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Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab
JGO-00890; No. of pages: 7; 4C: Journal of Geriatric Oncology xxx (2020) xxx
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Journal of Geriatric Oncology
Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab Doran Ksienski a,b,⁎, Elaine S. Wai a,b, Nicole S. Croteau c, Ashley T. Freeman a,b, Angela Chan b,d, Leathia Fiorino a,b, Zia Poonja a,b, David Fenton a,b, Tiffany Patterson a, Sarah Irons a, Mary Lesperance c a
BC Cancer- Victoria, British Columbia, Canada University of British Columbia, British Columbia, Canada c University of Victoria, Department of Mathematics and Statistics, British Columbia, Canada d BC Cancer- Surrey, British Columbia, Canada b
a r t i c l e
i n f o
Article history: Received 26 August 2019 Received in revised form 30 December 2019 Accepted 8 January 2020 Available online xxxx Keywords: Pembrolizumab Nivolumab Survival Toxicity Advanced nonsmall cell lung cancer
a b s t r a c t Objectives: To explore the association of age with development of immune related adverse events (irAE) and survival in patients with advanced nonsmall cell lung cancer (aNSCLC) receiving programmed cell death 1 antibodies (PD-1 Ab) outside of clinical trials. Methods: A multicenter retrospective study of PD-1 Ab prescription for patients with aNSCLC between 06/ 2015–11/2018 at BC Cancer. Multivariable (MVA) logistic regression identified baseline variables associated with irAE manifested within 3 months of PD-1 Ab initiation. Overall survival (OS) analyzed in a propensityscore matched cohort and survival outcomes compared between age groups by stratified log-rank. Six-week landmark analysis was performed and OS compared between patients with interrupted versus continuous treatment by log-rank. Results: Of 527 patients, 40.6% were age ≤ 64 years, 40.6% were 65–74 years, and 18.8% were ≥ 75 years. In MVA, ECOG performance status 2/3 (p = .034), squamous histology (p = .031), and nivolumab therapy (vs. pembrolizumab, p = .012) were associated with increased odds of irAE by 3 months of treatment. Across age groups no difference existed in any grade irAE (p = .98), hospitalization (p = 1.0), or corticosteroids use (p = .51). The propensity score–matched survival analysis comprised 77 patients from each age group; all covariates were balanced. OS did not differ significantly by age in the matched cohort (p = .17). Treatment interruption due to irAE at 6 weeks was more common in patient ≥75 years (vs. b75, p = .055) and correlated with lower OS (p = .002). Conclusion: In this cohort of patients with aNSCLC treated in routine clinical practice with PD-1 Ab, immunetoxicity and observed survival were similar amongst age groups. © 2020 Published by Elsevier Ltd.
1. Introduction Advanced nonsmall cell lung cancer (aNSCLC) is an aggressive malignancy with a five year overall survival (OS) of 5.2% [1]. With a median age at diagnosis of 70 years, NSCLC is a disease of older adults [1]. Despite the increasing prevalence of NSCLC with age, patient ≥75 years old are under-represented in clinical trials [2].
Immune checkpoint inhibition has emerged as a powerful element in the treatment of aNSCLC. Programmed cell death 1 (PD-1), a negative costimulatory receptor, is present on the surface of activated T-cells [3]; approximately 68% of NSCLC tumors express PD-1 ligand 1 (PD-L1.) Binding of PD-L1 to PD-1 can result in immunosuppression and tumor growth. PD-1 antibodies (PD-1 Ab) such as nivolumab and pembrolizumab function to disrupt this inhibitory signal and reactivate T cells.
Abbreviations: Ab, antibody; ALK, anaplastic lymphoma kinase; aNSCLC, advanced nonsmall cell lung cancer; CCI, Charlson comorbidity index; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, Epidermal growth factor receptor; irAE, immune related adverse events; n, number of patients; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; RT, radiotherapy; TPS, tumor proportion score. ⁎ Corresponding author at: BC Cancer- Victoria, 2410 Lee Avenue V8R 6V5, Victoria, British Columbia, Canada. E-mail address: [email protected] (D. Ksienski).
https://doi.org/10.1016/j.jgo.2020.01.006 1879-4068/© 2020 Published by Elsevier Ltd.
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
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Immune checkpoint inhibitors produce a unique spectrum of side effects called immune related adverse events (irAE). Dermatologic, endocrine, gastrointestinal, and pulmonary irAE are most common, although any organ can be involved [4]. Based on meta-analysis from PD-1 Ab trials in aNSCLC, the incidence of any grade irAE is 27% (95% CI, 18%–35%) and high grade irAE is 7% (95% CI, 2%–12%) [5]. Grade 2 or higher irAE typically requires treatment interruption, prolonged corticosteroid use, and occasionally immune modulating agents. Under-representation of older patients contributes to uncertainty regarding the risk-benefit ratio of immunotherapy. Immunosenescence, an age-associated remodelling of the innate and adaptive immune system, could alter efficacy and toxicity of immune checkpoint inhibitors. Furthermore, documentation of irAE in clinical trials has been criticized; Chen et al., performed a systematic review of 50 trials of immune checkpoint inhibition and found complete reporting of irAE onset, management, and reversibility in 14%, 8%, and 6% of studies, respectively [6]. In this multicenter retrospective analysis, we sought to compare the incidence and severity of irAE for younger and older patients with aNSCLC receiving PD-1 Ab outside of clinical trials. As a secondary goal, we aimed to describe survival outcomes of patients with aNSCLC treated with immune checkpoint inhibition based on age. 2. Methods 2.1. Patient Population British Columbia (BC) Cancer is the provincial institution responsible for providing cancer care for the five million residents of British Columbia, Canada. Pembrolizumab is publically funded for patients with aNSCLC who have PD-L1 tumor proportion score (TPS) ≥ 50% and are treatment naïve or have PD-L1 TPS ≥1% and have progressed on palliative-intent platinum doublet chemotherapy. Irrespective of PDL1 status, nivolumab is funded after disease progression on a palliative-intent platinum doublet. 2.2. Data Collection After approval from the University of British Columbia Research Ethics Board, clinical characteristics, treatment details, and survival outcomes were extracted by retrospective chart review. Comorbidity was calculated using the Charlson Comorbidity Index (CCI, aNSCLC not included as a ‘solid metastatic tumor’). 2.3. Study Objectives For the primary objective of reporting irAE incidence and severity, identification of irAE was based on the treating healthcare practitioner's assessment. Collected information included: grade (assigned by the abstractor utilizing the Common Terminology Criteria for Adverse Events, version 4), dose interruption (either temporary or permanent discontinuation), need for corticosteroids or immune modulating agents, and requirement for overnight hospitalization to treat immune toxicity [7]. For the secondary aim, OS was measured from PD-1 Ab initiation until death or censored at last follow-up. 2.4. Statistical Analysis Patients were stratified by age at time of aNSCLC diagnosis (≤64 years, 65–74 years, ≥75 years) and descriptive statistics of study variables were computed, including means, medians, ranges, counts, and proportions. Baseline characteristics were compared between the age groups using Pearson's Chi-squared, Fisher's exact, and KruskalWallis rank sum tests as appropriate. Post-hoc pairwise comparisons of significant baseline factors were performed and Bonferonni p-values are reported to control for multiple testing (Padj). Median follow-up times were computed (i) as the median of all survival times (ignoring
censoring) and (ii) by the reverse Kaplan-Meier method which provides an estimate of the potential follow-up [8]. Due to the time-dependent nature of immune toxicity, we define a 3-month cohort (interval during which most irAE occur) to analyze the distribution of irAE. Univariable and multivariable logistic regression analysis was undertaken to identify baseline variables (age at aNSCLC diagnosis, gender, Eastern Cooperative Oncology Group performance status (ECOG PS) at PD-1 Ab initiation, CCI, smoking status, histology, PD-L1 TPS, molecular aberration, treatment line, PD-1 Ab type, and history of autoimmune disease) associated with irAE within 3 months of PD-1 Ab treatment. Patients with b3 months follow-up who do not experience the outcome are excluded from the analysis. As there were imbalances in baseline covariates amongst age groups, propensity-score matching survival analysis was undertaken [9,10]. The propensity score for the indicator of age group ≥75 years was estimated using two multivariable logistic regression models (one without patients ≤64 years and the other without patients 65–74 years) including covariates gender, stage at first consult, ECOG PS at PD-1 Ab start, CCI, smoking status, histology, molecular aberration, PD-L1 TPS, liver metastases, brain metastases, type of PD-1 Ab, radiotherapy within a year prior to PD-1 Ab, and history of autoimmune disease. Patient's ≥ 75 years were matched to those ≤64 years and 65–74 years, respectively, on a propensity score in a 1:1 ratio by minimizing the total distance between matched triplets. Strata were defined from quintiles of an aggregate propensity score where, for patient's ≥ 75 years, the scores from the two propensity models were averaged. Kaplan-Meier curves for OS in the matched cohort were generated and age cohorts compared using the stratified log-rank test. Univariable and multivariable stratified Cox proportional hazard models were fitted to determine associations between survival outcomes and baseline variables (in addition to development of irAE, entered as a time-dependent covariate). Landmark analysis was used to minimize lead-time bias associated with the time- dependent variable treatment interruption (dose delay or cessation of PD-1 Ab) resulting from irAE [11,12]. We performed an exploratory 6-week landmark analysis (time point chosen based on prior analysis with a smaller cohort) [13]; survival outcomes for patients requiring treatment interruption due to irAE before the landmark versus those who received PD-1 Ab continuously were compared. Patients who died or were censored before the landmark time were excluded from the analysis. Kaplan-Meier curves for OS in the 6-week cohort were generated and age cohorts compared using the log-rank test. All p-values were based on two sided hypotheses tests and those b0.05 were considered statistically significant. Statistical analyses were performed using R version 3.6.1 and R packages ‘survival’ version 2.44, ‘survminer’ version 0.4.6, ‘tableone’ version 0.10.0 and ‘TriMatch’ version 0.9.9 [14–19].
