Abstract
Background
Population-level data regarding incidences of immune-related adverse events (irAEs) are lacking. This study evaluated the frequencies of irAEs among patients with non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitors.
Patients and methods
Administrative claims data from a large U.S. commercial insurance database (OptumLabs ® Data Warehouse) were used to retrospectively identify patients with NSCLC between January 1, 2015 to December 31, 2017 who received a PD(L)-1 inhibitor. Cumulative risks for irAEs were estimated at 1, 3, 6, 9, and 12 months after initiation of a PD-(L)1 inhibitor. Additionally, associations between patient characteristics and frequency of irAEs were investigated utilizing multivariate logistic modeling.
Results
The risk of developing any irAE was 52.5% (CI:49.9, 55.2) after 12 months in 3,164 patients with NSCLC who initiated a PD-(L)1 inhibitor (median age: 69.0 years, 1763 males [55.7%], 1401 [44.3%] females). Cumulative risks of irAEs increased over time: pneumonitis was recorded in 2.5% of patients 1 month after initiation of treatment, and increased to 14.3% after 9 months. Risks of hypophysitis and pericarditis were 3.6% and 1.7% at 9 months, respectively. Patients who received PD-(L)1 inhibitors in the first line had lower frequencies of irAEs (HR 0.77, CI: 0.67, 0.87).
Conclusion
Our findings suggest that the frequencies of some irAEs may be higher than the rates reported in the pivotal trials that led to the FDA approvals for PD-(L)1 inhibitors. These real world data refine provider and patient expectations for outcomes in a broader population beyond what is observed in clinical trials.
Keywords: immunotherapy, PD-L1, toxicity, immune-related adverse events, pneumonitis
Micro-Abstract
We sought to evaluate the incidence of immune-related adverse events (irAEs) patients with non-small cell lung cancer who received PD-(L)1 inhibitors. We found that the risks of irAEs increased with time and were higher than reported in the clinical trials that led to approval of these agents. Also, irAEs were less likely when PD-(L)1 inhibitors were used in the frontline than later lines of therapy.
Background:
Immune checkpoint inhibitor therapies provide overall survival benefits in selected patients with advanced non-small cell lung cancer (NSCLC), and have been approved for the treatment of NSCLC in a variety of settings (1–10). Patients treated with programmed death-ligand 1 and programmed cell death protein-1 (PD-L1 and PD-1) inhibitors appear to experience fewer reported grade 3–5 adverse events than patients receiving traditional chemotherapy (1–3, 11, 12); however, immune-related adverse events (irAEs), including pneumonitis, dermatitis, and colitis can be pronounced and contribute to drug discontinuation, as well as morbidity and mortality (13, 14).
Immune-related adverse events secondary to PD-(L)1 inhibitors may have been under-reported in the initial clinical trials that supported their use (15). One review of 50 of the early PD-(L)1 therapy clinical trials found that onset of irAEs were only reported in 14% of studies, with even fewer studies reporting on toxicity management (8%) and reversibility (6%) (15). Due to increased clinical recognition of these events, subsequent clinical trials have reported higher frequencies of irAEs. For instance, while the KEYNOTE-024 trial published in November 2016 reported that 5.8% of patients receiving pembrolizumab experienced pneumonitis, a subsequent KEYNOTE-042 trial presented at ASCO in June 2018 reported pneumonitis among 8.3% of patients (3, 16).
However, it is possible that irAEs continue to be under-reported in clinical trials, perhaps because irAEs may have a delayed onset. One recent single center, retrospective study of 205 patients with NSCLC treated with PD-(L)1 inhibitors reported 19% of patients experienced pneumonitis, with median time to onset of 89 days (17). Additionally, clinical trial participants may not reflect the entire population of patients with NSCLC and irAEs could be more common in these broader populations. Studies with larger populations are much needed to truly understand the nature, frequency and management of all irAEs.
Claims databases afford the opportunity to evaluate the nature and frequencies of adverse events among large populations of patients, and have been utilized in the past to assess toxicities of treatments such as direct oral anticoagulants (18). The aim of this study was to report the frequencies of irAEs among a large population of patients with NSCLC who received PD-(L)1 inhibitors, and to describe particular associations between such adverse events and baseline patient characteristics.
