenvironmental landscapes.
      ,
      • Williams G.R.
      • Mackenzie A.
      • Magnuson A.
      • et al.
      Comorbidity in older adults with cancer.
      ,
      • Wildiers H.
      • de Glas N.A.
      Anticancer drugs are not well tolerated in all older patients with cancer.
      ]. While by itself advanced age does not represent an exclusion criterion in most clinical trials, the increased vulnerability of older patients can partially explain their underrepresentation in clinical trials, irrespective of cancer type [
      • Hutchins L.F.
      • Unger J.M.
      • Crowley J.J.
      • et al.
      Underrepresentation of patients 65 years of age or older in cancer-treatment trials.
      ,
      • Yee K.W.L.
      • Pater J.L.
      • Pho L.
      • et al.
      Enrollment of older patients in cancer treatment trials in canada: why is age a barrier?.
      ]. Patient- and physician-related barriers to participation in clinical trials should also be taken into account [
      • Mills E.J.
      • Seely D.
      • Rachlis B.
      • et al.
      Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors.
      ]. Thus, such poor representation of older patients in randomized clinical trial makes so that truly evidence-based decisions on the best type of treatment for geriatric patients can sometimes difficultly be made. Cancer trials with immune checkpoint blockers (ICBs) are no exception to this phenomenon. The median age of patients with lung cancer treated in pivotal trials involving immunotherapy ranged between 61 and 65 years [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
      ,
      • Herbst R.S.
      • Baas P.
      • Kim D.-W.
      • et al.
      Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
      ,
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • 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.
      ,
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.
      ,
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer.
      ,
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      ,
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      ,
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      ,
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Hellmann M.D.
      • Paz-Ares L.
      • Bernabe Caro R.
      • et al.
      Nivolumab plus ipilimumab in advanced non–small-cell lung cancer.
      ,
      • Paz-Ares L.
      • Ciuleanu T.-E.
      • Cobo M.
      • et al.
      First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.
      ], which is lower than the median age at diagnosis [
      • Magee D.E.
      • Hird A.E.
      • Klaassen Z.
      • et al.
      Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials.
      ]. While immunotherapy alone has a better toxicity profile than chemotherapy [
      • Magee D.E.
      • Hird A.E.
      • Klaassen Z.
      • et al.
      Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials.
      ], combination regimens may have more significant adverse events and are currently proposed to patients with lung cancer aged 70 years or older only if “fit” and on a case-by-case evaluation [

      Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology. 2018;29:iv192–iv237.

      ].
      Geriatric frailty was suggested to have a greater prognostic impact than cancer characteristics among oldest old patients with lung cancer, highlighting the role of the geriatric assessment as a selection tool [
      • Couderc A.-L.
      • Tomasini P.
      • Rey D.
      • et al.
      Octogenarians treated for thoracic and lung cancers: Impact of comprehensive geriatric assessment.
      ]. Another way to select more accurately patients for immunotherapy could be based on their immune competence. Older subjects, especially frail subjects, may have impaired immune functions, which in principle could hamper ICBs efficacy. Nevertheless, this hypothesis is not necessarily supported by the available evidence, which shows that ICBs actually retain their activity in senior patients too [
      • Ferrara R.
      • Mezquita L.
      • Auclin E.
      • et al.
      Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?.
      ].
      This narrative review deepens the current evidence about efficacy and toxicity of ICBs in older patients with advanced stage non-small cell lung cancer (NSCLC), the role of geriatric tests in supporting the selection of patients for immunotherapy, as well as the value of circulating biomarkers, including markers of immunosenescence, in predicting the activity of these drugs.

      Older patients: Definition

      A univocal definition of “older” when referring to patient groups does not exist. The World Health Organization set the threshold at 60 years [
      • Scotté F.
      • Bossi P.
      • Carola E.
      • et al.
      Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide.
      ]. Nowadays, > 60% of patients with cancer are aged 65 or older [
      • Scotté F.
      • Bossi P.
      • Carola E.
      • et al.
      Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide.
      ,

      Berger NA, Savvides P, Koroukian SM, et al. Cancer in the elderly. Trans Am Clin Climatol Assoc. 2006;117:147–155; discussion 155-156.

      ], thus 65 years is the most commonly used cutoff to identify the older patients in subgroups analyses in clinical trials, including immunotherapy trials. On the other hand, the age of 70 has been used in clinical trials dedicated to the older population [
      • Soubeyran P.
      • Bellera C.
      • Goyard J.
      • et al.
      Validation of the G8 screening tool in geriatric oncology: The ONCODAGE project.
      ,

      Soubeyran P, Bellera C, Goyard J, et al. Screening for Vulnerability in Older Cancer Patients: The ONCODAGE Prospective Multicenter Cohort Study. Williams BO, editor. PLoS ONE. 2014;9:e115060.

      ]. This may indeed be a more appropriate threshold, taking into account the present life-expectancy and the fact that most subjects in their sixties currently maintain a good health status, show no sign of vulnerability or frailty and are thus indistinguishable from younger adults.
      That all being said, if, on the one hand, patient's age represents a straightforward criteria to define the “older” patient, there is little doubt that age per se is a poor indicator of the biological aging of a person, which is determined by several other factors in addition to chronological aging [
      • Loh K.P.
      • Soto-Perez-de-Celis E.
      • Hsu T.
      • et al.
      What every oncologist should know about geriatric assessment for older patients with cancer: young international society of geriatric oncology position paper.
      ].

      Efficacy of immunotherapy in older patients

      Immune checkpoint blockers as single agent

      Immunotherapy was first approved as second- or further line of treatment for metastatic lung cancer.
      In the phase III CheckMate 057 and 017 trials, nivolumab showed to improve overall survival (OS) compared to docetaxel in non-squamous and squamous histology, respectively (5-year pooled OS rates 13.4% vs. 2.6%, median OS 11.1 vs. 8.1 months, Hazard Ratio [HR] 0.68, 95% confidence interval [CI] 0.59–0.78). At subgroup analysis, the HR for OS was consistent in patients aged 65 or older but was 1.19 in patients older than 75 (n = 72), an effect driven by the HR in patients with squamous histology (HR 1.85, 95 %CI 0.76–4.51). These data, albeit indicative of a favorable therapeutic effect for docetaxel, are difficult to interpret given the small absolute number of patients in these subgroups [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
      ,
      • Borghaei H.
      • Gettinger S.
      • Vokes E.E.
      • et al.
      Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non–small-cell lung cancer.
      ]. In the CheckMate 171 trial, a phase 2 of nivolumab in previously treated advanced squamous NSCLC, out of 811 enrolled patients, 278 (34%) and 125 (15%) were aged ≥ 70 and ≥ 75 years, respectively. The median OS was similar in all treated patients (10 months) and across subgroups according to age (10 months in patients aged ≥ 70 and 11.2 months in those ≥ 75 years) [
      • Felip E.
      • Ardizzoni A.
      • Ciuleanu T.
      • et al.
      CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations.
      ]. The KEYNOTE-010 and OAK trials only reported subgroup analysis according to a 65 years cutoff, essentially demonstrating an increased OS with the use pembrolizumab and atezolizumab, respectively, compared to docetaxel regardless of age [
      • Herbst R.S.
      • Garon E.B.
      • Kim D.-W.
      • et al.
      Five year survival update from KEYNOTE-010: pembrolizumab versus docetaxel for previously treated, programmed death-ligand 1–positive advanced NSCLC.
      ,
      • Fehrenbacher L.
      • von Pawel J.
      • Park K.
      • et al.
      Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-Small Cell Lung cancer.
      ].
      The phase III KEYNOTE-024 study defined the role of pembrolizumab as first-line treatment in patients with untreated advanced stage NSCLC (both squamous and non-squamous), with a programmed death ligand 1 (PD-L1) tumor proportion score ≥ 50% and without EGFR/ALK alterations. At the updated analysis, the HR for the reduction in the risk of death (secondary endpoint) in patients receiving immunotherapy was comparable between patients who were younger or older than 65 (HR 0.60, 95 %CI 0.38–0.96 and HR 0.64, 95 %CI 0.42–0.98, respectively) [

      Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019;JCO1800149.