3. Results 3.1. Patients Of the 527 patients with aNSCLC treated with PD-1 Ab, 214 (40.6%) were ≤ 64 years old, 214 (40.6%) were 65–74 years, and 99 (18.8%) were ≥ 75 years. Baseline statistics are provided in Table 1. Compared to patients aged ≤64 and 65–74 year old, individuals in the oldest cohort were significantly more likely to be never/former smokers (padj b 0.001, padj = 0.006), have a PD-L1 TPS ≥ 50% (padj b 0.001, padj b 0.001), receive pembrolizumab (padj b 0.001, padj = 0.029), obtain PD-1 Ab as a first line treatment (padj b 0.001, padj b 0.003), and not have brain metastases at diagnosis of advanced disease (padj = 0.017, padj = 0.011). Delivery of radiotherapy within one year prior to PD-1 Ab initiation was more common amongst patients ≤64 than ≥75 years of age (padj = 0.014). Compared to the age 65–74 years patients, the youngest individuals were significantly less likely to be never/former smokers (padj = 0.047) and receive PD-1 Ab as a first line treatment (padj = 0.034).
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
D. Ksienski et al. / Journal of Geriatric Oncology xxx (2020) xxx
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Table 1 Baseline patient characteristics (unmatched cohort).
Characteristic Gender Female Male ECOG PS at PD-1 Ab initiation 0/1 2/3 CCI (median [range]) aNSCLC at presentation Smoking status Current Former Never Histology Non-squamous Squamous EGFR mutation ALK rearrangement PD-L1 TPS ≥50% b50%/unknown Liver metastases (%) Brain metastases (%) PD-1 Ab Pembrolizumab Nivolumab Line of PD-1 Ab 1st ≥2nd RT within 1 year of PD-1 Ab RT during PD-1 Ab Autoimmune disease
Overall
Age ≤ 64
Age 65–74
Age ≥ 75
(n = 527)
(n = 214)
(n = 214)
(n = 99)
n (%)
n (%)
n (%)
n (%)
266 (50.5) 261 (49.5)
114 (53.3) 100 (46.7)
99 (46.3) 115 (53.7)
363 (68.9) 164 (31.1) 2.0 (0.0–12.0) 410 (77.8)
158 (73.8) 56 (26.2) 2.0 (0.0–11.0) 168 (78.5)
136 (63.6) 78 (36.4) 2.5 (0.0–12.0) 166 (77.6)
53 (53.5) 46 (46.5) 0.070 69 (69.7) 30 (30.3) 3.0 (0.0–10.0) 76 (76.8)
169 (32.1) 292 (55.4) 66 (12.5)
90 (42.1) 92 (43.0) 32 (15.0)
65 (30.4) 126 (58.9) 23 (10.7)
14 (14.1) 74 (74.7) 11 (11.1)
404 (76.7) 123 (23.3) 35 (6.6) 4 (0.8)
164 (76.6) 50 (23.4) 17 (7.9) 4 (1.9)
161 (75.2) 53 (24.8) 14 (6.5) 0(0.0)
79 (79.8) 20 (20.2) 4 (4.0) 0 (0.0)
213 (40.4) 314 (59.6) 51 (9.7) 76 (14.4)
68 (31.8) 146 (68.2) 26 (12.1) 35 (16.4)
83 (38.8) 131 (61.2) 21 (9.8) 36 (16.8)
62 (62.6) 37 (37.4) 4 (4.0) 5 (5.1)
191 (36.2) 336 (63.8)
58 (27.1) 156 (72.9)
80 (37.4) 134 (62.6)
53 (53.5) 46 (46.5)
147 (27.9) 380 (72.1) 289 (54.8) 94 (17.8) 34 (6.5)
38 (17.8) 176 (82.2) 131 (61.2) 45 (21.0) 17 (7.9)
61 (28.5) 153 (71.5) 115 (53.7) 38 (17.8) 10 (4.7)
48 (48.5) 51 (51.5) 43 (43.4) 11 (11.1) 7 (7.1)
p-value⁎ 0.278
0.975a 0.937 b0.001
0.674
0.453b 0.076b b0.001
0.071b 0.007b b0.001
b0.001
0.012 0.103 0.373
Abbreviations: ALK, anaplastic lymphoma kinase; aNSCLC, advanced nonsmall cell lung cancer; CCI, Charlson Comorbidity Index; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, Epidermal Growth Factor Receptor; n, patients; PD-1 Ab, programmed cell death 1 antibody; PD-L1 TPS, programmed death ligand 1 tumor proportion score; RT, radiotherapy. Covariates in bold have p values b0.05. ⁎ p-values for Pearson’s Chi-squared test. a p-values for Kruskal-Wallis rank sum test b p-values for Fisher’s exact test.
Calculated simply, median follow-up time was 4.0 months (range 0.03–37.05) or 16.3 months by the reverse Kaplan-Meier method. At last follow-up, 341 (64.7%) of patients had died. The median number of PD-1 Ab doses (p = .63), duration of treatment (p = .68), and proportion of patients still receiving PD-1 Ab (p = .20) did not vary significantly in the age groups. However, individuals ≥75 years were less likely to receive systemic therapy after progression on immune checkpoint inhibition than patients 65–74 years (padj = 0.006) or ≤ 64 years (padj = 0.025). 3.2. Safety By November 2018, 426 patients (80.8%) had discontinued PD-1 Ab of whom 69 (13.1%) permanently discontinued immunotherapy. 110 patients (20.9%) needed treatment interruption (delay or discontinuation) due to irAE. A total of 274 irAE were observed: 210 (76.6%) were grade 1/2, 59 (21.5%) were grade 3/4, and 5 (1.8%) were grade 5. In the entire cohort, 198 patients (37.6%) experienced an irAE, most commonly dermatitis (11.0% of patients), thyroid changes (included hyperthyroidism or hypothyroidism, 10.6%), and colitis (6.6%) (Fig. 1). 59 patients (11.2%) experienced irAE ≥ grade 3 with pneumonitis (2.1%), hepatitis (2.1%), dermatitis (1.9%) being observed most frequently. Utilization of corticosteroids (19.5% of patients) and need for hospitalization (5.3% of patients) due to immune-toxicity was similar amongst age groups. For the 3-month irAE analyses, 95 non-irAE patients with b3 months follow-up were excluded. Of the 432 remaining patients, 121 (28%)
experienced an irAE within 3 months of treatment. There was no significant difference in the distribution of irAE developed within 3 months of PD-1 Ab initiation (any grade or grade ≥ 3) in the age cohorts (Fig. 1). In univariable logistic regression, squamous (vs. non-squamous) histology and treatment with nivolumab (vs. pembrolizumab) are associated with increase odds of irAE (Supplementary Table 1). Results from multivariable logistic regression analysis using stepwise elimination starting with all factors in the univariable analysis are presented in Table 2. Increased odds of developing immune toxicity was observed in patients with an ECOG PS 2/3 (vs. 0/1) at PD-1 Ab initiation (odds ratio, OR = 1.67, 95% CI 1.03–2.68, p = .034), squamous (vs. nonsquamous) histology (OR = 1.70, 95% CI 1.04–2.74, p = .031), and treatment with nivolumab (vs. pembrolizumab) (OR = 1.82, 95% CI 1.15–2.93, p = .012). 3.3. Overall Survival The propensity score–matched cohort comprised 77 patients from each age group; all baseline covariate imbalances were alleviated (Supplementary Table 2). There were 135 patient deaths (58.4%) in the matched cohort and OS did not differ significantly by age (≤64 years: median 15.4 months, 65–74 years: median 12.6 months, and ≥ 75 years: median 9.4 months, log-rank p = .17) (Fig. 2). Univariable analyses of factors associated with OS in matched cohort are shown in Supplementary Table 3. Due to potential collinearity of type of PD-1 Ab with PD-L1 TPS, EGFR/ALK status, and line of treatment, a multivariable stratified Cox proportional hazards model of factors
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
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D. Ksienski et al. / Journal of Geriatric Oncology xxx (2020) xxx
Fig. 1. Incidence of most common irAE (any grade) across age groups for whole cohort (N = 527, white bars) and 3-month cohort (N = 432, solid bars). P values are from Fisher's exact test comparing irAE incidence across age groups in the 3-month cohort. Note: thyroid changes include hyperthyroidism and hypothyroidism. Percentage = number of patients experiencing an irAE/total number of patients in cohort.
associated with OS was fit to the matched cohort using stepwise elimination beginning with all factors considered in univariable analysis (Table 3.) ECOG PS 2/3 at PD-1 Ab initiation (vs. 0/1, HR = 2.60, p b .001) and CCI ≥3 (vs. b3, HR = 1.68, p = .007) were significantly associated with reduced OS. Weaker correlations with OS were observed for smoking status (former vs. current smokers, HR = 1.82, p = .05) and brain metastases at baseline (present vs. none, HR = 0.53, p = .05.) 3.4. Exploratory Analysis of Differences in OS Based on Treatment Interruption at 6 Week Landmark There were 487 patients included in the 6-week landmark analysis (39.6% age ≤ 64 years, 41.9% 65–74 years, 18.5% ≥75 years) from the unmatched cohort; excluded were 40 patients who died within 6 weeks of PD-1 Ab initiation. During this time interval, 26 patients had their treatment interrupted due to irAE.
6 week landmark cohort baseline covariates were similar amongst patients needing treatment interruption versus those receiving PD-1 Ab continuously, with the exception of nivolumab therapy (p = .030) and a history of autoimmune disease (p = .019) being more common in the former. Median PD-1 Ab treatment duration was shorter in patients requiring treatment interruption versus those receiving PD-1 Ab on schedule (1.20 months vs. 4.83 months, p b .001). Individuals ≥75 years (vs. b75) were more likely to have treatment interrupted due to irAE (10% vs 4%, p = .055). The observed OS was lower for patients requiring treatment interruption due to irAE versus continuous therapy (median 6.2 months vs. 11.2 months, log-rank p = .002) (Fig. 3). When analyzed by aged groups, poorer survival outcomes for treatment interruption were observed for patients ≥75 years (median 5.9 months vs. 12.8 months, log-rank p = .007) and 65–74 years (median 4.4 months vs 10.5 months, p = .001) but not those ≤64 year (median 9.5 months vs 10.6 months, p = 1.0). Similar results were seen in the matched cohort.