Methods:
Data Source.
Administrative claims data from the OptumLabs® Data Warehouse (OLDW), which includes de-identified claims data for privately insured and Medicare Advantage enrollees in a large, private, U.S. health plan were utilized in this analysis (19, 20). The database contains longitudinal health information on enrollees, representing a diverse mixture of ages, ethnicities and geographical regions across the United States. The health plan provides comprehensive insurance coverage for physician, hospital, and prescription drug services.
There was no patient involvement in this study, and because this study involved analysis of pre-existing, de-identified data, Institutional Review Board approval was not required.
Study Population.
Patients over the age of 18 years with a diagnosis of lung cancer between January 1, 2015 to December 31, 2017 who subsequently received the PD-1 or PD-L1 inhibitors pembrolizumab, nivolumab, or atezolizumab, either as monotherapy or combined with chemotherapy, were considered for inclusion in this study. We were able to define this population as advanced NSCLC even though lung cancer type, stage, and progression data are not available in claims data sources because during the project timeframe insurer coverage (i.e., prior authorization) for these agents required evidence of advanced disease, and NSCLC. ICD-9 and ICD-10 codes were utilized to identify patients with lung cancer (ICD-9 162.3 – 162.9, ICD-10 C34-C34.92). Chemotherapy agents and PD-(L)1 inhibitors were identified by the Healthcare Common Procedure Coding System (HCPCS) (Supplementary Table 1). Diagnosis date was defined as the date of the first medical claim for lung cancer and required that patients have at least 6 months of continuous health plan enrollment pre-diagnosis (to identify incidence cases) and 30 days or more of coverage after diagnosis (to identify regimen). Those initiating treatment for lung cancer were identified based on administration dates and lines of therapy (Figure 1).
Figure 1.
Determination of line of therapy.
Line of therapy.
The timing of PD-(L)1 inhibitors within the sequence of cancer-directed therapies was documented (the “line” of therapy for which PD-(L)1 inhibitor therapy was given). These lines of therapy were identified based on the first date of receipt of any anticancer medication for treatment of NSCLC. A treatment regimen was defined as the combination of administered anticancer medications that were received within the first 30 days of treatment with the first administered anticancer drug (oral antineoplastic agents were not included when identifying regimen). The second line of therapy was identified after a gap of 120 days or more from last infusion date, or if the combination of drugs being received was changed (e.g., from gemcitabine plus cisplatin to nivolumab monotherapy). Subsequent lines of therapy were defined similarly.
Time on PD-(L)1inhibitors.
Time on PD-(L)1 inhibitors was calculated as the length of time from the date patients initiated treatment with PD-(L)1 inhibitors to the date the patient discontinued the PD(L)-1 inhibitors. Patients still on treatment were censored at the end of follow-up. The study treatment discontinuation dates were defined as the last administration of a drug contained within the PD-(L)1 inhibitor regimen. Discontinuation was defined as having a subsequent systemic therapy after the initial PD-(L)1 inhibitor- containing regimen, having a gap of more than 120 days with no systemic therapy following the last administration, or having a date of death while on the PD-(L)1- containing regimen. Patients without a discontinuation event were censored at their last known PD-(L)1 inhibitor usage.
Patient characteristics, including gender, age at diagnosis, age at PD-(L)1 inhibitor initiation, region, race, and type of PD-(L)1 inhibitor therapy were documented.
irAE Outcomes.
Potential immune-related adverse events were identified if patients had a new medical claim diagnosis with a corresponding irAE ICD-9 or ICD-10 code submitted from time of initiation of PD-(L)1 inhibitors to 12 months after the PD-(L)1 inhibitors. Outcome data collection was also concluded if the participant had disenrollment from the health plan or at the end of the study period. Only new diagnoses were considered. Diagnoses that were present both prior to and after the initiation of PD-(L)1 inhibitors were not classified as adverse events. Primary or first secondary diagnoses present on outpatient or inpatient claims were eligible for inclusion.