      ]. Similarly, no major difference in the effect of pembrolizumab on OS was observed within the KEYNOTE-042 trial when using a 65 years age threshold among patients with PD-L1 expressing metastatic and untreated NSCLC [
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      ].
      A pooled analysis from the intention-to-treat populations of the KEYNOTE-010, KEYNOTE-024 and KEYNOTE-042 trials was performed, including 264 older patients (≥ 75 years) with NSCLC and PD-L1 TPS ≥ 1% (out of 2612 total patients). Half of the patients (n = 132) had a PD-L1 expression ≥ 50%. The median age was 77 years (range 75–90), 172 (65%) had a non-squamous disease, 204 (77%) had a history of tobacco smoking, 15 (5.7%) had stable brain metastases. 65.5% (n = 173) and 26.1% (n = 69) of the patients received pembrolizumab as first or second line treatment, respectively. Pembrolizumab significantly improved the OS compared with chemotherapy regardless of age. Among older patients, at a median follow-up of 11.7 months, immunotherapy was shown to improve the OS compared with chemotherapy in patients whose tumors had a high PD-L1 expression (23.1 vs. 8.3 months, HR 0.40, 95%CI 0.25–0.64) as well as for PD-L1 ≥ 1% (15.7 vs. 11.7 months, HR 0.76, 95 %CI 0.56–1.02). This advantage was seen across each single study. At the pooled analysis of studies including only older patients with advanced untreated tumors (KEYNOTE-024 and -042), the median OS was 27.4 months with pembrolizumab vs. 7.7 months with chemotherapy (HR 0.41, 95 %CI 0.23–0.73). Similar results were observed in younger patients [
      • Nosaki K.
      • Saka H.
      • Hosomi Y.
      • et al.
      Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1–positive advanced non–small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
      ]. Unfortunately, this pooled analysis did not report data on the subgroup of tumors with PD-L1 between 1 and 49%. Nevertheless, in a pooled-analysis of 8 randomized controlled trials with first line anti-PD-(L)1 in combination with chemotherapy or in ICBs-only regimens (i.e., KEYNOTE-042 and CkeckMate 227), among tumors with PD-L1 scores of 1–49% chemotherapy-based regimens performed better than ICBs alone. Patients aged ≥ 75 (n = 132) experienced similar outcomes across therapeutic options (HR 0.95, 95 %CI 0.42–2.14) [
      • Akinboro O.
      • Vallejo J.J.
      • Mishra-Kalyani P.S.
      • et al.
      Outcomes of anti-PD-(L1) therapy in combination with chemotherapy versus immunotherapy (IO) alone for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 score 1–49%: FDA pooled analysis.
      ].
      The IMpower110 was a phase 3 study that randomized patients with metastatic untreated NSCLC with PD-L1 expression on at least 1% of the tumor cells (TC) or of the tumor-infiltrating immune cells (IC) to receive atezolizumab or platinum-based chemotherapy. Both squamous and non-squamous histologic subtypes were included. Among patients with EGFR and ALK wild-type tumors who had high PD-L1 expression (at least 50% of TC or at least 10% of tumor-infiltrating IC, i.e., TC3 or IC3), median OS was significantly longer in the atezolizumab group than in the chemotherapy group (20.2 vs.. 13.1 months, HR 0.59, 95 %CI 0.40–0.89). In the subgroup of patients aged between 65 and 74 years, the HR was 0.63 with a 95 %CI of 0.34 to 1.19, while among the 23 patients (11.2%) who were older than 74 the HR was 0.79 with a 95 %CI of 0.18 to 3.56 [
      • Herbst R.S.
      • Giaccone G.
      • de Marinis F.
      • et al.
      Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC.
      ].
      Several non-randomized studies and real-world series included older patients and reported outcomes by age groups. A monocentric retrospective study including 245 patients with NSCLC receiving PD-(L)1 inhibitors at any line between 2013 and 2017 showed a median OS of 12.92 months in those age 70 to 79 (n = 76) with a HR for death of 0.60 (95 %CI 0.40–0.90, p = 0.015) compared to younger patients (n = 141). To note, in patients older than 80 median the OS was only 3.63 months, with an HR of 2.74 (p = 0.002) as compared with younger ones. Progression-free survival (PFS) analysis also showed a trend toward a more pronounced benefit in older patients, that was instead not demonstrated in the oldest old subjects. Patients aged ≥ 80 had less frequently an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 but, on the contrary, had more frequently a localized disease stage at diagnosis compared to younger patients [
      • Lichtenstein M.R.L.
      • Nipp R.D.
      • Muzikansky A.
      • et al.
      Impact of age on outcomes with immunotherapy in patients with non-small cell lung cancer.
      ].
      The Italian nivolumab expanded access program (EAP), reporting real life data of 371 patients with metastatic squamous NSCLC progressing on at least one line of therapy, showed an overall response rate (ORR) of 20%, which was comparable across different age subgroups, but reduced median PFS and OS (3.2 and 5.8 months, respectively) in the 70 patients who were older than 75 (HR vs. younger patients not available) [
      • Grossi F.
      • Crinò L.
      • Logroscino A.
      • et al.
      Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme.
      ]. Only the presence of liver and bone metastases was found to be correlated with the OS at the multivariate analysis, and their incidence was balanced between subgroups [
      • Grossi F.
      • Crinò L.
      • Logroscino A.
      • et al.
      Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme.
      ]. Similarly, 1588 patients with pretreated non-squamous NSCLC received nivolumab within the EAP. Older patients (n = 522 ≥ 70 years; n = 232 ≥ 75 years) had outcomes comparable to the global study population (median OS 11.3 months, 95 %CI 10.2–12.4) [
      • Grossi F.
      • Genova C.
      • Crinò L.
      • et al.
      Real-life results from the overall population and key subgroups within the Italian cohort of nivolumab expanded access program in non-squamous non–small cell lung cancer.
      ].
      A retrospective study specifically evaluated outcomes of single agent ICBs in oldest old patients with solid tumors, most of them receiving anti PD-1. Among 345 patients with NSCLC, ORR was 39.3%, median PFS 6.7 months and median OS 10.9 months. Outcomes did not differ between patients aged 85 or older and younger patients [
      • Nebhan C.A.
      • Cortellini A.
      • Ma W.
      • et al.
      Clinical outcomes and toxic effects of single-agent immune checkpoint inhibitors among patients aged 80 years or older with cancer: a multicenter international cohort study.
      ].
      A large analysis of the SEER-Medicare database including 535 patients with stage IV NSCLC treated with ICBs in different lines did not find an association between age and survival. Comorbidities, squamous histology, need for palliative radiotherapy and time to immunotherapy initiation were negative prognostic factors [
      • Youn B.
      • Trikalinos N.A.
      • Mor V.
      • et al.
      Real-world use and survival outcomes of immune checkpoint inhibitors in older adults with non–small cell lung cancer.
      ].
      The Dutch national registry collected data from 2,302 patients with NSCLC who were treated with ICBs after failure of platinum-based chemotherapy. ORR was 21.8 % and median OS 12.6 months, with no significant difference between patients aged ≥ 75 years vs. younger patients. Non-smokers, patients with a PS ≥ 2 and those who received any palliative radiotherapy had worse prognosis [
      • Smit H.J.M.
      • Aerts J.
      • van den Heuvel M.
      • et al.
      Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the National Immunotherapy Registry.
      ]. Similarly, age was not associated with OS of 902 patients with advanced pretreated NSCLC who received nivolumab within the French EAP [
      • Molinier O.
      • Besse B.
      • Barlesi F.
      • et al.
      IFCT-1502 CLINIVO: real-world evidence of long-term survival with nivolumab in a nationwide cohort of patients with advanced non-small-cell lung cancer.
      ].
      To summarize, several prospective and retrospective studies have addressed the efficacy of immunotherapy as single agent according to the age of patients, by the means of prespecified purpose or by subgroups analyses. Overall, ICBs as monotherapy did not shown to be less effective in older patients as compared with younger patients.