Table 2 Multivariable logistic stepwise elimination regression of irAE development within 3 months of PD-1 Ab initiation with age at diagnosis forced into model (unmatched cohort). Characteristic
OR
95% CI
p-value
Age at diagnosis 65–74 vs. ≤64 ≥75 vs. ≤64
1.00 1.25
0.61–1.64 0.66–2.35
1.00 0.48
ECOG PS 2/3 vs. 0/1
1.67
1.03–2.68
0.034
Smoking status Former vs. never
0.63
0.40–1.01
0.056
Histology Squamous vs. non-squamous
1.70
1.04–2.74
0.031
PD-1 Ab Nivolumab vs. pembrolizumab
1.82
1.15–2.93
0.012
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; irAE, immune related adverse events; PD-1 Ab, programmed cell death 1 antibody. Covariates in bold have p values b0.05
Fig. 2. Kaplan-Meier curves of OS by age in matched cohort, compared by stratified logrank test.
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
D. Ksienski et al. / Journal of Geriatric Oncology xxx (2020) xxx Table 3 Multivariable stratified Cox stepwise elimination regression of OS forcing age at diagnosis into the model (matched cohort). Characteristic
HR
95% CI
p-value
Age at diagnosis 65–74 vs. ≤64 ≥75 vs. ≤64
0.73 1.12
0.46–1.16 0.73–1.73
0.18 0.60
ECOG PS 2/3 vs. 0/1
2.60
1.78–3.80
b0.001
1.68
1.15–2.44
0.007
1.82 1.19
1.01–3.28 0.58–2.42
0.05 0.63
Brain metastases at baseline Present vs. none
0.53
0.28–1.00
0.05
Development of irAE None vs. any
1.37
0.91–2.08
0.13
CCI ≥3 vs. b3 Smoking status Former vs. current Never vs. current
Abbreviations: CCI, Charlson Comorbidity Index; ECOG PS, Eastern Cooperative Oncology Group performance status; irAE, immune related adverse events. Covariates in bold have p values b0.05
4. Discussion The current multicenter retrospective analysis describes real-world toxicity and observed survival of 527 patients with aNSCLC receiving PD-1 Ab. In the studied population, poor ECOG PS (but not chronological age) was associated with both an increased risk of developing an irAE within 3 months of treatment initiation and poorer survival outcomes. Patient's ≥ 75 years (vs. b75 years) were more likely to have PD-1 Ab therapy delayed or discontinued due to immune toxicity.
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In the current series, we did not observe differences in immunetoxicity between the three age cohorts (≤64, 65–74, and ≥ 75.) Keeping in mind that treatment exposure was similar amongst the age groups, the incidence of irAE (both any grade and high grade) were comparable. Furthermore the proportion of patients needing hospitalization or corticosteroids, both markers of significant immune toxicity, did not vary by age. In the entire cohort, the incidence of any grade irAE (37.6%) occurred, in general, more often than in clinical trials [20–23]. However, the proportion of irAE ≥ grade 3 (11.2%) was in line with that seen registration trials. It is possible that prompt diagnosis and treatment of low grade irAE as per online guidelines, prevented the development of severe immune toxicity [24]. We observed that poor ECOG PS, squamous histology, and receipt of nivolumab (vs. pembrolizumab) were associated with increased risk of any grade irAE within 3 month of PD-1 Ab initiation. Baseline ECOG PS 2/3 (compared to 0/1) was correlated with both a 2.60 fold increased risk of death on Cox proportional hazard regression models and 1.67 fold greater odds of irAE at the 3 month landmark. This highlights the urgent need for prospective clinical trials in poor ECOG PS patients with aNSCLC to clarify the benefit and toxicity of immunotherapy. An association between histologic subtype and development of irAE has previously been observed but the underlying reason is unclear. Suresh et al. noted a higher risk of pneumonitis amongst patients with squamous (vs. adenocarcinoma) subtype aNSCLC receiving PD-(L)1 Ab and hypothesized that histology might be a marker for some other clinical or biologic patient characteristic [25]. It is also possible, that patients with squamous histology (more highly associated with tobacco use) could have developed smoking related complications that were diagnosed and treated as irAE. Higher odds or irAE with nivolumab, as compared to pembrolizumab, likely relates to patients in the former group being seen more often (i.e., every 2 weeks vs. every 3 weeks) and as
Fig. 3. Kaplan-Meier curves of OS for treatment interruption (delay or discontinuation) due to irAE versus continuous drug delivery at the 6 week landmark, compared by log rank test for: (A) entire cohort, (B) patients ≥75 years, (C) patients 65–74 years, and (D) patients≤64 years.
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
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such there is a greater opportunity to diagnose immune toxicity. To our knowledge, there have never been any head-to-head clinical trials of nivolumab compared to pembrolizumab so it is unknown whether their toxicity profiles are different. In a network meta-analysis by Xu et al., there was no difference in odds of experiencing an adverse event between nivolumab and pembrolizumab [26]. It is noteworthy that increasing age was not associated with risk of irAE in the logistic regression analysis; this is consistent with other retrospective studies [27]. Interestingly, active autoimmune disease, thought to be one of the strongest risk factors for immune toxicity (either disease flare or development of irAE) was not significantly associated with immune toxicity in our multivariable logistic regression analysis; albeit only a small number of patients with a history of autoimmune disease had active autoimmune disease. PD-1 Ab discontinuation due to adverse events in registration trials ranges from 3.0%–7.1% [20–23]. In the current series, 20.9% of patients required PD-1 Ab interruption relating to irAE. Due to the small number of discontinuation events from immune-toxicity in each age group (as opposed to the whole cohort), comparisons based on age would likely be underpowered; as such, we describe a composite endpoint of treatment delay and discontinuation. In an exploratory analysis using a 6week landmark, treatment interruption was associated with lower overall survival than continuous drug delivery for the whole cohort. Interestingly when analyzed by age group, we observed poorer survival outcomes with treatment interruption for patients aged 65–74 years and ≥ 75 but not those ≤64. An explanation for this difference in survival based on age in the studied population is unclear. Development of particular irAE has been correlated with both improved outcomes (dermatitis) and worse survival (pneumonitis) in retrospective series [12,28]; it is possible that the types of irAE leading to treatment interruption in younger patients were correlated with favorable survival. Treatment interruption was more common in patient's ≥ 75 years old (vs. b75 years) and this might reflect safety concerns regarding retreatment with PD-1 Ab after development of irAE [29]. Last, chemotherapy on progression could have been prescribed less often in older patients who required treatment discontinuation due to irAE. These findings are hypothesis generating and require validation in large prospective trials. A number of retrospective series have examined safety of nivolumab in older patients with aNSCLC outside of clinical trial; however, very few ‘real-world’ studies on pembrolizumab recipient's ≥ 75 years of age have been published. Lichenstein et al. retrospectively analyzed outcomes for 245 patients treated with PD-(L)1 Ab at a large academic center in the United States of America. The incidence of irAE, corticosteroid use and hospitalization did not vary by age (b60, 60–69, 70–79, and ≥ 80) [30]. Muchnik et al. evaluated the toxicity of 75 patients aged ≥70 years who received PD-1 Ab (86.7% nivolumab) in a multicenter retrospective study. 47% of patients needed treatment interruption due to an irAE and colitis was more commonly observed in patient's ≥ 80 years of age [31]. It is likely that clinicians were more selective in starting PD-1 Ab therapy in older patients and this could explain differences in baseline characteristics between the age cohorts. Patient's ≥ 75 years of age were more likely to have a PDL1 TPS ≥ 50% and receive pembrolizumab. This might reflect a reluctance of clinicians to prescribe frontline platinum-based chemotherapy to older patients (and subsequent nivolumab upon progression). However, PD-L1 TPS is an imperfect biomarker of response to pembrolizumab (response rate in KEYNOTE-024 was 44.8%) [32]. Novel biomarkers being investigated to predict benefit from immunotherapy including tumor mutational burden and specific immune gene signatures [33]. In the present series, patient's ≥ 75 years of age (compared to the younger cohorts) were less likely to have brain metastases at baseline. While traditionally considered a negative prognostic factor, advances in local therapy such as stereotactic brain radiotherapy and treatment with immunotherapy might improve outcomes [34]. Furthermore, on multivariable analysis presence of baseline brain metastases was not significantly correlated with worse OS.