A list of ICD9/10 codes corresponding to potential irAEs noted in immunotherapy clinical trials, those corresponding to irAEs noted in chemotherapy clinical trials, and those noted in case reports were reviewed [EC] and then re-reviewed by two additional authors [AM, LS] for consideration of inclusion. For the purposes of this work, these potential irAEs are referred to simply as irAEs for the remainder of this manuscript. Patients who had ICD-9 or ICD-10 codes corresponding to claims for the aforementioned variables prior to receiving PD-(L)1 inhibitor therapy were excluded from analysis for that variable. See Supplementary Table 2 for list of adverse events and ICD-9 and ICD-10 codes.
Statistical Analysis.
Baseline demographic characteristics and clinical characteristics of patients were reported using frequencies, means (standard deviations), and medians (interquartile range). Cumulative risks for the development of any irAE were calculated at 1, 3, 6, 9, and 12 months, using the first incident of irAE. Cumulative risks for the development of individual irAEs were estimated at 1, 3, 6, and 9 months, as there were limited data corresponding to risks of individual irAEs 12 months after initiation of PD-(L)1 inhibitors, with the exception of pneumonitis and hypophysitis rates, which were thought to be particularly notable. Cox proportional hazards models were used to estimate the adjusted effect of each covariate on having irAEs. For the irAE analysis, patients were censored if they dis-enrolled from the health plan, discontinued immunotherapy treatment or at the end of study period (2017). SAS software version 9.4 (SAS Institute Inc, Carey, NC) and Stata version 15 (Stata Corp, College Station, Texas) were used for all analyses.
Results:
3,164 patients met all inclusion criteria and included in our study cohort of advanced NSCLC patients who received PD-(L)1 inhibitors. Notably, the median age of patients was 69 years, and patients were most likely to have received nivolumab, the first PD-1 inhibitor approved for NSCLC in the United States, as a part of second-line therapy (Table 1). Patients may have had more than one regimen prior to immunotherapy. For patients who received a PD-(L)1 inhibitor in the second or later line, the regimens utilized prior to PD-(L)1 inhibitors are reported in Table 2. Of note, the majority of patients received a combination of an alkylating agent (which includes platinum agents) and an antimetabolite prior to receiving PD-(L)1 inhibitors (medications included in these classifications are reported in supplemental material).
Table 1.
Characteristics of patients included in study.
| Characteristic | Statistics |
|---|---|
| N | 3,164 |
| Age at PD-(L)1 Initiation | |
| Mean (SD) | 67.7 (10.6) |
| Median (Q1, Q3) | 69.0 (61.0, 75.0) |
| Age categories at PD-(L)1 Initiation | |
| < 49 | 142 (4.5%) |
| 50–64 | 1063 (33.6%) |
| 65–74 | 1063 (33.6%) |
| >/=75 | 896 (28.3%) |
| Age at Diagnosis | |
| Mean (SD) | 66.8 (10.6) |
| Median (Q1, Q3) | 68.0 (60.0, 74.0) |
| Gender | |
| Male | 1763 (55.7%) |
| Female | 1401 (44.3%) |
| Census Region | |
| Midwest | 980 (31.1%) |
| Northeast | 519 (16.5%) |
| South | 1362 (43.2%) |
| West | 303 (9.6%) |
| Race | |
| White | 2117 (66.9%) |
| Black | 357 (11.3%) |
| Hispanic | 163 (5.2%) |
| Asian | 61 (1.9%) |
| Unknown | 466 (14.7%) |
| PD-(L)1 therapy type | |
| Nivolumab | 2145 (67.8%) |
| Pembrolizumab | 905 (28.6%) |
| Atezolizumab | 114 (3.6%) |
| Days from diagnosis to first immunotherapy | |
| Mean (SD) | 366.1(401.6) |
| Median (Q1,Q3) | 236.0 (95.5, 472.5) |
| Time on Treatment | |
| Mean (SD) | 160.58 (160.12) |
| Median (Q1, Q3) | 112 (49, 215) |
| Line number of first immunotherapy | |
| First | 1047 (33.1%) |
| Second | 1623 (51.3%) |
| Third | 404 (12.8%) |
| Fourth or higher | 90 (2.8%) |
Table 2.