      Combination regimens with immune checkpoint blockers and chemotherapy

      In KEYNOTE-189 and KEYNOTE-407 trials the addition of pembrolizumab to platinum-based chemotherapy for the treatment of non-squamous and squamous previously untreated metastatic lung cancer resulted in longer PFS and OS both in young (< 65) and in older (≥ 65) patients [
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.
      ,
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer.
      ].
      Within the IMpower 150 trial, a four-drugs regimen with carboplatin, paclitaxel, bevacizumab and atezolizumab (ABCP) was compared to the same regimen without immunotherapy (BCP) in patients affected by untreated advanced stage NSCLC, including tumors harboring EGFR or ALK alterations [
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      ]. Median age of enrolled patients was 63, 149 patients (37.2%) were aged 65 to 74, only 33 (8.2%) were aged 75 to 84, and 3 (0.8%) were older than 85. The primary endpoint was met, since the study showed longer PFS in the intention-to-treat (ITT) population wild type for molecular alterations (8.3 vs. 6.8 months, HR 0.62, 95 %CI 0.52–0.74). In patients aged between 65 and 74, as well as in those who were older than 75, the HR remained consistent (HR 0.52 and 0.78, respectively), with a median PFS of 9.7 months in the atezolizumab group compared with 6.9 months in the control group [
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      ].
      At the updated analysis, median OS with ABCP compared to BCP in the ITT wild-type population and in the overall ITT population was 19.5 vs. 14.7 months (HR 0.8, 95 %CI 0.67–0-95) and 19.8 vs. 15.0 months (HR 0.8, 95 %CI 0.69–0-95), respectively. A benefit in OS with ABCP was observed also in the subgroup of patients aged 65 to 74 years, but not in patients > 74, although this analysis was limited by the small number of patients [
      • Socinski M.A.
      • Nishio M.
      • Jotte R.M.
      • et al.
      IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC.
      ].
      Older patients were also underrepresented in the phase III IMpower131 trial, which evaluated the addition of atezolizumab to carboplatin plus nab-paclitaxel as first line treatment for squamous-cell lung cancer. Only one patient aged > 85 was enrolled in this trial, and patients aged 75–84 (n = 39) accounted for only the 11.5% of the total number of enrolled patients. The gain in PFS observed with the addition of immunotherapy was also maintained in these subgroups, while an advantage in terms of OS was not found at the two interim analyses [
      • Jotte R.
      • Cappuzzo F.
      • Vynnychenko I.
      • et al.
      Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial.
      ,

      Socinski MA, Rittmeyer A, Shapovalov D, et al. IMpower131: Progression-free survival (PFS) and overall survival (OS) analysis of a randomised phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel in 1L advanced squamous NSCLC. Annals of Oncology. 2018;29:viii750–viii751.

      ].
      A retrospective study evaluated 203 patients with metastatic NSCLC who received the combination of pembrolizumab with platinum-pemetrexed (n = 122) or carboplatin-(nab)paclitaxel (n = 81) [
      • Morimoto K.
      • Yamada T.
      • Yokoi T.
      • et al.
      Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.
      ]. Forty-three patients (21.2%) were aged 75 years or older, 137 patients (67.5%) had a squamous histology, 60 (29.6%) had a high PD-L1 expression, 193 (95%) had an ECOG PS of 0 or 1. Patient’s characteristics were well balanced between older and younger groups. The PFS and OS of older patients (≥ 75) were significantly shorter than those of younger patients (6.2 vs. 9.7 months, p = 0.004, and 11 months vs. not reached, p < 0.001, respectively), while ORR was not. When evaluated according to different treatment regimens, PFS and OS were significantly shorter only in patients receiving a pemetrexed-containing regimen. The 81.5% of patients who received a taxane-based therapy had a squamous histology. Similar results were obtained when lowering the age threshold to 70 years. Serum level of albumin lower than 3.5 g/dL and ECOG PS 2 were negative predictors for survival outcomes [
      • Morimoto K.
      • Yamada T.
      • Yokoi T.
      • et al.
      Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.
      ]. Another small retrospective analysis demonstrated no differences in ORR and OS between 33 patients treated with first-line chemotherapy-immunotherapy combination vs. 38 patients treated with single agent immunotherapy [
      • Isono T.
      • Kagiyama N.
      • Shibata S.
      • et al.
      A retrospective analysis of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy for advanced or recurrent non-small cell lung cancer.
      ].
      The randomized CheckMate 9LA study investigated whether a short course chemotherapy (2 cycles of histology-based platinum-containing doublet) added to nivolumab and ipilimumab improved the OS over the immunotherapy doublet in patients with advanced stage, untreated NSCLC without driver molecular alterations. Overall, 295 patients (41%) were aged 65 to75 years, while only 70 (10%) were aged 75 or older. 69% of the patients had non-squamous tumors and 17% had stable brain metastases. The addition of chemotherapy to immunotherapy increased median OS by 4.7 months (15.6 vs. 10.9 months, HR 0.66; 95 %CI 0.55–0.80; data maturity 60%). At subgroups analysis, HR in patients aged 65–75 was similar to that of patients who were < 65, while among patients aged > 75 the HR did not favor the experimental arm (HR 1.21, 95 %CI 0.69–2.12) [
      • Paz-Ares L.
      • Ciuleanu T.-E.
      • Cobo M.
      • et al.
      First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.
      ].
      A large retrospective study evaluated 4271 patients with advanced NSCLC without EGFR or ALK alterations, who received different combinations of chemotherapy and immunotherapy as first line treatment [
      • Waterhouse D.
      • Lam J.
      • Betts K.A.
      • et al.
      Real-world outcomes of immunotherapy–based regimens in first-line advanced non-small cell lung cancer.
      ]. Median age was 69 years, 63% (n = 2694) had an ECOG PS 0 or 1, 19% (n = 814) had squamous histology. Median OS was 10.6 (95 %CI 9.3–11.8) and 12.0 (95 %CI, 11.3–12.8) months in patients with squamous and non-squamous disease, respectively. With respect to squamous histology, patients aged 65 to 74 years (n = 318) had a longer median OS than patients < 65 (n = 230) or ≥ 75 years (n = 266) (14.5 vs. 8.9 vs. 9.3 months, respectively). In those with non-squamous histology, older age was associated with shorter median OS: 10.1 vs. 12.3 vs. 13.2 months in patients older than 75 (n = 931), 65 to 75 (n = 1296) and younger than 65 (n = 1230), respectively [
      • Waterhouse D.
      • Lam J.
      • Betts K.A.
      • et al.
      Real-world outcomes of immunotherapy–based regimens in first-line advanced non-small cell lung cancer.
      ].
      At a glance, older patients with NSCLC were underrepresented in several clinical trials testing chemotherapy and ICBs combinations, whereas data derived from retrospective experiences are controversial on this regard. Overall, results of randomized controlled trials did not suggest that older patients get less benefit from the combination approach, that should therefore be considered, where possible, as a standard treatment option regardless of the age of patients.

      Immune checkpoint blockers doublet

      In the phase III randomized CheckMate 227 trial, the combination of nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) was compared to nivolumab alone, to its combination with chemotherapy, or to chemotherapy alone in patients with stage IV NSCLC that was not previously treated with chemotherapy. PFS in the population with a high tumor mutational burden (> 10 mutations per megabase) was significantly longer with dual immunotherapy as compared to platinum-based chemotherapy. In patients selected based on a positive PD-L1 expression, the combination of the two ICBs resulted in a longer OS compared to chemotherapy, an effect that was confirmed at 4 years follow-up (17.1 vs. 14.9 months, HR 0.76, 95 %CI 0.65–0.90) [

      Paz-Ares LG, Ramalingam SS, Ciuleanu T-E, et al. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thoracic Oncol. 2021;S155608642103207X.

      ]. In this trial < 10% of the patients were aged > 75 years. PFS in older patients was hardly evaluable since only 13 patients with high TMB received nivolumab and ipilimumab. On the contrary, 81 patients with PD-L1 ≥ 1% and older than 75 were evaluable for the OS. The HR for death with the use of immunotherapy doublet compared to chemotherapy was 0.93, with a 95 %CI that crossed the unit (0.58–1.49) [
      • Hellmann M.D.
      • Paz-Ares L.
      • Bernabe Caro R.
      • et al.
      Nivolumab plus ipilimumab in advanced non–small-cell lung cancer.
      ,

      Paz-Ares LG, Ramalingam SS, Ciuleanu T-E, et al. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thoracic Oncol. 2021;S155608642103207X.