Propensity scores are a statistical technique which can be used to minimize selection bias in observation studies [35]. Within the context of a retrospective study, we did not observe differences in OS between the age cohorts using propensity score matching. On multivariable analysis, ECOG PS 2/3 and CCI score ≥ 3 were negatively associated with survival outcome. PD-L1 TPS was not significantly associated with OS likely due to the number of unknown scores (PD-L1 TPS not required for second line nivolumab.) Poor ECOG PS is a known negative prognostic factor, however it is unknown whether it is also a predictive factor [36,37]. Comorbidity has been correlated with poorer lung cancer survival [38]. Patients with aNSCLC tend to have smoking related diseases such as chronic obstructive pulmonary disease (COPD); corticosteroids and antibiotics, both commonly utilized in COPD exacerbations, have been associated with decreased response to immune checkpoint inhibition [39,40]. Older adults with cancer comprise a heterogeneous population in domains such as cognition, functional status, and nutrition. The American Society of Clinical Oncology and the International Society of Geriatric Oncology recommend a geriatric assessment to aide in decision making for older patients with cancer [41,42]. Few published studies have addressed the utility of geriatric assessment-based tools to predict benefit or safety of immunotherapy. Welaya et al. performed a single-institution retrospective study of 28 patient's ≥ 65 years old with advanced cancer to determine if geriatric assessment domains were associated with efficacy and immune-toxicity [43]. While impairment of instrumental activities of daily living was associated with shorter treatment duration, no geriatric assessment domains studied predicted best response or development of irAE. The present analysis has several limitations. Identification of irAE was based on the opinion of the treating healthcare practitioner and not independently verified. We did not collect data regarding patient reported outcomes. Last, this is a retrospective study and subject to potential selection bias. In conclusion, in the current large multicenter retrospective series poor ECOG PS and squamous histology (but not advanced age) were risk factors for development of irAE. Patient's ≥ 75 years were more likely to have treatment interrupted due to irAE and this was associated with lower overall survival on exploratory analysis. In the studied population, OS was similar amongst age cohorts. Randomized aNSCLC trials involving older patients are urgently required to clarify the risk and benefits of immune checkpoint inhibition. Supplementary data to this article can be found online at https://doi. org/10.1016/j.jgo.2020.01.006. Author Contributions Study concepts, DK ESW MLNC Study design, DK ESW MLNC Data acquisition, All authors Quality control of data and algorithms, SI DK NC Data analysis and interpretation, DK ESW ML NC AC Statistical analysis, DK ESW ML NC AC Manuscript preparation, DK ESW ML NC Manuscript editing, All authors Manuscript review, All authors Declaration of Competing Interest Dr. Doran Ksienski- honoraria for continuing medical education events from Merck Canada and Bristol Myers Squibb Canada. Unrestricted education grant received from AstraZeneca Canada. Dr. Zia Poonja- honoraria for continuing medical education events from Merck Canada, Bristol Myers Squibb Canada, and AstraZeneca Canada. Dr. Angela Chan- Honoria for continuing medical education events from Merck Canada, Bristol Myers Squibb Canada, AstraZeneca Canada,
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
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Genomic Health, Sanofi-Aventis Canada, EMD Serono, Genomic Health, Novartis, Pfizer, Roche, Takeda. Acknowledgements This work was supported by the BC Cancer Foundation. References [1] Surveillance E, and End Results (SEER) program. Cancer stat facts: cancer of any site; 2019 [cited 2019, Aug 10]. Available from https://seer.cancer.gov/statfacts/html/all. html. [2] Sacher AG, Le LW, Leighl NB. Elderly patients with advanced NSCLC in phase III clinical trials: are the elderly excluded from practice-changing trials in advanced NSCLC? J Thorac Oncol 2013;8(3):366–8. https://doi.org/10.1097/JTO. 0b013e31827e2145. [3] Garon EB, Rizvi NA, Hui R. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372(21):2018–28. https://doi.org/10.1056/ NEJMoa1501824. [4] Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44:51–60. https://doi.org/10.1016/j.ctrv.2016.02.001. [5] Sun X, Roudi R, Dai T, Chen S, Fan B, Li H, et al. Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and metaanalysis. BMC Cancer 2019;19:558. https://doi.org/10.1186/s12885-019-5701-6. [6] Chen TW, Razak AR, Bedard PL, Siu LL, Hansen AR. A systematic review of immunerelated adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Onc 2015;26(9):1824–9. https://doi.org/10.1093/annonc/mdv182. [7] U.S. Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0 https://evs.nci.nih.gov/ftp1/CTCAE/ CTCAE_4.03/Archive/ CTCAE_4.0_2009-05-29_Quick Reference_8.5x11.pdf ; 2009 (Accessed date: 20 November 2019). [8] Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 1996;17(4):343–6. https://doi.org/10.1016/0197-2456(96)00075-x. [9] Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res 2011;46:399–424. https://doi.org/10.1080/00273171.2011.568786. [10] Ahmed A, Aban IB, Vaccarino V, et al. A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age. Heart 2007; 93(12):1584–90. https://doi.org/10.1136/hrt.2006.113522. [11] Dafni U. Landmark analysis at the 25-year landmark point. Circ Cardiovasc Qual Outcomes 2011;4:363–71. https://doi.org/10.1161/CIRCOUTCOMES.110.957951. [12] Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of immune-related adverse events with Nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018;4(3):374–8. https://doi.org/10.1001/jamaoncol.2017.2925. [13] Ksienski D, Wai ES, Croteau N, Fiorino L, Brooks E, Poonja Z, et al. Efficacy of nivolumab and pembrolizumab in patients with advanced non-small-cell lung cancer needing treatment interruption because of adverse events: a retrospective multicenter analysis. Clin Lung Cancer 2019;20(1):e97-106. https://doi.org/10.1016/j. cllc.2018.09.005. [14] R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R foundation for statistical computing; 2019. https://www.R-project.org/; Accessed date: 20 November 2019. [15] Therneau TM, Grambsch PM. Modeling survival data: Extending the cox model. New York: Springer; 2000. https://doi.org/10.1007/978-1-4757-3294-8 Accessed date: 20 November 2019. [16] Therneau T. A Package for survival analysis in S. R package version 2.44; 2019 https://CRAN.R-project.org/package=survival. (Accessed date: 20 November 2019). [17] Kassambara A, Kosinski M, Biecek P. Survminer: Drawing survival curves using ‘ggplot2’. R package version 0.4.6; 2019 https://CRAN.R-project.org/package= survminer. (Accessed date: 20 November 2019). [18] Yoshida K. Tableone: Create ‘Table 1’ to describe baseline characteristics. R package version 0.10.0; 2019 https://CRAN.R-project.org/package=tableone. (Accessed date: 20 November 2019). [19] TriMatch Bryer J. Propensity score matching of non-binary treatments. R package version 0.9.9; 2017 https://CRAN.R-project.org/package=TriMatch. (Accessed date: 20 November 2019). [20] Herbst RS, Baas P, Kim D, Felip E, Pérez-gracia JL, Han J, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016;387(10027): 1540–50. https://doi.org/10.1016/S0140-6736(15)01281-7. [21] Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, 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;37(7):537–46. https://doi.org/10.1200/JCO.18. 00149.
7
[22] Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Pddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373(2):123–35. https://doi.org/10.1056/NEJMoa1504627. [23] Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643. [24] BC Cancer. BC Cancer protocol summary ULUAVPMBF. Vancouver. BC. http://www. bccancer.bc.ca/chemotherapy-protocols-site/Documents/Lung/ULUAVPMBF_ Protocol.pdf; 2019. (Accessed date: 18 November 2019). [25] Suresh K, Voong KR, Shankar B, Forde PM, Ettinger DS, Marrone KA, et al. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol 2018;13(12):1930–9. https://doi. org/10.1016/j.jtho.2018.08.2035. [26] Xu C, Chen YP, Du XJ, Liu JQ, Huang CL, Chen L, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 2018;363:k4226. https://doi.org/10.1136/bmj.k4226. [27] Eun Y, InYoung K, Sun J-M, Lee J, Cha H-S, Koh E-M, et al. Risk factors for immunerelated adverse events associated with anti-PD-1 pembrolizumab. Sci Rep 2019;9: 14039. https://doi.org/10.1038/s41598-019-50574-6. [28] Suresh K, Psoter KJ, Voong KR, Shankar B, Forde PM, Ettinger DS, et al. Impact of checkpoint inhibitor pneumonitis on survival of NSCLC patients receiving immune checkpoint immunotherapy. J Thorac Oncol 2019;14(3):494–502. https://doi.org/ 10.1016/j.jtho.2018.11.016. [29] Simonaggio A, Michot JM, Voisin AL, Le Pavec J, Collins M, Lallart A, et al. Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer. JAMA Oncol 2019;5(9):1310–7. https://doi.org/10. 1001/jamaoncol.2019.1022. [30] Lichtenstein MRL, Nipp RD, Muzikansky A, Goodwink K, Anderson D, Newcomb RA, et al. Impact of age on outcomes with immunotherapy in patients with non-small cell lung cancer. J Thorac Oncol 2019;14(3):547–52. https://doi.org/10.1016/j.jtho. 2018.11.011. [31] Muchnik E, Loh KP, Strawderman M, Magnuson A, Mohile SG, Estrah V, et al. Immune checkpoint inhibitors in real-world treatment of older adults with nonsmall cell lung cancer. J Am Geriatr Soc 2019;67(5):905–12. https://doi.org/10. 1111/jgs.15750. [32] Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33. https://doi.org/10.1056/NEJMoa1606774. [33] Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non – small cell lung cancer. Science 2016;348(6230):124–8. https://doi.org/10.1126/science.aaa1348. [34] Hendriks LEL, Henon C, Auclin E, Mezquita L, Ferrara R, Audigier-Valette C, et al. Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J Thorac Oncol 2019;14(7):1244–54. https://doi.org/10.1016/ j.jtho.2019.02.009. [35] Hemmila MR, Birkmeyer NJ, Arbabi S, Osborne NH, Wahl WL, Dimick JB. Introduction to propensity scores: a case study on the comparative effectiveness of laparoscopic vs open appendectomy. Arch Surg 2010;145(10):939–45. https://doi.org/ 10.1001/archsurg.2010.193. [36] Passaro A, Spitaleri G, Gyawali B, De MF. Immunotherapy in non – small-cell lung Cancer patients with performance status 2 : clinical decision making with scant evidence. J Clin Oncol 2019;37:1863–8. https://doi.org/10.1200/JCO.18.02118. [37] Ksienski D, Wai ES, Croteau N, Freeman AT, Chan A, Fiorino L, et al. Lung Cancer Pembrolizumab for advanced nonsmall cell lung cancer : E ffi cacy and safety in everyday clinical practice. Lung Cancer 2019;133:110–6. https://doi.org/10.1016/j. lungcan.2019.05.005. [38] Tammemagi CM, Neslund-Dudas C, Simoff M, Kvale P. Impact of comorbidity on lung cancer survival. Int J Cancer 2003;103(6):792–802. https://doi.org/10.1002/ ijc.10882. [39] Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2019;36. https:// doi.org/10.1200/JCO.2018.79.0006. [40] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Dailière R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–7. https://doi.org/10.1126/science.aan3706. [41] Mohile SG, Dale W, Somerfield MR, Schonberg MA, Boyd CM, Burhenn PS, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol 2018;36(22): 2326–47. https://doi.org/10.1200/JCO.2018.78.8687. [42] Wildiers H, Heeren P, Puts M, Topinkova E, Janssens-Heijnen ML, Extermann M, et al. International society of geriatric oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 2014;32(24):2595–603. https://doi.org/10. 1200/JCO.2013.54.8347. [43] Welaya K, Loh KP, Messing S, Szuba E, Magnuson A, Mohile SG, et al. Geriatric assessment and treatment outcomes in older adults with cancer receiving immune checkpoint inhibitors. J Geriatr Oncol 2019;19:S1879–4068. https://doi.org/10.1016/j.jgo. 2019.05.021.