Regimens utilized prior to immunotherapy.
| Regimens* | Patients, N (% of total population) |
|---|---|
| Alkylating agents1 and Antimetabolites2 | 794 (25.1%) |
| Alkylating agents | 565 (17.9%) |
| Alkylating agents and Taxanes3 | 351 (11.1%) |
| Alkylating agents and Topoisomerase inhibitors4 | 278 (8.8%) |
Full list of agents and their corresponding codes are listed in the Supplemental Materials
Alkylating agents include carboplatin, cisplatin, oxaliplatin, cyclophosphamide
Antimetabolites include gemcitabine, pemetrexed
Taxanes include docetaxel, paclitaxel
Topoisomerase inhibitors include topotecan, irinotecan
Cumulative risks of developing any irAE increased over time (Figure 2); for instance, while 31.2% experienced an irAE at 3 months, 52.5% experienced an irAE at 12 months. Cumulative risks for individual irAEs also increased over time (Table 3, Figure 2B and 2C). Pneumonitis was only recorded among 2.5% of patients at 1 month, but increased to 17.4% at 12 months after PD-(L)1 initiation. Notable irAEs at 9 months include type I diabetes mellitus seen in 1.5% of patients, and pericarditis seen in 1.7% of patients.
Figure 2.
(A) Cumulative occurrence of irAEs over time. (B) Cumulative occurrence of hypophysitis. (C) Cumulative occurrence of pneumonitis.
Table 3.
Cumulative Rates of Individual irAEs.
| Month 1 % (95% CI) | Month 3 % (95% CI) | Month 6 % (95% CI) | Month 9 % (95% CI) | |
|---|---|---|---|---|
| Hematologic | ||||
| Anemia | 1.79% (1.38, 2.32) | 4.41% (3.73, 5.21) | 7.79% (6.78, 8.94) | 9.93% (8.62, 11.42) |
| Thrombocytopenia | 0.51% (0.31, 0.83) | 0.96% (0.66, 1.37) | 1.63% (1.20, 2.23) | 1.91% (1.40, 2.62) |
| Leukopenia | 0.41% (0.24, 0.71) | 1.02% (0.71, 1.45) | 1.76% (1.31, 2.36) | 2.48% (1.84, 3.35) |
| Pulmonary | ||||
| Pneumonitis | 2.49% (2.00, 3.10) | 5.90% (5.11, 6.81) | 10.55% (9.38, 11.85) | 14.26% (12.67, 16.02) |
| Endocrine | ||||
| Hypothyroidism | 0.80 (0.54, 1.18) | 2.61% (2.09, 3.25) | 6.79% (5.79, 7.95) | 10.16% (8.68, 11.87) |
| Hyperthyroidism | 0.10% (0.03, 0.30) | 1.01% (0.70, 1.45) | 1.48% (1.08, 2.04) | 1.91% (1.37, 2.65) |
| Hypophysitis/PGA | 0.57% (0.36, 0.91) | 1.55% (1.16, 2.06) | 2.86% (2.25, 3.63) | 3.56% (2.79, 4.52) |
| Hypo/Hyperparathyroid | 0.00% | 0.07% (0.02, 0.27) | 0.07% (0.02, 0.27) | 0.07% (0.02, 0.27) |
| Diabetes Type I | 0.16% (0.07, 0.38) | 0.44% (0.26, 0.76) | 1.08% (0.72, 1.63) | 1.49% (1.00, 2.23) |
| Dysfunctional Uterine Bleeding/Infertility | 0.06% (0.02, 0.26) | 0.16% (0.07, 0.39) | 0.25% (0.12, 0.52) | 0.25% (0.12, 0.52) |
| Renal | ||||
| AKI | 1.09% (0.78, 1.52) | 3.07% (2.51, 3.76) | 5.24% (4.41, 6.23) | 7.33% (6.18, 8.69) |
| Neurologic | ||||
| Neuritis | 0.54% (0.34, 0.87) | 1.27% (0.93, 1.75) | 2.04% (1.55, 2.69) | 2.46% (1.85, 3.28) |
| Meningitis | 0.00% | 0.16% (0.07, 0.39) | 0.21% (0.09, 0.48) | 0.49% (0.23, 1.01) |
| Encephalitis/Myelitis/Encephalomyelitis | 0.13% (0.05, 0.34) | 0.47% (0.28, 0.79) | 0.94% (0.62, 1.44) | 1.12% (0.74, 1.71) |
| Hepatic | ||||
| Hepatitis | 0.58% (0.36, 0.91) | 1.45% (1.08, 1.95) | 3.05% (2.41, 3.87) | 3.73% (2.93, 4.75) |
| Gastrointestional | ||||