      ,
      • Hellmann M.D.
      • Ciuleanu T.-E.
      • Pluzanski A.
      • et al.
      Nivolumab plus ipilimumab in lung cancer with a high tumor mutational Burden.
      ]. Of note, in large comprehensive genomic profiling analysis, the TMB was reported being higher in late life as compared to younger patients, albeit with a small effect size [
      • Chalmers Z.R.
      • Connelly C.F.
      • Fabrizio D.
      • et al.
      Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
      ]. On the contrary PD-L1 does not appear to be associated with age [
      • Schoenfeld A.J.
      • Rizvi H.
      • Bandlamudi C.
      • et al.
      Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas.
      ].
      Table 1 summarizes survival outcomes by age groups in randomized clinical trials with immunotherapy for patients with advanced stage NSCLC.
      Table 1Overall survival by age of patients in randomized clinical trials with immunotherapy for advanced stage NSCLC.
      StudyLine(s) of treatmentStudy

      Population
      Study treatmentsOverall survival by age

      HR (95% CI)
      CheckMate 057Second or third line582 patients, non-squamous NSCLC



      <65 n = 339

      65–74 n = 200

      ≥75 n = 43
      Nivolumab 3 mg/kg q2w vs. docetaxel 75 mg/m2 q3w<65: 0.81 (0.62–1.04)

      65–74: 0.63 (0.45–0.89)

      ≥75: 0.90 (0.43–1.87)
      CheckMate 017Second line272 patients, squamous-cell NSCLC



      <65 n = 152

      65–74 n = 91

      ≥75 n = 29
      Nivolumab 3 mg/kg q2w vs. docetaxel 75 mg/m2 q3w<65: 0.62 (0.44–0.89)

      65–74: 0.51 (0.32–0.82)

      ≥75: 1.76 (0.77–4.05)
      OAKSecond or third line850 patients, NSCLC



      <65 n = 453

      ≥65 n = 397
      Atezolizumab 1200 mg q3w vs. docetaxel 75 mg/m2 q3w<65: 0.80 (0.64–1.00)

      ≥65: 0.66 (0.52–0.83)
      KEYNOTE-010Second or further line1034 patients, NSCLC

      (PD-L1 ≥ 1%)



      <65 n = 604

      ≥65 n = 429



      <75 n = 943

      ≥75 n = 90
      Pembrolizumab 2 mg/kg or 10 mg/kg q3w vs. docetaxel 75 mg/m2 q3w<65: 0.63 (0.50–0.79)

      ≥65: 0.76 (0.57–1.02)





      <75: 0.64

      (0.55–0.75) #

      ≥75: 0.72 (0.43–1.21) #
      KEYNOTE-024First line305 patients, NSCLC (PD-L1 ≥ 50%)



      <65 n = 141

      ≥65 n = 164



      <75 n = 260

      ≥75 n = 45
      Pembrolizumab 200 mg q3w vs. platinum-based chemotherapy<75: 0.64 (0.42–0.97) #

      ≥75: 0.49 (0.17–1.39) #
      KEYNOTE-042First line1274 patients, NSCLC (PD-L1 ≥ 1%)



      <65 n = 707

      ≥65 n = 567



      <75 n = 1145

      ≥75 n = 129
      Pembrolizumab 200 mg q3w vs. platinum-based chemotherapy<65: 0.81 (0.67–0.98)

      ≥65: 0.82 (0.66–1.01)





      <75: 0.79

      (0.68–0.92) #

      ≥75: 0.89 (0.59–1.35) #
      IMpower110First line572 patients, NSCLC (PD-L1 ≥ 1%) *

      of whom 205 with PD-L1 ≥ 50%



      <65 n = 102

      65–74 n = 80

      ≥75 n = 23
      Atezolizumab 1200 mg q3w vs. platinum-based chemotherapy<65: 0.59 (0.34–1.04)

      65–74: 0.63 (0.34–1.19)

      ≥75: 0.79 (0.18–3.56)
      EMPOWER-Lung 1First line563 patients, NSCLC (PD-L1 ≥ 50%)



      <65 n = 304

      ≥65 n = 259
      Cemiplimab 350 mg q3w vs. platinum-based chemotherapy<65: 0.66 (0.44–1.00)

      ≥65: 0.48 (0.30–0.76)
      KEYNOTE-189First line616 patients, non-squamous NSCLC



      <65 n = 312

      ≥65 n = 304
      Platinum-based chemotherapy + pembrolizumab 200 mg q3w or placebo<65: 0.43 (0.31–0.61)

      ≥65: 0.64 (0.43–0.95)
      KEYNOTE-407First line559 patients, squamous NSCLC



      <65 n = 254

      ≥65 n = 305
      Platinum-based chemotherapy + pembrolizumab 200 mg q3w or placebo<65: 0.52 (0.34–0.80)

      ≥65: 0.74 (0.51–1.62)
      IMpower 150First line692 patients, non-squamous NSCLC +



      <65 n = 376

      65–74 n = 251

      ≥75 n = 65
      Platinum-based chemotherapy and bevacizumab +/- atezolizumab 1200 mg q3w<65: 0.83 (0.65–1.04)

      65–74: 0.72 (0.54–0.97)

      ≥75: 0.97 (0.58–3.56)
      IMpower 130First line723 patients, non-squamous NSCLC



      <65 n = 362

      65–74 n = 276

      75–84 n = 82

      ≥85 n = 3
      Platinum-based chemotherapy +/-atezolizumab 1200 mg q3w<65: 0.64 (0.50–0.82)

      ≥65: 0.64 (0.50–0.82)
      CheckMate 9LAFirst line719 patients, NSCLC



      <65 n = 354

      65–74 n = 295

      ≥75 n = 70
      2 cycles platinum-based chemotherapy + nivolumab 360 mg q3w + ipilimumab 1 mg/kg q6w vs. platinum-based chemotherapy<65: 0.61 (0.47–0.80)

      65–74: 0.62 (0.46–0.85)

      ≥75: 1.21 (0.69–2.12)
      CheckMate 227First line793 patients, NSCLC

      (PD-L1 ≥ 1%) ^



      <65 n = 406

      65–74 n = 306

      ≥75 n = 81
      Nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg q6w vs. platinum-based chemotherapy (vs. nivolumab 240 mg q2w)<65: 0.70 (0.56–0.89)

      65–74: 0.84 (0.65–1.08)

      ≥75: 0.93 (0.58–1.49)
      # data from the pooled analysis by Nosaki et al, Lung Cancer 2019.
      * tested on tumor cells or tumor-infiltrating immune cells.
      + intention-to-treat population, EGFR and ALK wild type, Atezolizumab-Bevacizumab-Carboplatin-Paclitaxel (ABCP) vs. BCP.
      ^ Part 1 trial.
      Abbreviations. HR: hazard ratio; CI: confidence interval; NSCLC: non-small cell lung cancer; q2w: every 2 weeks; q3w: every 3 weeks.