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Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab Doran Ksienski a,b,⁎, Elaine S. Wai a,b, Nicole S. Croteau c, Ashley T. Freeman a,b, Angela Chan b,d, Leathia Fiorino a,b, Zia Poonja a,b, David Fenton a,b, Tiffany Patterson a, Sarah Irons a, Mary Lesperance c a
BC Cancer- Victoria, British Columbia, Canada University of British Columbia, British Columbia, Canada c University of Victoria, Department of Mathematics and Statistics, British Columbia, Canada d BC Cancer- Surrey, British Columbia, Canada b
a r t i c l e
i n f o
Article history: Received 26 August 2019 Received in revised form 30 December 2019 Accepted 8 January 2020 Available online xxxx Keywords: Pembrolizumab Nivolumab Survival Toxicity Advanced nonsmall cell lung cancer
a b s t r a c t Objectives: To explore the association of age with development of immune related adverse events (irAE) and survival in patients with advanced nonsmall cell lung cancer (aNSCLC) receiving programmed cell death 1 antibodies (PD-1 Ab) outside of clinical trials. Methods: A multicenter retrospective study of PD-1 Ab prescription for patients with aNSCLC between 06/ 2015–11/2018 at BC Cancer. Multivariable (MVA) logistic regression identified baseline variables associated with irAE manifested within 3 months of PD-1 Ab initiation. Overall survival (OS) analyzed in a propensityscore matched cohort and survival outcomes compared between age groups by stratified log-rank. Six-week landmark analysis was performed and OS compared between patients with interrupted versus continuous treatment by log-rank. Results: Of 527 patients, 40.6% were age ≤ 64 years, 40.6% were 65–74 years, and 18.8% were ≥ 75 years. In MVA, ECOG performance status 2/3 (p = .034), squamous histology (p = .031), and nivolumab therapy (vs. pembrolizumab, p = .012) were associated with increased odds of irAE by 3 months of treatment. Across age groups no difference existed in any grade irAE (p = .98), hospitalization (p = 1.0), or corticosteroids use (p = .51). The propensity score–matched survival analysis comprised 77 patients from each age group; all covariates were balanced. OS did not differ significantly by age in the matched cohort (p = .17). Treatment interruption due to irAE at 6 weeks was more common in patient ≥75 years (vs. b75, p = .055) and correlated with lower OS (p = .002). Conclusion: In this cohort of patients with aNSCLC treated in routine clinical practice with PD-1 Ab, immunetoxicity and observed survival were similar amongst age groups. © 2020 Published by Elsevier Ltd.
1. Introduction Advanced nonsmall cell lung cancer (aNSCLC) is an aggressive malignancy with a five year overall survival (OS) of 5.2% [1]. With a median age at diagnosis of 70 years, NSCLC is a disease of older adults [1]. Despite the increasing prevalence of NSCLC with age, patient ≥75 years old are under-represented in clinical trials [2].
Immune checkpoint inhibition has emerged as a powerful element in the treatment of aNSCLC. Programmed cell death 1 (PD-1), a negative costimulatory receptor, is present on the surface of activated T-cells [3]; approximately 68% of NSCLC tumors express PD-1 ligand 1 (PD-L1.) Binding of PD-L1 to PD-1 can result in immunosuppression and tumor growth. PD-1 antibodies (PD-1 Ab) such as nivolumab and pembrolizumab function to disrupt this inhibitory signal and reactivate T cells.
Abbreviations: Ab, antibody; ALK, anaplastic lymphoma kinase; aNSCLC, advanced nonsmall cell lung cancer; CCI, Charlson comorbidity index; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, Epidermal growth factor receptor; irAE, immune related adverse events; n, number of patients; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; RT, radiotherapy; TPS, tumor proportion score. ⁎ Corresponding author at: BC Cancer- Victoria, 2410 Lee Avenue V8R 6V5, Victoria, British Columbia, Canada. E-mail address: [email protected] (D. Ksienski).
https://doi.org/10.1016/j.jgo.2020.01.006 1879-4068/© 2020 Published by Elsevier Ltd.
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006
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Immune checkpoint inhibitors produce a unique spectrum of side effects called immune related adverse events (irAE). Dermatologic, endocrine, gastrointestinal, and pulmonary irAE are most common, although any organ can be involved [4]. Based on meta-analysis from PD-1 Ab trials in aNSCLC, the incidence of any grade irAE is 27% (95% CI, 18%–35%) and high grade irAE is 7% (95% CI, 2%–12%) [5]. Grade 2 or higher irAE typically requires treatment interruption, prolonged corticosteroid use, and occasionally immune modulating agents. Under-representation of older patients contributes to uncertainty regarding the risk-benefit ratio of immunotherapy. Immunosenescence, an age-associated remodelling of the innate and adaptive immune system, could alter efficacy and toxicity of immune checkpoint inhibitors. Furthermore, documentation of irAE in clinical trials has been criticized; Chen et al., performed a systematic review of 50 trials of immune checkpoint inhibition and found complete reporting of irAE onset, management, and reversibility in 14%, 8%, and 6% of studies, respectively [6]. In this multicenter retrospective analysis, we sought to compare the incidence and severity of irAE for younger and older patients with aNSCLC receiving PD-1 Ab outside of clinical trials. As a secondary goal, we aimed to describe survival outcomes of patients with aNSCLC treated with immune checkpoint inhibition based on age. 2. Methods 2.1. Patient Population British Columbia (BC) Cancer is the provincial institution responsible for providing cancer care for the five million residents of British Columbia, Canada. Pembrolizumab is publically funded for patients with aNSCLC who have PD-L1 tumor proportion score (TPS) ≥ 50% and are treatment naïve or have PD-L1 TPS ≥1% and have progressed on palliative-intent platinum doublet chemotherapy. Irrespective of PDL1 status, nivolumab is funded after disease progression on a palliative-intent platinum doublet. 2.2. Data Collection After approval from the University of British Columbia Research Ethics Board, clinical characteristics, treatment details, and survival outcomes were extracted by retrospective chart review. Comorbidity was calculated using the Charlson Comorbidity Index (CCI, aNSCLC not included as a ‘solid metastatic tumor’). 2.3. Study Objectives For the primary objective of reporting irAE incidence and severity, identification of irAE was based on the treating healthcare practitioner's assessment. Collected information included: grade (assigned by the abstractor utilizing the Common Terminology Criteria for Adverse Events, version 4), dose interruption (either temporary or permanent discontinuation), need for corticosteroids or immune modulating agents, and requirement for overnight hospitalization to treat immune toxicity [7]. For the secondary aim, OS was measured from PD-1 Ab initiation until death or censored at last follow-up. 2.4. Statistical Analysis Patients were stratified by age at time of aNSCLC diagnosis (≤64 years, 65–74 years, ≥75 years) and descriptive statistics of study variables were computed, including means, medians, ranges, counts, and proportions. Baseline characteristics were compared between the age groups using Pearson's Chi-squared, Fisher's exact, and KruskalWallis rank sum tests as appropriate. Post-hoc pairwise comparisons of significant baseline factors were performed and Bonferonni p-values are reported to control for multiple testing (Padj). Median follow-up times were computed (i) as the median of all survival times (ignoring
censoring) and (ii) by the reverse Kaplan-Meier method which provides an estimate of the potential follow-up [8]. Due to the time-dependent nature of immune toxicity, we define a 3-month cohort (interval during which most irAE occur) to analyze the distribution of irAE. Univariable and multivariable logistic regression analysis was undertaken to identify baseline variables (age at aNSCLC diagnosis, gender, Eastern Cooperative Oncology Group performance status (ECOG PS) at PD-1 Ab initiation, CCI, smoking status, histology, PD-L1 TPS, molecular aberration, treatment line, PD-1 Ab type, and history of autoimmune disease) associated with irAE within 3 months of PD-1 Ab treatment. Patients with b3 months follow-up who do not experience the outcome are excluded from the analysis. As there were imbalances in baseline covariates amongst age groups, propensity-score matching survival analysis was undertaken [9,10]. The propensity score for the indicator of age group ≥75 years was estimated using two multivariable logistic regression models (one without patients ≤64 years and the other without patients 65–74 years) including covariates gender, stage at first consult, ECOG PS at PD-1 Ab start, CCI, smoking status, histology, molecular aberration, PD-L1 TPS, liver metastases, brain metastases, type of PD-1 Ab, radiotherapy within a year prior to PD-1 Ab, and history of autoimmune disease. Patient's ≥ 75 years were matched to those ≤64 years and 65–74 years, respectively, on a propensity score in a 1:1 ratio by minimizing the total distance between matched triplets. Strata were defined from quintiles of an aggregate propensity score where, for patient's ≥ 75 years, the scores from the two propensity models were averaged. Kaplan-Meier curves for OS in the matched cohort were generated and age cohorts compared using the stratified log-rank test. Univariable and multivariable stratified Cox proportional hazard models were fitted to determine associations between survival outcomes and baseline variables (in addition to development of irAE, entered as a time-dependent covariate). Landmark analysis was used to minimize lead-time bias associated with the time- dependent variable treatment interruption (dose delay or cessation of PD-1 Ab) resulting from irAE [11,12]. We performed an exploratory 6-week landmark analysis (time point chosen based on prior analysis with a smaller cohort) [13]; survival outcomes for patients requiring treatment interruption due to irAE before the landmark versus those who received PD-1 Ab continuously were compared. Patients who died or were censored before the landmark time were excluded from the analysis. Kaplan-Meier curves for OS in the 6-week cohort were generated and age cohorts compared using the log-rank test. All p-values were based on two sided hypotheses tests and those b0.05 were considered statistically significant. Statistical analyses were performed using R version 3.6.1 and R packages ‘survival’ version 2.44, ‘survminer’ version 0.4.6, ‘tableone’ version 0.10.0 and ‘TriMatch’ version 0.9.9 [14–19].