| Colitis | 0.26% (0.13, 0.51) | 1.30% (0.95, 1.79) | 2.49% (1.93, 3.22) | 3.24% (2.51, 4.17) |
| Pancreatitis | 0.06% (0.02, 0.25) | 0.24% (0.11, 0.51) | 0.45% (0.26, 0.80) | 0.53% (0.30, 0.94) |
| Mucositis | 0.00% | 0.07% (0.02, 0.27) | 0.39% (0.20, 0.76) | 0.51% (0.26, 1.01) |
| Cardiac | ||||
| Arrhythmia | 1.47% (1.10, 1.95) | 3.22% (2.65, 3.92) | 5.98% (5.10, 7.02) | 9.07% (7.73, 10.61) |
| Acute MI | 0.51% (0.31, 0.83) | 0.99% (0.70, 1.42) | 2.07% (1.56, 2.76) | 2.85% (2.15, 3.78) |
| Myocarditis | 0.16% (0.07, 0.38) | 0.37% (0.21, 0.67) | 0.60% (0.36, 1.02) | 0.89% (0.53, 1.49) |
| Pericarditis | 0.19% (0.09, 0.42) | 0.67% (0.44, 1.04) | 1.56% (1.11, 2.19) | 1.65% (1.18, 2.31) |
| Cardiomyopathy | 0.22% (0.11, 0.47) | 0.33% (0.18, 0.62) | 0.85% (0.53, 1.37) | 1.02% (0.65, 1.61) |
| Skin | ||||
| Vitiligo | 0.06% (0.02, 0.26) | 0.13% (0.05, 0.36) | 0.13% (0.05, 0.36) | 0.22% (0.08, 0.57) |
While there were no associations between frequencies of irAEs and age, gender, or region, hispanics appeared to have higher frequencies of irAEs when compared with patients of other racial and ethnic backgrounds with a hazard ratio of 1.30 (CI: 1.03, 1.65), whereas patients who received a PD-(L)1 inhibitor in the first line had lower frequencies of irAEs with an hazard ratio of 0.77 (CI: 0.67, 0.87) (Table 4).
Table 4.
Associations between baseline variables and irAEs.
| Parameter | P-value | Hazard Ratio | 95% Hazard Ratio Confidence Limits | |
|---|---|---|---|---|
| Year | 0.58 | 1.02 | 0.94 | 1.11 |
| Sex, Male vs. Female | 0.42 | 1.05 | 0.94 | 1.17 |
| Age group, year (ref=18–49) | ||||
| 50–64 | 0.18 | 1.23 | 0.91 | 1.65 |
| 65–74 | 0.11 | 1.28 | 0.95 | 1.72 |
| 75+ | 0.14 | 1.26 | 0.93 | 1.70 |
| Line of Treatment (ref=1st) | ||||
| 2nd + | <.0001 | 0.77 | 0.67 | 0.87 |
| Census Region (ref=Midwest) | ||||
| Northeast | 0.21 | 1.11 | 0.94 | 1.32 |
| South | 0.57 | 1.04 | 0.91 | 1.18 |
| West | 0.57 | 1.06 | 0.86 | 1.31 |
| Race (ref=White) | ||||
| Asian | 0.60 | 1.11 | 0.75 | 1.64 |
| Black | 0.16 | 1.13 | 0.95 | 1.35 |
| Hispanic | 0.03 | 1.30 | 1.03 | 1.65 |
| Unknown | 0.29 | 1.09 | 0.93 | 1.29 |
| I/O (ref=Atezolizumab) Nivolumab Pembrolizumab | ||||
| Nivolumab | 0.14 | 1.28 | 0.92 | 1.78 |
| Pembrolizumab | 0.42 | 1.15 | 0.82 | 1.63 |
Discussion:
Many of the frequencies of potential irAEs coded among this large cohort of patients are higher than those originally described in clinical trials, particularly those that occurred many months after initiation of a PD-(L)1 inhibitor. For instance, while pneumonitis was a recorded diagnosis among approximately 6% of patients when measured at 3 months after PD-(L)1 inhibitor initiation, this rate increased to over 17% when measured one year after initiation. This finding is concordant with results of a recent retrospective review, which showed that the development of irAEs may occur months after the last dose of a PD-(L)1 inhibitor (17). Our analyses suggest that irAEs are less frequent among patients receiving PD-(L)1 inhibitors as a first line therapy, which is contrary to a recent meta-analysis of nineteen clinical trials, which suggested that treatment-naïve patients were more likely to experience pneumonitis (21).