      Toxicity of immunotherapy in older patients

      Immune checkpoint blockers as single agent

      Few clinical studies reported on adverse events (AEs) in relation to the age of patients.
      A pooled FDA analysis of patients receiving nivolumab for advanced renal cell carcinoma, melanoma and NSCLC (the latter were from the CheckMate 057 and 017 trials) revealed a comparable rate of any grade AEs in patients > 70 (n = 212) or younger (n = 818). However, a higher rate of grade ≥ 3 AEs among older patients (71.7% in patients > 65 vs. 58.4% in patients under 65) was found. Diarrhea/colitis, skin rash and renal dysfunction were the conditions that most frequently required immune modulating treatment [
      • Singh H.
      • Kim G.
      • Maher V.E.
      • et al.
      FDA subset analysis of the safety of nivolumab in elderly patients with advanced cancers.
      ]. Conversely, a multicenter retrospective study from UK, analyzing 2049 patients with the same cancer types, but treated with anti PD-1 in any setting, did not find a different toxicity profile between patients > 75 years vs. younger patients, with a rate of grade ≥ 3 AEs of 25–50% [
      • Olsson-Brown A.C.
      • Baxter M.
      • Dobeson C.
      • et al.
      Real-world outcomes in older adults treated with immunotherapy: a United Kingdom multicenter series of 2,049 patients.
      ].
      A pooled safety analysis of KEYNOTE-010/024/042 studies included 254 older patients (≥ 75 years). ICBs treatment was associated with lower grade ≥ 3 treatment-related AEs compared to chemotherapy in older as well as in younger patients, with a slightly higher rate in older than in younger patients (24.2% vs. 16.9%). Grade ≥ 3 immune-related AEs (irAEs) were comparable between the two age groups (9.4% vs. 7.1%), as well as AEs leading to treatment discontinuation (10.7% vs. 6.8%) and serious AEs (16.1% vs. 12.8) [
      • Nosaki K.
      • Saka H.
      • Hosomi Y.
      • et al.
      Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1–positive advanced non–small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
      ].
      In the cohort study by Nebhan et al. including 928 geriatric patients with cancer (median age 83 years, of whom 345 with NSCLC) treated with single agent ICBs, 113 (12.2%) experienced grade ≥ 3 irAES; the rate of treatment discontinuation was 16.1%. No significant difference in the rate of irAEs was observed between patients < 85, 85 to 89, and > 90. Treatment interruption was significantly more frequent in patients aged > 90 [
      • Nebhan C.A.
      • Cortellini A.
      • Ma W.
      • et al.
      Clinical outcomes and toxic effects of single-agent immune checkpoint inhibitors among patients aged 80 years or older with cancer: a multicenter international cohort study.
      ].
      The French pharmacovigilance registry collected irAEs related to ICBs since 2014. An analysis conducted in 603 patients with solid cancer treated at Gustave Roussy, that included 229 patients with NSCLC, reported a higher incidence of grade ≥ 2 irAEs in patients older than 70 as compared with younger patients (33% vs. 25%, p = 0.035). When stratifying irAEs according to severity, no significant difference between age groups was observed. Skin toxicity was significantly more frequent in older patients, while endocrine toxicity in younger patients [
      • Baldini C.
      • Martin Romano P.
      • Voisin A.-L.
      • et al.
      Impact of aging on immune-related adverse events generated by anti–programmed death (ligand)PD-(L)1 therapies.
      ].
      Five hundred and twenty-seven patients with NSCLC, treated with ICBs as first or second line, were included in a multicenter retrospective study. 99 out of 527 (18.8%) were older than 75 years and 214 (40.6%) aged 65 to 75. The incidence of irAEs did not differ between groups by age, but treatment interruption due to irAE at 6 weeks was more common in patient older than 75 [
      • Ksienski D.
      • Wai E.S.
      • Croteau N.S.
      • et al.
      Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab.
      ].
      Finally, no safety concerns were found respective to age in a retrospective monocentric study evaluating 290 patients (38% aged > 70) with NSCLC treated with ICBs monotherapy [
      • Galli G.
      • De Toma A.
      • Pagani F.
      • et al.
      Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.
      ].
      In summary, ICBs as single agent have a comparable toxicity profile, in terms of incidence of high-grade AEs and irAEs, between older and younger patients with advanced stage NSCLC, as suggested by safety analyses of prospective studies and retrospective series. On the contrary, the rate of treatment discontinuation due to irAes if often more frequent with increasing age.

      Immune checkpoint blockers in combination regimens

      Clinical trials that established the role of immunotherapy and chemotherapy combination for the treatment of previously untreated metastatic NSCLC did not report on safety results by age of patients [
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.
      ,
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer.
      ,
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
      ,
      • Jotte R.
      • Cappuzzo F.
      • Vynnychenko I.
      • et al.
      Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial.
      ].
      In the retrospective study by Morimoto et al. among patients with NSCLC treated with pembrolizumab plus chemotherapy, grade ≥ 3 treatment-related AEs were more frequent in patients aged ≥ 75 compared with those < 75, although not statistically different. More in detail, with pemetrexed-platinum combination, the incidence of non-hematologic and hematologic AEs was 36.0% vs. 26.8% (p = 0.46) and 32.0% vs. 26.8% (p = 0.62), respectively, while in the taxane-platinum cohort it was 27.8% vs. 28.6% (p = 1.0) and 55.6% vs. 30.2% (p = 0.09), respectively [
      • Morimoto K.
      • Yamada T.
      • Yokoi T.
      • et al.
      Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.
      ]. Regarding irAEs, incidence of grade 3–5 pneumonitis was significantly higher in older patients treated with pembrolizumab and pemetrexed-based regimen (16.0% vs. 2.1%, p = 0.02), but it was not higher in those treated with taxane-based regimens [
      • Morimoto K.
      • Yamada T.
      • Yokoi T.
      • et al.
      Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.
      ].
      A recently published multicenter retrospective cohort study reported of 299 patients with treatment-naïve NSCLC who received platinum, pemetrexed and pembrolizumab [
      • Fujimoto D.
      • Miura S.
      • Yoshimura K.
      • et al.
      A real-world study on the effectiveness and safety of pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer1.
      ]. The median age was 68; 43 elderly patients (14%) were included. Most patient had adenocarcinoma, were tobacco smokers, and had an ECOG PS 0 to 1. No difference in OS and PFS was found between patients > 75 and < 75, but after stratifying patients by age groups (<65, 65 to 74, ≥ 75) a trend of increased rates of severe AEs (16%, 21%, and 26%, respectively) and treatment discontinuation due to AEs (14%, 27%, and 40%, respectively) was observed [
      • Fujimoto D.
      • Miura S.
      • Yoshimura K.
      • et al.
      A real-world study on the effectiveness and safety of pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer1.
      ].
      The pivotal clinical trials that investigated the use of ICBs-based combination regimens did not evaluate the toxicity profile according to the age of patients, thus data in this setting are largely lacking.

      The role of the geriatric assessment in selecting patients to immunotherapy treatment

      The complexity behind the management of older patients with cancer has led to the progressive development of a dedicated branch of interest. Geriatric oncology aims at addressing the wide heterogeneity of older patients with cancer, hardly captured by ECOG PS and by age itself [
      • Hamaker M.E.
      • Rostoft S.
      Geriatric assessment in older patients with cancer: a new standard of care.
      ]. Several screening tools can help identifying patients who are at higher risk of being vulnerable or frail, hence deserving a comprehensive geriatric assessment (CGA). The Geriatric-8 (G8) and Vulnerable Elders Survey-13 (VES-13) are among the most commonly used tools that can be used to select those patients who are to be referred to a geriatrician [
      • Soubeyran P.
      • Bellera C.
      • Goyard J.
      • et al.
      Validation of the G8 screening tool in geriatric oncology: The ONCODAGE project.
      ,

      Soubeyran P, Bellera C, Goyard J, et al. Screening for Vulnerability in Older Cancer Patients: The ONCODAGE Prospective Multicenter Cohort Study. Williams BO, editor. PLoS ONE. 2014;9:e115060.