3. Results 3.1. Patients Of the 527 patients with aNSCLC treated with PD-1 Ab, 214 (40.6%) were ≤ 64 years old, 214 (40.6%) were 65–74 years, and 99 (18.8%) were ≥ 75 years. Baseline statistics are provided in Table 1. Compared to patients aged ≤64 and 65–74 year old, individuals in the oldest cohort were significantly more likely to be never/former smokers (padj b 0.001, padj = 0.006), have a PD-L1 TPS ≥ 50% (padj b 0.001, padj b 0.001), receive pembrolizumab (padj b 0.001, padj = 0.029), obtain PD-1 Ab as a first line treatment (padj b 0.001, padj b 0.003), and not have brain metastases at diagnosis of advanced disease (padj = 0.017, padj = 0.011). Delivery of radiotherapy within one year prior to PD-1 Ab initiation was more common amongst patients ≤64 than ≥75 years of age (padj = 0.014). Compared to the age 65–74 years patients, the youngest individuals were significantly less likely to be never/former smokers (padj = 0.047) and receive PD-1 Ab as a first line treatment (padj = 0.034).
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Table 1 Baseline patient characteristics (unmatched cohort).
Characteristic Gender Female Male ECOG PS at PD-1 Ab initiation 0/1 2/3 CCI (median [range]) aNSCLC at presentation Smoking status Current Former Never Histology Non-squamous Squamous EGFR mutation ALK rearrangement PD-L1 TPS ≥50% b50%/unknown Liver metastases (%) Brain metastases (%) PD-1 Ab Pembrolizumab Nivolumab Line of PD-1 Ab 1st ≥2nd RT within 1 year of PD-1 Ab RT during PD-1 Ab Autoimmune disease
Overall
Age ≤ 64
Age 65–74
Age ≥ 75
(n = 527)
(n = 214)
(n = 214)
(n = 99)
n (%)
n (%)
n (%)
n (%)
266 (50.5) 261 (49.5)
114 (53.3) 100 (46.7)
99 (46.3) 115 (53.7)
363 (68.9) 164 (31.1) 2.0 (0.0–12.0) 410 (77.8)
158 (73.8) 56 (26.2) 2.0 (0.0–11.0) 168 (78.5)
136 (63.6) 78 (36.4) 2.5 (0.0–12.0) 166 (77.6)
53 (53.5) 46 (46.5) 0.070 69 (69.7) 30 (30.3) 3.0 (0.0–10.0) 76 (76.8)
169 (32.1) 292 (55.4) 66 (12.5)
90 (42.1) 92 (43.0) 32 (15.0)
65 (30.4) 126 (58.9) 23 (10.7)
14 (14.1) 74 (74.7) 11 (11.1)
404 (76.7) 123 (23.3) 35 (6.6) 4 (0.8)
164 (76.6) 50 (23.4) 17 (7.9) 4 (1.9)
161 (75.2) 53 (24.8) 14 (6.5) 0(0.0)
79 (79.8) 20 (20.2) 4 (4.0) 0 (0.0)
213 (40.4) 314 (59.6) 51 (9.7) 76 (14.4)
68 (31.8) 146 (68.2) 26 (12.1) 35 (16.4)
83 (38.8) 131 (61.2) 21 (9.8) 36 (16.8)
62 (62.6) 37 (37.4) 4 (4.0) 5 (5.1)
191 (36.2) 336 (63.8)
58 (27.1) 156 (72.9)
80 (37.4) 134 (62.6)
53 (53.5) 46 (46.5)
147 (27.9) 380 (72.1) 289 (54.8) 94 (17.8) 34 (6.5)
38 (17.8) 176 (82.2) 131 (61.2) 45 (21.0) 17 (7.9)
61 (28.5) 153 (71.5) 115 (53.7) 38 (17.8) 10 (4.7)
48 (48.5) 51 (51.5) 43 (43.4) 11 (11.1) 7 (7.1)
p-value⁎ 0.278
0.975a 0.937 b0.001
0.674
0.453b 0.076b b0.001
0.071b 0.007b b0.001
b0.001
0.012 0.103 0.373
Abbreviations: ALK, anaplastic lymphoma kinase; aNSCLC, advanced nonsmall cell lung cancer; CCI, Charlson Comorbidity Index; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, Epidermal Growth Factor Receptor; n, patients; PD-1 Ab, programmed cell death 1 antibody; PD-L1 TPS, programmed death ligand 1 tumor proportion score; RT, radiotherapy. Covariates in bold have p values b0.05. ⁎ p-values for Pearson’s Chi-squared test. a p-values for Kruskal-Wallis rank sum test b p-values for Fisher’s exact test.
Calculated simply, median follow-up time was 4.0 months (range 0.03–37.05) or 16.3 months by the reverse Kaplan-Meier method. At last follow-up, 341 (64.7%) of patients had died. The median number of PD-1 Ab doses (p = .63), duration of treatment (p = .68), and proportion of patients still receiving PD-1 Ab (p = .20) did not vary significantly in the age groups. However, individuals ≥75 years were less likely to receive systemic therapy after progression on immune checkpoint inhibition than patients 65–74 years (padj = 0.006) or ≤ 64 years (padj = 0.025). 3.2. Safety By November 2018, 426 patients (80.8%) had discontinued PD-1 Ab of whom 69 (13.1%) permanently discontinued immunotherapy. 110 patients (20.9%) needed treatment interruption (delay or discontinuation) due to irAE. A total of 274 irAE were observed: 210 (76.6%) were grade 1/2, 59 (21.5%) were grade 3/4, and 5 (1.8%) were grade 5. In the entire cohort, 198 patients (37.6%) experienced an irAE, most commonly dermatitis (11.0% of patients), thyroid changes (included hyperthyroidism or hypothyroidism, 10.6%), and colitis (6.6%) (Fig. 1). 59 patients (11.2%) experienced irAE ≥ grade 3 with pneumonitis (2.1%), hepatitis (2.1%), dermatitis (1.9%) being observed most frequently. Utilization of corticosteroids (19.5% of patients) and need for hospitalization (5.3% of patients) due to immune-toxicity was similar amongst age groups. For the 3-month irAE analyses, 95 non-irAE patients with b3 months follow-up were excluded. Of the 432 remaining patients, 121 (28%)
experienced an irAE within 3 months of treatment. There was no significant difference in the distribution of irAE developed within 3 months of PD-1 Ab initiation (any grade or grade ≥ 3) in the age cohorts (Fig. 1). In univariable logistic regression, squamous (vs. non-squamous) histology and treatment with nivolumab (vs. pembrolizumab) are associated with increase odds of irAE (Supplementary Table 1). Results from multivariable logistic regression analysis using stepwise elimination starting with all factors in the univariable analysis are presented in Table 2. Increased odds of developing immune toxicity was observed in patients with an ECOG PS 2/3 (vs. 0/1) at PD-1 Ab initiation (odds ratio, OR = 1.67, 95% CI 1.03–2.68, p = .034), squamous (vs. nonsquamous) histology (OR = 1.70, 95% CI 1.04–2.74, p = .031), and treatment with nivolumab (vs. pembrolizumab) (OR = 1.82, 95% CI 1.15–2.93, p = .012). 3.3. Overall Survival The propensity score–matched cohort comprised 77 patients from each age group; all baseline covariate imbalances were alleviated (Supplementary Table 2). There were 135 patient deaths (58.4%) in the matched cohort and OS did not differ significantly by age (≤64 years: median 15.4 months, 65–74 years: median 12.6 months, and ≥ 75 years: median 9.4 months, log-rank p = .17) (Fig. 2). Univariable analyses of factors associated with OS in matched cohort are shown in Supplementary Table 3. Due to potential collinearity of type of PD-1 Ab with PD-L1 TPS, EGFR/ALK status, and line of treatment, a multivariable stratified Cox proportional hazards model of factors
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D. Ksienski et al. / Journal of Geriatric Oncology xxx (2020) xxx
Fig. 1. Incidence of most common irAE (any grade) across age groups for whole cohort (N = 527, white bars) and 3-month cohort (N = 432, solid bars). P values are from Fisher's exact test comparing irAE incidence across age groups in the 3-month cohort. Note: thyroid changes include hyperthyroidism and hypothyroidism. Percentage = number of patients experiencing an irAE/total number of patients in cohort.
associated with OS was fit to the matched cohort using stepwise elimination beginning with all factors considered in univariable analysis (Table 3.) ECOG PS 2/3 at PD-1 Ab initiation (vs. 0/1, HR = 2.60, p b .001) and CCI ≥3 (vs. b3, HR = 1.68, p = .007) were significantly associated with reduced OS. Weaker correlations with OS were observed for smoking status (former vs. current smokers, HR = 1.82, p = .05) and brain metastases at baseline (present vs. none, HR = 0.53, p = .05.) 3.4. Exploratory Analysis of Differences in OS Based on Treatment Interruption at 6 Week Landmark There were 487 patients included in the 6-week landmark analysis (39.6% age ≤ 64 years, 41.9% 65–74 years, 18.5% ≥75 years) from the unmatched cohort; excluded were 40 patients who died within 6 weeks of PD-1 Ab initiation. During this time interval, 26 patients had their treatment interrupted due to irAE.
6 week landmark cohort baseline covariates were similar amongst patients needing treatment interruption versus those receiving PD-1 Ab continuously, with the exception of nivolumab therapy (p = .030) and a history of autoimmune disease (p = .019) being more common in the former. Median PD-1 Ab treatment duration was shorter in patients requiring treatment interruption versus those receiving PD-1 Ab on schedule (1.20 months vs. 4.83 months, p b .001). Individuals ≥75 years (vs. b75) were more likely to have treatment interrupted due to irAE (10% vs 4%, p = .055). The observed OS was lower for patients requiring treatment interruption due to irAE versus continuous therapy (median 6.2 months vs. 11.2 months, log-rank p = .002) (Fig. 3). When analyzed by aged groups, poorer survival outcomes for treatment interruption were observed for patients ≥75 years (median 5.9 months vs. 12.8 months, log-rank p = .007) and 65–74 years (median 4.4 months vs 10.5 months, p = .001) but not those ≤64 year (median 9.5 months vs 10.6 months, p = 1.0). Similar results were seen in the matched cohort.