Claims-based studies, including the current analysis, are inherently retrospective in nature, limiting conclusions regarding causality between therapy and events. While insurance claims can be used to identify lung cancer, they lack information on histology and stage, and so we exploited the fact that the insurance coverage of PD-(L)1 inhibitors required the patient have advanced NSCLC. Furthermore, ICD-9 and ICD-10 codes are imperfect surrogates for adverse events. In an attempt to utilize specific codes, some adverse events may have been missed; likewise, general codes, such as those for acute kidney injury, may lead to an over-estimation of the frequency of events. These codes also do not include severity or attribution. Claims data are only able to capture the codes that physicians import into the medical record, and so diagnoses that are not reported are also missed. In this study, hypothyroidism was noted at a lower frequency noted in clinical trials, potentially reflective of reduced reporting of side effects with low morbidity that are easily treated. Supplementing our findings with data on prescriptions for levothyroxine or steroids, or hospitalization records, may be particularly helpful for future analyses and would help to distinguish small abnormalities from life-threatening events. Another limitation to our study is that practice patterns with immunotherapy changed significantly during our analysis and immunotherapy is primarily used in the frontline as a single agent or in combination with chemotherapy. Lastly, identification of regimens did not include oral antineoplastic agents or drugs that were provided to patients enrolled in clinical trials.
Despite limitations, claims data complement clinical trial data, allowing for a broader view of adverse events from cancer-directed therapies. Due to the large populations of patients in claims-based datasets, such studies may be particularly helpful in reporting upon the likelihood of low-frequency, yet highly morbid and/or mortal side effects of therapy, such as hypophysitis or myocarditis, which are unlikely to be represented in trials involving smaller populations of patients. Events such as hypophysitis are unlikely to be sporadic, or a result of other cancer-directed therapies, and so frequencies reported in this study are especially meaningful. Additionally, methods are being developed to assess survival outcomes from large datasets and may further complement our findings (22). In summary, our data help refine provider and patient expectations for outcomes in a broader population beyond what has been reported in clinical trials.
Supplementary Material
Clinical Points.
PD-(L)1 inhibitors are commonly used in the front or second-line management of non-small cell lung cancer. Population-level data regarding incidences of immune-related adverse events (irAEs) are lacking. We found that the frequencies of some irAEs may be higher than the rates reported in the pivotal trials that led to the FDA approvals for PD-(L)1 inhibitors. These real world data refine provider and patient expectations for outcomes in a broader population beyond what is observed in clinical trials.
Acknowledgements:
This work was supported by the National Institutes of Health [K12 CA 90628 and P30CA015083 to ASM]
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Disclosure:
ASM reports honoraria to his institution from advisory boards or other activities with Abbvie, Astra-Zeneca, BMS and Genentech, as well as institutional grants from BMS, Novartis and Verily. ASM is a non-remunerated director of the Mesothelioma Applied Research Foundation.
This study was reported as an oral presentation by Dr. Cathcart-Rake at the American Society of Clinical Oncology Palliative and Supportive Care in Oncology Symposium
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