      ,
      • Garcia M.V.
      • Agar M.R.
      • Soo W.-K.
      • et al.
      Screening tools for identifying older adults with cancer who may benefit from a geriatric assessment: a systematic review.
      ].
      The CGA is a multidimensional evaluation that explores different health domains, such as functional status, cognitive functions, psychological status, comorbidities, polypharmacy, social support and nutritional status, but can easily extend to include many other domains such as sexual function, continence, financial issues, vision and hearing, oral health and spirituality [
      • Owusu C.
      • Berger N.A.
      Comprehensive geriatric assessment in the older cancer patient: coming of age in clinical cancer care.
      ,
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • et al.
      International society of geriatric oncology consensus on geriatric assessment in older patients with cancer.
      ,
      • Mohile S.G.
      • Dale W.
      • Somerfield M.R.
      • et al.
      Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
      ]. CGA can drive treatment decisions in oncology by identifying unrecognized issues revealing a high risk of treatment toxicities, patient’s resilience and potential interferences with treatment efficacy [
      • Rostoft S.
      • O’Donovan A.
      • Soubeyran P.
      • et al.
      Geriatric assessment and management in cancer.
      ,
      • Mohile S.G.
      • Mohamed M.R.
      • Xu H.
      • et al.
      Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study.
      ]. Up to 40% of oncological treatment plans are modified after a multicomponent geriatric assessment [
      • Hamaker M.E.
      • Schiphorst A.H.
      • ten Bokkel H.D.
      • et al.
      The effect of a geriatric evaluation on treatment decisions for older cancer patients – a systematic review.
      ]. CGA improves treatments adherence and tolerance [
      • Hamaker M.E.
      • te Molder M.
      • Thielen N.
      • et al.
      The effect of a geriatric evaluation on treatment decisions and outcome for older cancer patients – a systematic review.
      ]. Two large randomized clinical studies demonstrated that CGA combined with the integration of a geriatrician in patient’s management resulted in reduced severe chemotherapy-emergent AEs in older patients [
      • Mohile S.G.
      • Mohamed M.R.
      • Xu H.
      • et al.
      Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study.
      ,
      • Li D.
      • Sun C.-L.
      • Kim H.
      • et al.
      Geriatric assessment-driven intervention (GAIN) on chemotherapy-related toxic effects in older adults with cancer: a randomized clinical trial.
      ]. Nevertheless, the lack of geriatricians, the actual costs and need for structural organization, as well as the lack of evidence of a positive impact of CGA on patient survival [
      • Corre R.
      • Greillier L.
      • Le Caër H.
      • et al.
      Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non–small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08–02 study.
      ], have hampered the implementation of CGA and of geriatric co-management in geriatric oncology so far [
      • Hamaker M.E.
      • Rostoft S.
      Geriatric assessment in older patients with cancer: a new standard of care.
      ].
      While the relevance of CGA-based chemotherapy allocation in terms of safety outcomes was shown even in randomized studies [
      • Mohile S.G.
      • Mohamed M.R.
      • Xu H.
      • et al.
      Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study.
      ,
      • Li D.
      • Sun C.-L.
      • Kim H.
      • et al.
      Geriatric assessment-driven intervention (GAIN) on chemotherapy-related toxic effects in older adults with cancer: a randomized clinical trial.
      ], no prospective studies have focused on ICBs treatment. A single center retrospective study of 28 patients with solid tumors (40% with lung cancer) with a median age of 78 years receiving ICBs showed a shorter treatment duration in patients with impairment in at least one CGA domain, while no correlations were found with tumor response nor with irAES [
      • Welaya K.
      • Loh K.P.
      • Messing S.
      • et al.
      Geriatric assessment and treatment outcomes in older adults with cancer receiving immune checkpoint inhibitors.
      ].
      The ELDERS prospective study provided useful information on the role of the G8 scale screening and of the CGA in predicting the occurrence of irAES in patients receiving ICBs [
      • Gomes F.
      • Lorigan P.
      • Woolley S.
      • et al.
      A prospective cohort study on the safety of checkpoint inhibitors in older cancer patients – the ELDERS study.
      ]. It evaluated 140 patients with advanced NSCLC (53%) or melanoma (47%), who were equally distributed by age in two cohorts (70 years was used as a threshold). In patients with a positive G8 screening (< 15 points), a CGA was performed at baseline and every three months during ICBs treatment for a maximum of four times, as suggested by the International Society of Geriatric Oncology (SIOG) [
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • et al.
      International society of geriatric oncology consensus on geriatric assessment in older patients with cancer.
      ]. Baseline geriatric screening was performed in all older patients and was positive in half of them. Overall, patients addressed to CGA had a worse ECOG PS, and a higher burden in terms of polypharmacy and comorbidities as compared to patients aged > 70 but who scored negative at the G8 screen. The incidence of any grade and grade ≥ 3 irAEs was not significantly different between older and younger cohorts (60% vs. 51.4% and 18.6% vs. 12.9%, respectively). A positive G8 screening correlated with a higher rate of hospital admission, which was largely not due to treatment-related AEs, and with a higher risk of death. No definitive conclusion could be drown with respect to the impact of CGA on treatment outcomes [
      • Gomes F.
      • Lorigan P.
      • Woolley S.
      • et al.
      A prospective cohort study on the safety of checkpoint inhibitors in older cancer patients – the ELDERS study.
      ].

      Immunosenescence

      Immunosenescence is a phenomenon involving innate and adaptive immunity and characterized by a progressive remodeling of immune functioning during aging [
      • Ferrara R.
      • Mezquita L.
      • Auclin E.
      • et al.
      Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?.
      ]. On one hand, primary and secondary immune organs (i.e., thymus, bone marrow, spleen, lymph nodes) undergo a physiological involution [
      • Ferrara R.
      • Mezquita L.
      • Auclin E.
      • et al.
      Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?.
      ]. On the other hand, due to a long-lasting exposure to antigens, terminally differentiated T cells accumulate in the immunological “space”, reducing the naïve compartment [
      • Franceschi C.
      • Valensin S.
      • Fagnoni F.
      • et al.
      Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load.
      ]. Some hallmarks of immunosenescence have been described: the increase in memory to naïve T cells ratio, the increased proportion of circulating senescent T cells, an oligoclonal T cell receptor repertoire and reduced capacity to recognize antigenic diversity of immune cells [
      • Franceschi C.
      • Valensin S.
      • Fagnoni F.
      • et al.
      Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load.
      ]. Moreover, an increased secretion of proinflammatory cytokines combined with a low-grade inflammation affecting many organs and tissues (“inflammaging”), as well as changes in the adaptive immune system involving antigen presenting cells, macrophages, NK cells, also participate to this complex immunological scenario [
      • Elias R.
      • Karantanos T.
      • Sira E.
      • et al.
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      ]. Senescent T cells are characterized by low proliferative activity, conserved cytotoxic potential and proinflammatory cytokines production [
      • Chattopadhyay P.K.
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      The cytolytic enzymes granyzme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression.
      ,
      • Bandrés E.
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      The increase of IFN-γ production through aging correlates with the expanded CD8+highCD28−CD57+ subpopulation.
      ], associated with the expression of defined phenotypic markers. Specifically, the loss of CD28 and CD27 and an increased expression of CD57 and of killer-cell lectin-like receptor G1 (KLRG1) in CD8+ T cells correlate with lower proliferation and shorter telomeres [
      • Voehringer D.
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      Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1).
      ]. In a study of Ferrara et al., a “senescent immune phenotype” (SIP) was assessed by measuring the percentage of CD28-CD57+KLRG1+ cells among CD8+ circulating T cells in blood samples from patients with advanced NSCLC treated with ICBs. A high pretreatment SIP (> 39.5% SIP+ cells) was shown to be associated with reduced activity and efficacy (ORR, PFS and OS) of single agent ICBs [
      • Ferrara R.
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      Circulating T-cell immunosenescence in patients with advanced non–small cell lung cancer treated with single-agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy.
      ]. Interestingly, baseline SIP status was not significantly associated with age (SIP+ patients had a median age of 68 years [59–73.5] vs. 61.5 years [

      Paz-Ares LG, Ramalingam SS, Ciuleanu T-E, et al. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thoracic Oncol. 2021;S155608642103207X.

      ,
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      ,
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      Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
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      ,
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      ,
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      ,
      • Baldini C.
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      Impact of aging on immune-related adverse events generated by anti–programmed death (ligand)PD-(L)1 therapies.
      ,
      • Ksienski D.
      • Wai E.S.
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      • et al.
      Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab.
      ,
      • Galli G.
      • De Toma A.
      • Pagani F.
      • et al.
      Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.
      ,
      • Fujimoto D.
      • Miura S.
      • Yoshimura K.
      • et al.
      A real-world study on the effectiveness and safety of pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer1.
      ,
      • Hamaker M.E.
      • Rostoft S.
      Geriatric assessment in older patients with cancer: a new standard of care.
      ,
      • Garcia M.V.
      • Agar M.R.
      • Soo W.-K.
      • et al.
      Screening tools for identifying older adults with cancer who may benefit from a geriatric assessment: a systematic review.
      ,
      • Owusu C.
      • Berger N.A.
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      ,
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • et al.
      International society of geriatric oncology consensus on geriatric assessment in older patients with cancer.
      ] in SIP-) [
      • Ferrara R.
      • Naigeon M.
      • Auclin E.
      • et al.
      Circulating T-cell immunosenescence in patients with advanced non–small cell lung cancer treated with single-agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy.
      ]. Similarly, > 13% of peripheral blood CD8 EM1 cells (CD27+CD28+) at baseline was found to positively correlate with OS among 137 patients with metastatic melanoma, while the frequency of CD8 EMRA (T cells with terminally differentiated phenotype, CD45RA+CCR7CD27CD28) showed a negative association [
      • Wistuba-Hamprecht K.
      • Martens A.
      • Heubach F.
      • et al.
      Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients.
      ]. A small pilot study showed a correlation between CD27-CD28- T cells and Tim-3+CD57+ T cells, on one hand, and primary resistance to ICBs, on other hand, in patients with metastatic melanoma. Again, the role of chronological age was unclear [
      • Moreira A.
      • Gross S.
      • Kirchberger M.C.
      • et al.
      Senescence markers: predictive for response to checkpoint inhibitors.
      ].
      Preclinical data also suggest a role of immunosenescence in enhancing the risk of severe irAES in older subjects, through the so called ‘‘inflammaging” [
      • Franceschi C.
      • Bonafè M.
      • Valensin S.
      • et al.
      Inflamm-aging: an evolutionary perspective on immunosenescence.
      ]. Mounting evidence indeed links inflammaging with many aging-related diseases. However, whether this phenomenon translates into an increased risk of irAEs during ICBs therapy remains to be established.
      Finally, aging also profoundly affects the microbiome composition and its interaction with the immune system [
      • Routy B.
      • Le Chatelier E.
      • Derosa L.
      • et al.
      Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
      ]. Animal models and clinical data suggest that changes in the microbiota influence the efficacy of ICBs. Modification of probiotics, prebiotics or postbiotics can affect or be affected by the Firmicutes/Bacteroidetes ratio. High Firmicutes/Bacteroidetes ratio was shown to enhance the innate immune functions in mice models and was associated with clinical benefit from immunotherapy in patients with cancer [
      • Sivan A.
      • Corrales L.
      • Hubert N.
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      ,
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      ,
      • Gopalakrishnan V.
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      • Nezi L.
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      Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients.
      ,
      • Coutzac C.
      • Jouniaux J.-M.
      • Paci A.
      • et al.
      Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.
      ]. Conversely, the aging-associated decline in microbiota diversity may hamper ICBs efficacy [
      • Ferrara R.
      • Mezquita L.
      • Auclin E.
      • et al.
      Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?.
      ].