Table 2 Multivariable logistic stepwise elimination regression of irAE development within 3 months of PD-1 Ab initiation with age at diagnosis forced into model (unmatched cohort). Characteristic
OR
95% CI
p-value
Age at diagnosis 65–74 vs. ≤64 ≥75 vs. ≤64
1.00 1.25
0.61–1.64 0.66–2.35
1.00 0.48
ECOG PS 2/3 vs. 0/1
1.67
1.03–2.68
0.034
Smoking status Former vs. never
0.63
0.40–1.01
0.056
Histology Squamous vs. non-squamous
1.70
1.04–2.74
0.031
PD-1 Ab Nivolumab vs. pembrolizumab
1.82
1.15–2.93
0.012
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; irAE, immune related adverse events; PD-1 Ab, programmed cell death 1 antibody. Covariates in bold have p values b0.05
Fig. 2. Kaplan-Meier curves of OS by age in matched cohort, compared by stratified logrank test.
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D. Ksienski et al. / Journal of Geriatric Oncology xxx (2020) xxx Table 3 Multivariable stratified Cox stepwise elimination regression of OS forcing age at diagnosis into the model (matched cohort). Characteristic
HR
95% CI
p-value
Age at diagnosis 65–74 vs. ≤64 ≥75 vs. ≤64
0.73 1.12
0.46–1.16 0.73–1.73
0.18 0.60
ECOG PS 2/3 vs. 0/1
2.60
1.78–3.80
b0.001
1.68
1.15–2.44
0.007
1.82 1.19
1.01–3.28 0.58–2.42
0.05 0.63
Brain metastases at baseline Present vs. none
0.53
0.28–1.00
0.05
Development of irAE None vs. any
1.37
0.91–2.08
0.13
CCI ≥3 vs. b3 Smoking status Former vs. current Never vs. current
Abbreviations: CCI, Charlson Comorbidity Index; ECOG PS, Eastern Cooperative Oncology Group performance status; irAE, immune related adverse events. Covariates in bold have p values b0.05
4. Discussion The current multicenter retrospective analysis describes real-world toxicity and observed survival of 527 patients with aNSCLC receiving PD-1 Ab. In the studied population, poor ECOG PS (but not chronological age) was associated with both an increased risk of developing an irAE within 3 months of treatment initiation and poorer survival outcomes. Patient's ≥ 75 years (vs. b75 years) were more likely to have PD-1 Ab therapy delayed or discontinued due to immune toxicity.
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In the current series, we did not observe differences in immunetoxicity between the three age cohorts (≤64, 65–74, and ≥ 75.) Keeping in mind that treatment exposure was similar amongst the age groups, the incidence of irAE (both any grade and high grade) were comparable. Furthermore the proportion of patients needing hospitalization or corticosteroids, both markers of significant immune toxicity, did not vary by age. In the entire cohort, the incidence of any grade irAE (37.6%) occurred, in general, more often than in clinical trials [20–23]. However, the proportion of irAE ≥ grade 3 (11.2%) was in line with that seen registration trials. It is possible that prompt diagnosis and treatment of low grade irAE as per online guidelines, prevented the development of severe immune toxicity [24]. We observed that poor ECOG PS, squamous histology, and receipt of nivolumab (vs. pembrolizumab) were associated with increased risk of any grade irAE within 3 month of PD-1 Ab initiation. Baseline ECOG PS 2/3 (compared to 0/1) was correlated with both a 2.60 fold increased risk of death on Cox proportional hazard regression models and 1.67 fold greater odds of irAE at the 3 month landmark. This highlights the urgent need for prospective clinical trials in poor ECOG PS patients with aNSCLC to clarify the benefit and toxicity of immunotherapy. An association between histologic subtype and development of irAE has previously been observed but the underlying reason is unclear. Suresh et al. noted a higher risk of pneumonitis amongst patients with squamous (vs. adenocarcinoma) subtype aNSCLC receiving PD-(L)1 Ab and hypothesized that histology might be a marker for some other clinical or biologic patient characteristic [25]. It is also possible, that patients with squamous histology (more highly associated with tobacco use) could have developed smoking related complications that were diagnosed and treated as irAE. Higher odds or irAE with nivolumab, as compared to pembrolizumab, likely relates to patients in the former group being seen more often (i.e., every 2 weeks vs. every 3 weeks) and as
Fig. 3. Kaplan-Meier curves of OS for treatment interruption (delay or discontinuation) due to irAE versus continuous drug delivery at the 6 week landmark, compared by log rank test for: (A) entire cohort, (B) patients ≥75 years, (C) patients 65–74 years, and (D) patients≤64 years.
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such there is a greater opportunity to diagnose immune toxicity. To our knowledge, there have never been any head-to-head clinical trials of nivolumab compared to pembrolizumab so it is unknown whether their toxicity profiles are different. In a network meta-analysis by Xu et al., there was no difference in odds of experiencing an adverse event between nivolumab and pembrolizumab [26]. It is noteworthy that increasing age was not associated with risk of irAE in the logistic regression analysis; this is consistent with other retrospective studies [27]. Interestingly, active autoimmune disease, thought to be one of the strongest risk factors for immune toxicity (either disease flare or development of irAE) was not significantly associated with immune toxicity in our multivariable logistic regression analysis; albeit only a small number of patients with a history of autoimmune disease had active autoimmune disease. PD-1 Ab discontinuation due to adverse events in registration trials ranges from 3.0%–7.1% [20–23]. In the current series, 20.9% of patients required PD-1 Ab interruption relating to irAE. Due to the small number of discontinuation events from immune-toxicity in each age group (as opposed to the whole cohort), comparisons based on age would likely be underpowered; as such, we describe a composite endpoint of treatment delay and discontinuation. In an exploratory analysis using a 6week landmark, treatment interruption was associated with lower overall survival than continuous drug delivery for the whole cohort. Interestingly when analyzed by age group, we observed poorer survival outcomes with treatment interruption for patients aged 65–74 years and ≥ 75 but not those ≤64. An explanation for this difference in survival based on age in the studied population is unclear. Development of particular irAE has been correlated with both improved outcomes (dermatitis) and worse survival (pneumonitis) in retrospective series [12,28]; it is possible that the types of irAE leading to treatment interruption in younger patients were correlated with favorable survival. Treatment interruption was more common in patient's ≥ 75 years old (vs. b75 years) and this might reflect safety concerns regarding retreatment with PD-1 Ab after development of irAE [29]. Last, chemotherapy on progression could have been prescribed less often in older patients who required treatment discontinuation due to irAE. These findings are hypothesis generating and require validation in large prospective trials. A number of retrospective series have examined safety of nivolumab in older patients with aNSCLC outside of clinical trial; however, very few ‘real-world’ studies on pembrolizumab recipient's ≥ 75 years of age have been published. Lichenstein et al. retrospectively analyzed outcomes for 245 patients treated with PD-(L)1 Ab at a large academic center in the United States of America. The incidence of irAE, corticosteroid use and hospitalization did not vary by age (b60, 60–69, 70–79, and ≥ 80) [30]. Muchnik et al. evaluated the toxicity of 75 patients aged ≥70 years who received PD-1 Ab (86.7% nivolumab) in a multicenter retrospective study. 47% of patients needed treatment interruption due to an irAE and colitis was more commonly observed in patient's ≥ 80 years of age [31]. It is likely that clinicians were more selective in starting PD-1 Ab therapy in older patients and this could explain differences in baseline characteristics between the age cohorts. Patient's ≥ 75 years of age were more likely to have a PDL1 TPS ≥ 50% and receive pembrolizumab. This might reflect a reluctance of clinicians to prescribe frontline platinum-based chemotherapy to older patients (and subsequent nivolumab upon progression). However, PD-L1 TPS is an imperfect biomarker of response to pembrolizumab (response rate in KEYNOTE-024 was 44.8%) [32]. Novel biomarkers being investigated to predict benefit from immunotherapy including tumor mutational burden and specific immune gene signatures [33]. In the present series, patient's ≥ 75 years of age (compared to the younger cohorts) were less likely to have brain metastases at baseline. While traditionally considered a negative prognostic factor, advances in local therapy such as stereotactic brain radiotherapy and treatment with immunotherapy might improve outcomes [34]. Furthermore, on multivariable analysis presence of baseline brain metastases was not significantly correlated with worse OS.
Propensity scores are a statistical technique which can be used to minimize selection bias in observation studies [35]. Within the context of a retrospective study, we did not observe differences in OS between the age cohorts using propensity score matching. On multivariable analysis, ECOG PS 2/3 and CCI score ≥ 3 were negatively associated with survival outcome. PD-L1 TPS was not significantly associated with OS likely due to the number of unknown scores (PD-L1 TPS not required for second line nivolumab.) Poor ECOG PS is a known negative prognostic factor, however it is unknown whether it is also a predictive factor [36,37]. Comorbidity has been correlated with poorer lung cancer survival [38]. Patients with aNSCLC tend to have smoking related diseases such as chronic obstructive pulmonary disease (COPD); corticosteroids and antibiotics, both commonly utilized in COPD exacerbations, have been associated with decreased response to immune checkpoint inhibition [39,40]. Older adults with cancer comprise a heterogeneous population in domains such as cognition, functional status, and nutrition. The American Society of Clinical Oncology and the International Society of Geriatric Oncology recommend a geriatric assessment to aide in decision making for older patients with cancer [41,42]. Few published studies have addressed the utility of geriatric assessment-based tools to predict benefit or safety of immunotherapy. Welaya et al. performed a single-institution retrospective study of 28 patient's ≥ 65 years old with advanced cancer to determine if geriatric assessment domains were associated with efficacy and immune-toxicity [43]. While impairment of instrumental activities of daily living was associated with shorter treatment duration, no geriatric assessment domains studied predicted best response or development of irAE. The present analysis has several limitations. Identification of irAE was based on the opinion of the treating healthcare practitioner and not independently verified. We did not collect data regarding patient reported outcomes. Last, this is a retrospective study and subject to potential selection bias. In conclusion, in the current large multicenter retrospective series poor ECOG PS and squamous histology (but not advanced age) were risk factors for development of irAE. Patient's ≥ 75 years were more likely to have treatment interrupted due to irAE and this was associated with lower overall survival on exploratory analysis. In the studied population, OS was similar amongst age cohorts. Randomized aNSCLC trials involving older patients are urgently required to clarify the risk and benefits of immune checkpoint inhibition. Supplementary data to this article can be found online at https://doi. org/10.1016/j.jgo.2020.01.006. Author Contributions Study concepts, DK ESW MLNC Study design, DK ESW MLNC Data acquisition, All authors Quality control of data and algorithms, SI DK NC Data analysis and interpretation, DK ESW ML NC AC Statistical analysis, DK ESW ML NC AC Manuscript preparation, DK ESW ML NC Manuscript editing, All authors Manuscript review, All authors Declaration of Competing Interest Dr. Doran Ksienski- honoraria for continuing medical education events from Merck Canada and Bristol Myers Squibb Canada. Unrestricted education grant received from AstraZeneca Canada. Dr. Zia Poonja- honoraria for continuing medical education events from Merck Canada, Bristol Myers Squibb Canada, and AstraZeneca Canada. Dr. Angela Chan- Honoria for continuing medical education events from Merck Canada, Bristol Myers Squibb Canada, AstraZeneca Canada,
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Genomic Health, Sanofi-Aventis Canada, EMD Serono, Genomic Health, Novartis, Pfizer, Roche, Takeda. Acknowledgements This work was supported by the BC Cancer Foundation. References [1] Surveillance E, and End Results (SEER) program. Cancer stat facts: cancer of any site; 2019 [cited 2019, Aug 10]. Available from https://seer.cancer.gov/statfacts/html/all. html. [2] Sacher AG, Le LW, Leighl NB. Elderly patients with advanced NSCLC in phase III clinical trials: are the elderly excluded from practice-changing trials in advanced NSCLC? J Thorac Oncol 2013;8(3):366–8. https://doi.org/10.1097/JTO. 0b013e31827e2145. [3] Garon EB, Rizvi NA, Hui R. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372(21):2018–28. https://doi.org/10.1056/ NEJMoa1501824. [4] Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44:51–60. https://doi.org/10.1016/j.ctrv.2016.02.001. [5] Sun X, Roudi R, Dai T, Chen S, Fan B, Li H, et al. Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and metaanalysis. BMC Cancer 2019;19:558. https://doi.org/10.1186/s12885-019-5701-6. [6] Chen TW, Razak AR, Bedard PL, Siu LL, Hansen AR. A systematic review of immunerelated adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Onc 2015;26(9):1824–9. https://doi.org/10.1093/annonc/mdv182. [7] U.S. Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0 https://evs.nci.nih.gov/ftp1/CTCAE/ CTCAE_4.03/Archive/ CTCAE_4.0_2009-05-29_Quick Reference_8.5x11.pdf ; 2009 (Accessed date: 20 November 2019). [8] Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 1996;17(4):343–6. https://doi.org/10.1016/0197-2456(96)00075-x. [9] Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res 2011;46:399–424. https://doi.org/10.1080/00273171.2011.568786. [10] Ahmed A, Aban IB, Vaccarino V, et al. A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age. Heart 2007; 93(12):1584–90. https://doi.org/10.1136/hrt.2006.113522. [11] Dafni U. Landmark analysis at the 25-year landmark point. Circ Cardiovasc Qual Outcomes 2011;4:363–71. https://doi.org/10.1161/CIRCOUTCOMES.110.957951. [12] Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of immune-related adverse events with Nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018;4(3):374–8. https://doi.org/10.1001/jamaoncol.2017.2925. [13] Ksienski D, Wai ES, Croteau N, Fiorino L, Brooks E, Poonja Z, et al. Efficacy of nivolumab and pembrolizumab in patients with advanced non-small-cell lung cancer needing treatment interruption because of adverse events: a retrospective multicenter analysis. Clin Lung Cancer 2019;20(1):e97-106. https://doi.org/10.1016/j. cllc.2018.09.005. [14] R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R foundation for statistical computing; 2019. https://www.R-project.org/; Accessed date: 20 November 2019. [15] Therneau TM, Grambsch PM. Modeling survival data: Extending the cox model. New York: Springer; 2000. https://doi.org/10.1007/978-1-4757-3294-8 Accessed date: 20 November 2019. [16] Therneau T. A Package for survival analysis in S. R package version 2.44; 2019 https://CRAN.R-project.org/package=survival. (Accessed date: 20 November 2019). [17] Kassambara A, Kosinski M, Biecek P. Survminer: Drawing survival curves using ‘ggplot2’. R package version 0.4.6; 2019 https://CRAN.R-project.org/package= survminer. (Accessed date: 20 November 2019). [18] Yoshida K. Tableone: Create ‘Table 1’ to describe baseline characteristics. R package version 0.10.0; 2019 https://CRAN.R-project.org/package=tableone. (Accessed date: 20 November 2019). [19] TriMatch Bryer J. Propensity score matching of non-binary treatments. R package version 0.9.9; 2017 https://CRAN.R-project.org/package=TriMatch. (Accessed date: 20 November 2019). [20] Herbst RS, Baas P, Kim D, Felip E, Pérez-gracia JL, Han J, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016;387(10027): 1540–50. https://doi.org/10.1016/S0140-6736(15)01281-7. [21] Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, 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;37(7):537–46. https://doi.org/10.1200/JCO.18. 00149.
7
[22] Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Pddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373(2):123–35. https://doi.org/10.1056/NEJMoa1504627. [23] Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643. [24] BC Cancer. BC Cancer protocol summary ULUAVPMBF. Vancouver. BC. http://www. bccancer.bc.ca/chemotherapy-protocols-site/Documents/Lung/ULUAVPMBF_ Protocol.pdf; 2019. (Accessed date: 18 November 2019). [25] Suresh K, Voong KR, Shankar B, Forde PM, Ettinger DS, Marrone KA, et al. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol 2018;13(12):1930–9. https://doi. org/10.1016/j.jtho.2018.08.2035. [26] Xu C, Chen YP, Du XJ, Liu JQ, Huang CL, Chen L, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 2018;363:k4226. https://doi.org/10.1136/bmj.k4226. [27] Eun Y, InYoung K, Sun J-M, Lee J, Cha H-S, Koh E-M, et al. Risk factors for immunerelated adverse events associated with anti-PD-1 pembrolizumab. Sci Rep 2019;9: 14039. https://doi.org/10.1038/s41598-019-50574-6. [28] Suresh K, Psoter KJ, Voong KR, Shankar B, Forde PM, Ettinger DS, et al. Impact of checkpoint inhibitor pneumonitis on survival of NSCLC patients receiving immune checkpoint immunotherapy. J Thorac Oncol 2019;14(3):494–502. https://doi.org/ 10.1016/j.jtho.2018.11.016. [29] Simonaggio A, Michot JM, Voisin AL, Le Pavec J, Collins M, Lallart A, et al. Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer. JAMA Oncol 2019;5(9):1310–7. https://doi.org/10. 1001/jamaoncol.2019.1022. [30] Lichtenstein MRL, Nipp RD, Muzikansky A, Goodwink K, Anderson D, Newcomb RA, et al. Impact of age on outcomes with immunotherapy in patients with non-small cell lung cancer. J Thorac Oncol 2019;14(3):547–52. https://doi.org/10.1016/j.jtho. 2018.11.011. [31] Muchnik E, Loh KP, Strawderman M, Magnuson A, Mohile SG, Estrah V, et al. Immune checkpoint inhibitors in real-world treatment of older adults with nonsmall cell lung cancer. J Am Geriatr Soc 2019;67(5):905–12. https://doi.org/10. 1111/jgs.15750. [32] Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33. https://doi.org/10.1056/NEJMoa1606774. [33] Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non – small cell lung cancer. Science 2016;348(6230):124–8. https://doi.org/10.1126/science.aaa1348. [34] Hendriks LEL, Henon C, Auclin E, Mezquita L, Ferrara R, Audigier-Valette C, et al. Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J Thorac Oncol 2019;14(7):1244–54. https://doi.org/10.1016/ j.jtho.2019.02.009. [35] Hemmila MR, Birkmeyer NJ, Arbabi S, Osborne NH, Wahl WL, Dimick JB. Introduction to propensity scores: a case study on the comparative effectiveness of laparoscopic vs open appendectomy. Arch Surg 2010;145(10):939–45. https://doi.org/ 10.1001/archsurg.2010.193. [36] Passaro A, Spitaleri G, Gyawali B, De MF. Immunotherapy in non – small-cell lung Cancer patients with performance status 2 : clinical decision making with scant evidence. J Clin Oncol 2019;37:1863–8. https://doi.org/10.1200/JCO.18.02118. [37] Ksienski D, Wai ES, Croteau N, Freeman AT, Chan A, Fiorino L, et al. Lung Cancer Pembrolizumab for advanced nonsmall cell lung cancer : E ffi cacy and safety in everyday clinical practice. Lung Cancer 2019;133:110–6. https://doi.org/10.1016/j. lungcan.2019.05.005. [38] Tammemagi CM, Neslund-Dudas C, Simoff M, Kvale P. Impact of comorbidity on lung cancer survival. Int J Cancer 2003;103(6):792–802. https://doi.org/10.1002/ ijc.10882. [39] Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2019;36. https:// doi.org/10.1200/JCO.2018.79.0006. [40] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Dailière R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–7. https://doi.org/10.1126/science.aan3706. [41] Mohile SG, Dale W, Somerfield MR, Schonberg MA, Boyd CM, Burhenn PS, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol 2018;36(22): 2326–47. https://doi.org/10.1200/JCO.2018.78.8687. [42] Wildiers H, Heeren P, Puts M, Topinkova E, Janssens-Heijnen ML, Extermann M, et al. International society of geriatric oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 2014;32(24):2595–603. https://doi.org/10. 1200/JCO.2013.54.8347. [43] Welaya K, Loh KP, Messing S, Szuba E, Magnuson A, Mohile SG, et al. Geriatric assessment and treatment outcomes in older adults with cancer receiving immune checkpoint inhibitors. J Geriatr Oncol 2019;19:S1879–4068. https://doi.org/10.1016/j.jgo. 2019.05.021.
Please cite this article as: D. Ksienski, E.S. Wai, N.S. Croteau, et al., Association of age with differences in immune related adverse events and survival of patients with a..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.01.006