      Discussion

      The underrepresentation of older patients in oncology trials with ICBs makes reason for a continuous interrogation around the efficacy and safety of these agents among this population. Moreover, the increasing prevalence of patients with cancer aged 70 years or older will inevitably enhance the discrepancy between the characteristics of patients enrolled in clinical trials and those of the patients who are treated in the everyday clinical practice. Among these latter, a higher level of treatment attrition may for example be observed, as well a worse PS [
      • Cortellini A.
      • Cannita K.
      • Tiseo M.
      • et al.
      Post-progression outcomes of NSCLC patients with PD-L1 expression ≥ 50% receiving first-line single-agent pembrolizumab in a large multicentre real-world study.
      ].
      As a consequence, a large number of real-life studies have been performed to investigate the performance of ICBs therapy in older patients, sometimes with contrasting results likely related to the heterogeneity of the study populations.
      Similarly, systematic reviews and meta-analyses of randomized controlled trial, that assessed the clinical outcomes in response to ICBs (anti PD-1, anti PD-L1, anti CTLA-4) in patients with solid tumors according to their age, also found discordant results. A doubtful OS benefit in patients aged > 75 was seen in two metanalysis from 2015 and 2016, respectively [
      • Nishijima T.F.
      • Muss H.B.
      • Shachar S.S.
      • et al.
      Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis.
      ,
      • Landre T.
      • Taleb C.
      • Nicolas P.
      • et al.
      Is there a clinical benefit of anti-PD-1 in patients older than 75 years with previously treated solid tumour?.
      ]. However, no conclusions can be drawn with respect to patients with NSCLC included in these analyses since only the CheckMate 017 and 057 trials were considered. Overall, no difference in OS was observed in any meta-analysis when the age threshold was set at 65 years [
      • Nishijima T.F.
      • Muss H.B.
      • Shachar S.S.
      • et al.
      Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis.
      ,
      • Landre T.
      • Taleb C.
      • Nicolas P.
      • et al.
      Is there a clinical benefit of anti-PD-1 in patients older than 75 years with previously treated solid tumour?.
      ,

      Jiang Y, Su Z. Cancer immunotherapy efficacy and patients’ age: A systematic review and meta-analysis. Annals of Oncology. 2019;30:ix154.

      ,
      • Sun Y.-M.
      • Wang Y.
      • Sun X.-X.
      • et al.
      Clinical efficacy of immune checkpoint inhibitors in older non-small-cell lung cancer patients: a meta-analysis.
      ].
      A study presented at the 2021 World Conference on Lung Cancer sheds light on this topic [

      Takamori S, Komiya T, Powell E. MA15.07 Survival Benefit From Immunocheckpoint Inhibitors in Stage IV Non-small Cell Lung Cancer Patients ≥75 Years Old of Age. Journal of Thoracic Oncology. 2021;16:S936.

      ]. It included 86,173 patients with stage IV NSCLC, 24,136 aged ≥ 75 and 62,037 aged < 75, and was performed by querying the National Cancer Database between 2014 and 2015. Patients ≥ 75 who received ICBs had a significantly longer OS than those who did not receive ICBs (11.9 vs. 5.4 months, HR 0.61, 95 %CI 0.58–0.64). At multivariate Cox analysis, the HR for OS benefit from ICBs in patients ≥ 75 was 0.61 (95 %CI 0.58–0.65), similar to that of patients aged < 75 (HR 0.68, 95 %CI 0.66–0.70). The negative prognostic impact of age on OS was higher in patients not treated with ICBs [

      Takamori S, Komiya T, Powell E. MA15.07 Survival Benefit From Immunocheckpoint Inhibitors in Stage IV Non-small Cell Lung Cancer Patients ≥75 Years Old of Age. Journal of Thoracic Oncology. 2021;16:S936.

      ]. It has to be said that the OS as endpoint can be influenced by causes of death other than cancer, particularly among patients with significant comorbidities [
      • Burdett N.
      • Vincent A.D.
      • O’Callaghan M.
      • et al.
      Competing risks in older patients with cancer: a systematic review of geriatric oncology trials.
      ].
      Regarding the safety of ICBs treatment, there are no conclusive data to state that older patients have higher risk of severe irAEs as compared with younger patients when treated with single agent immunotherapy. However, it must be considered that some studies reported a potential increase in pulmonary toxicity in older subjects as well as an increased rate of recurrence of irAEs at ICBs rechallenge [
      • Dolladille C.
      • Ederhy S.
      • Sassier M.
      • et al.
      Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer.
      ], and a large meta-analysis including different cancer types treated with anti CTLA-4 or anti PD-(L)1 reported that fatal toxicities, however rare, occurred more frequently in older patients [
      • Wang D.Y.
      • Salem J.-E.
      • Cohen J.V.
      • et al.
      Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.
      ]. Notably, a tendency to autoimmunity, but not necessarily to a development of autoimmune diseases, has biological bases in senior patients, irrespective to cancer [

      Ramos-Casals M, Brito-Zerón P, López-Soto A, et al. Systemic autoimmune diseases in elderly patients: Autoimmunity Reviews. 2004;3:376–382.

      ,
      • Vadasz Z.
      • Haj T.
      • Kessel A.
      • et al.
      Age-related autoimmunity.
      ].
      Most studies of immunotherapy in older patients focused on ICBs as a monotherapy. The emergence of combinations of ICBs with chemotherapy regimens as first line treatment highlights the need to obtain new efficacy and safety data based on age subgroups. Although clinical evidence in this setting is limited, older patients may benefit less from chemo-immunotherapy, and are likely to experience a higher incidence of grade ≥ 3 AEs and of AEs-related treatment discontinuation in response to both ICBs and chemotherapy [
      • Morimoto K.
      • Yamada T.
      • Yokoi T.
      • et al.
      Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.
      ,
      • Fujimoto D.
      • Miura S.
      • Yoshimura K.
      • et al.
      A real-world study on the effectiveness and safety of pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer1.
      ]. Whether the increased treatment discontinuation rate may be responsible for reduced survival outcomes has not been explored.
      Pembrolizumab monotherapy represents a good first line treatment alternative to the chemotherapy-combined regimens in vulnerable older patients with high PD-L1-expressing tumors, with a toxicity profile that is acceptable and overall comparable to that observed in younger patients [
      • Nosaki K.
      • Saka H.
      • Hosomi Y.
      • et al.
      Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1–positive advanced non–small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
      ]. However, making a treatment decision only based on chronological age of an older patient could ultimately lead to undertreatment (or to overtreatment). It is worth noting that in the CheckMate 153 trial, patients aged > 70 years and with an ECOG PS 2 treated with ICBs monotherapy also demonstrated to have improvement in quality of life (QoL) endpoints and decrease in symptoms. Similarly, immunotherapy was found to be associated with improvement in many patient-reported outcomes when combined to chemotherapy over chemotherapy alone [
      • Boutros A.
      • Bruzzone M.
      • Tanda E.T.
      • et al.
      Health-related quality of life in cancer patients treated with immune checkpoint inhibitors in randomised controlled trials: A systematic review and meta-analysis.
      ].
      Growing evidence is emerging on the role of CGA to allocate patients to anticancer treatments, in order to spare toxicities, enhance the adherence to the therapeutic plan and maintaining an adequate dose intensity. While we acknowledge that including a CGA in the pretreatment evaluation of all patients with advanced NSCLC is not feasible, a G8 screening could instead be useful to identify vulnerable or frail patients who will profit from a CGA and, potentially, from geriatric interventions addressing issues in geriatric domains. Fig. 1 reports the current first line treatment options for older patients with advanced stage NSCLC without molecular driver alterations.
      Figure thumbnail gr1
      Fig. 1Therapeutic options for the first line treatment of older patients with advanced NSCLC without driver molecular alterations, according to PD-L1 expression.
      Overall, considering that a single biomarker, even though it may be crucial for posing the indication for a specific agent, is not able to catch the complexity of a patient, all known prognostic and predictive factors should be considered during the pretreatment evaluation (Fig. 2), including some parameters that are fairly easy to assess, such as the tumor burden, both radiologically and laboratory evaluated [

      Dall’Olio FG, Marabelle A, Caramella C, et al. Tumour burden and efficacy of immune-checkpoint inhibitors. Nat Rev Clin Oncol [Internet]. 2021 [cited 2021 Dec 21]; Available from: https://www.nature.com/articles/s41571-021-00564-3.

      ], the ECOG PS [
      • Tomasik B.
      • Bieńkowski M.
      • Braun M.
      • et al.
      Effectiveness and safety of immunotherapy in NSCLC patients with ECOG PS score ≥2 – systematic review and meta-analysis.
      ] and the tobacco smoking status [
      • Dai L.
      • Jin B.
      • Liu T.
      • et al.
      The effect of smoking status on efficacy of immune checkpoint inhibitors in metastatic non-small cell lung cancer: a systematic review and meta-analysis.
      ]. Among immuno-inflammatory indexes, the Lung Immune Prognostic Index (LIPI) score [
      • Mezquita L.
      • Auclin E.
      • Ferrara R.
      • et al.
      Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.
      ,
      • Yang T.
      • Hao L.
      • Yang X.
      • et al.
      Prognostic value of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with non-small cell lung cancer receiving immune checkpoint inhibitors: a meta-analysis.
      ] was retrospectively tested in a cohort of 191 patients aged ≥ 70 with advanced tumors (27% NSCLC) treated with ICBs. Its prognostic value in identifying patients at worse outcome was retained in this selected population, thus suggesting being not age-related [
      • Belmaachi A.
      • Auclin E.
      • Vincent H.
      • et al.
      Association of LIPI score with immunotherapy outcomes in elderly population.
      ].
      Figure thumbnail gr2
      Fig. 2Complexity behind the management of older patients with advanced NSCLC.
      In those patients who screen positive at the G8, VES-13 or similar tools and who consequently receive a CGA, the key findings of such assessment should also be taken into account in the treatment decision process. Notably, by tackling at least some of the health problems that were diagnosed with the CGA (e.g., depression, malnutrition, lack of physical activity/immobilization, cognitive issues, social issues, etc.), geriatric interventions have the potential to make patients, who were initially not eligible for aggressive treatments, suitable again for such regimes. Thus, the re-gaining of older patients to active treatment is expected to be another key advantage of applying geriatric tools and of involving a geriatrician in the care of older patients with cancer.
      Clinical trials focused on older patients are currently running to assess the use of alternative chemotherapy backbone to be combined with ICBs, to compare immunotherapy alone or in combination with chemotherapy, or to explore different treatment sequences (Table 2). Going beyond, strategies to revert immunosenescence processes or senolytic drugs are of even greater interest in oncology and may will have practical implications in the next future, not exclusively for older patients.
      Table 2Ongoing clinical trials with immunotherapy focused on older patients with advanced stage NSCLC.
      StudyPopulationStudy designTreatment armsPrimary endpoint
      NCT03977194 (ELDERLY)Patients with stage IIIB-IV NSCLC aged 70 to 89 yearsPhase 3 randomizedCarboplatin AUC 6 day 1 + paclitaxel 90 mg/m2 day 1, 8, 15 every 4 weeks alone (A) or with atezolizumab 1200 mg q3w (B)OS
      NCT03975114 (MILES-5)Patients with untreated stage IIIB-IV NSCLC aged ≥ 70 yearsPhase 2

      randomized
      (A) Standard chemotherapy followed at progression by durvalumab 1500 mg q4w.

      (B) Durvalumab 1500 mg followed at progression by chemotherapy.

      (C) Combination immunotherapy with durvalumab 1500 mg + tremelimumab 75 mg q4w (4 cycles) followed at progression by chemotherapy
      12-month OS
      NCT04533451Patients with untreated stage IV or recurrent lung adenocarcinomaNon-randomized, allocation at oncologist's choicePembrolizumab 200 mg q3w or 400 mg every 42 days alone (A) or with carboplatin AUC 5 and pemetrexed 500 mg/m2 q3w (B)Incidence of grade ≥ 3 AEs
      NCT03345810 (DURATION)Patients with metastatic NSCLC aged ≥ 70 years and/or with a Charlson-Comorbidity-Index > 1 and/or ECOG PS > 1 not eligible to platinum-doubletPhase 2

      randomized
      (A) CARG-Score ≤ 3: Carboplatin AUC 5 day 1 + nab-Paclitaxel 100 mg/m2 day 1, 8 q3w.

      (B) CARG-Score ≤ 3: Carboplatin AUC day 1 + nab-Paclitaxel 100 mg/m2 day 1, 8 q3w (2 cycles) followed by durvalumab 1125 mg q3w (2 cycles) and durvalumab maintenance 1500 mg q4w.

      (C) CARG-score > 3: vinorelbine 30 mg/m2 day 1,8 (2 cycles) or gemcitabine 1000 mg/m2 day 1, 8 (2 cycles) q3w followed by durvalumab 1125 mg q3w (2 cycles) and durvalumab maintenance 1500 mg q4w.

      (D) CARG-score > 3: vinorelbine 30 mg/m2 day 1,8 or gemcitabine 1000 mg/m2 day 1, 8 q3w
      Incidence of grade ≥ 3 treatment-related AEs
      Abbreviations. NSCLC: non-small cell lung cancer; AUC: area under curve; OS: overall survival; q2w: every 2 weeks; q3w: every 3 weeks; q4w: every 4 weeks; ECOG PS: Eastern Cooperative Oncology Group Performance Status; AEs: adverse events.

      Conclusions

      The management of older patients with metastatic NSCLC without targetable molecular alterations should be tailored based on an individual evaluation, that should account expected survival outcome, risk of toxicity, QoL, as well as patient’s preferences. Unjustified undertreatment should be avoided.
      The enrollment of older patients in clinical trials in oncology remains a crucial topic to be addressed. Therefore, future oncology studies (including studies of ICBs) should probably consider enrolling patients based on age plus “geriatric”/functional criteria rather than just on age, as there is the assumption that older patients who are “fit” should be treated as younger patients anyway. This type of patient profiling would also have the added benefit of a better annotation of the study population, potentially allowing to identify those health domains that, when compromised, are associated with reduced benefits from the experimental treatment.

      Role of the funding source

      This work received no funding.

      Disclosures

      Marco Tagliamento: Travel grants: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly. Honoraria as medical writer: Novartis, Amgen. None related to the current manuscript.
      Nathalie Chaput: Grants: BMS, SANOFI, Astra Zeneca, GSK. Personal fees: Astra Zeneca, Servier. None related to the current manuscript.
      Benjamin Besse: Sponsored Research at Gustave Roussy Cancer Center: 4D Pharma, Abbvie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. None related to the current manuscript.

      CRediT authorship contribution statement

      Marco Tagliamento: Conceptualization, Project administration, Writing – original draft, Writing – review & editing. Maxime Frelaut: Conceptualization, Writing – original draft, Writing – review & editing. Capucine Baldini: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. Marie Naigeon: Data curation, Writing – original draft, Writing – review & editing. Alessio Nencioni: Data curation, Writing – original draft, Writing – review & editing. Nathalie Chaput: Data curation, Writing – original draft, Writing – review & editing. Benjamin Besse: Conceptualization, Project administration, Writing – original draft, Writing – review & editing.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      Dr. Marco Tagliamento was the recipient of the grant for the DUERTECC (Diplôme Universitaire Européen de Recherche Translationnelle Et Clinique en Cancérologie) 2021-2022.
      Fig. 1 was adapted from “Intracellular Metabolic Pathway Comparison (Layout)”, by BioRender.com (2022), and Fig. 2 was adapted from “Panels in a Circular Layout”, by BioRender.com (2022), retrieved from https://app.biorender.com/biorender-templates.

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