https://orcid.org/0000-0002-3088-7453
Abstract
Aim: Real-world adverse event (AE) data are limited for first-line (1L) treatments in advanced non-small-cell lung cancer (NSCLC). Methods: Using Flatiron Health Spotlight data, information for a pre-specified list of AEs was abstracted and described among patients with advanced NSCLC receiving 1L nivolumab + ipilimumab (NIVO + IPI), NIVO + IPI + chemotherapy and other approved immuno-oncology (IO) therapy + chemotherapy combination therapies. Results: Fatigue, pain, dyspnea, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash were the most common AEs. Rates of AEs were generally numerically similar across the three cohorts. The majority of patients received treatment for AEs and approximately one fourth of the patients had hospitalization due to their AEs. Conclusion: The real-world safety experiences of patients treated with 1L NIVO + IPI-based regimens were in general similar to those treated with other approved IO + chemotherapy combination therapies.
Plain language summary
Immuno-oncology (IO) therapies boost the immune system to fight cancer cells and have been approved to treat non-small-cell lung cancer (NSCLC). The IO combination of nivolumab + ipilimumab (NIVO + IPI) is approved to treat NSCLC that has spread to other parts of the body or come back and at least 1% of the tumor cells express a protein called PD-L1; NIVO + IPI is also approved in combination with a short course chemotherapy, independent of tumor PD-L1 expression. While NIVO + IPI-based regimens are generally safe, some patients experienced side effects during the clinical trial. However, there is limited information on the side effects of these treatments in a real-world setting. This study analyzed data on side effects from a de-identified database of patients with advanced NSCLC who were treated with NIVO + IPI, NIVO + IPI + chemotherapy, or other approved IO + chemotherapy combinations based on information obtained from physicians’ notes in clinical practice settings. The most common side effects among patients in all groups were tiredness, pain, shortness of breath, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash. The rates at which the side effects occurred were numerically similar regardless of the specific treatment that patients received. Approximately one-quarter of patients in each treatment group were hospitalized because of a side effect. These results show that in a real-world setting, NIVO + IPI-based regimens have similar safety to other IO + chemotherapy combinations when used as a first treatment for NSCLC that has spread or come back.
The introduction of immuno-oncology (IO) agents has expanded the available treatment options for advanced or metastatic non-small-cell lung cancer (NSCLC) [Citation1]. These therapies have different antitumor mechanisms, including targeting immune checkpoint pathway components such as PD-1 inhibitors (nivolumab [Citation2], pembrolizumab [Citation3] and cemiplimab [Citation4]), PD-L1 inhibitors (atezolizumab [Citation5] and durvalumab [Citation6]), CTLA-4 blockers (ipilimumab [Citation7] and tremelimumab [Citation8]), as well as suppressing tumor angiogenesis (bevacizumab [Citation9]). Clinical trials have established the efficacy and safety of these IO therapies compared with chemotherapy [Citation10,Citation11].
In May 2020, the combination of nivolumab + ipilimumab (NIVO + IPI) was approved for the first-line (1L) treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) without EGFR or ALK genomic tumor aberrations and the combination of NIVO + IPI with 2 cycles of platinum-doublet chemotherapy was approved for the 1L treatment of adult patients with metastatic NSCLC with no EGFR or ALK genomic tumor aberrations regardless of tumor PD-L1 expression [Citation12–14]. The approvals were based on results from the CheckMate 227 [Citation15–17] and CheckMate 9LA [Citation18–20] trials, which showed superior overall survival with NIVO + IPI (+2 cycles of platinum doublet chemotherapy in CheckMate 9LA) versus chemotherapy alone. With their complementary mechanisms of action, PD-1/CTLA-four inhibitor combinations have the potential for synergistic antitumor activity [Citation21,Citation22]. While the NIVO + IPI regimens (with or without chemotherapy) had manageable safety profiles in these pivotal trials, adverse events (AEs) including fatigue, diarrhea, rash, pruritus, nausea and musculoskeletal pain were reported. As toxicities with IO combination therapies may differ from those observed with IO monotherapy [Citation23] or have additive effects [Citation24], AEs related to NIVO + IPI (with or without chemotherapy) as well as other approved IO + chemotherapy combination therapies warrant examination.
The effectiveness of some IO therapies as 1L treatment for advanced NSCLC has been described in real-world patient populations [Citation25–27], but safety data are limited as collecting comprehensive safety data in the real-world setting has always presented a significant challenge. To address this gap, AE information was curated from physician notes in the Flatiron Health Database for patients with advanced NSCLC who received 1L IO combination therapies categorized by three regimens: NIVO + IPI (Cohort 1), NIVO + IPI + chemotherapy (Cohort 2) and other approved IO + chemotherapy combination therapies (Cohort 3). This study aims to describe the real-world safety experiences of patients with advanced NSCLC when being treated with these regimens, offering insights to enhance patient care.
Methods
Data source & study design
This retrospective, observational study analyzed data from the Flatiron Health database (the October 2021 data cut), which contains structured data derived from electronic health records and unstructured data abstracted from physicians’ notes and other documents. The database includes various information such as demographics, diagnoses, disease stage and histologic subtype, laboratory results, visits and treatments. To extract safety outcomes for the study population, the Deep Spotlight model [Citation28] was utilized. As the data were de-identified, institutional review board approval was not required for this study.
Study population
Patients were eligible for inclusion if they were recorded in the advanced NSCLC Core Registry (i.e., Stage IIIB, IIIC, IVA, IVB NSCLC, or non-metastatic NSCLC that subsequently developed recurrent or progressive disease) on or after 1 January 2011 and received one of the following 1L therapies before 30 April 2021 (i.e., 6 months before the data cut-off date): NIVO + IPI (Cohort 1); NIVO + IPI + chemotherapy (Cohort 2); or other approved IO (excluding Nivo) + chemotherapy combinations (Cohort 3). Patients were excluded if they: lacked relevant unstructured data in the Flatiron Health database for review by the abstraction team; had unknown histology, a positive EGFR or ALK mutation test result at any time before the start of 1L therapy, or a gap greater than 90 days between advanced NSCLC diagnosis and the first structured activity after the diagnosis. In the end, all eligible patients from Cohort 1 and Cohort 2, and a randomly selected sample of patients from Cohort 3 were included for the abstraction of safety data.
Outcomes
Data on the following AEs that occurred during 1L therapy were abstracted: fatigue, pain, dyspnea, weight loss, decreased appetite, nausea/vomiting, cough, diarrhea, constipation, rash, peripheral edema, dizziness, pruritus, headache, insomnia, lung infection, peripheral neuropathy, hemoptysis, urinary tract infection, hypothyroidism, colitis, pneumonitis, syncope, pulmonary embolism, atrial fibrillation, hyperthyroidism and febrile neutropenia.
Although information on AE grades was not available, the available data on the incidents related to the AEs, including strategies used for their management, were described. Therapy discontinuation was defined as discontinuation (without restarting) of any component of the reference 1L regimen resulting from the AE. Therapy dose or schedule change was defined as modification of the dose or treatment schedule, respectively, of any component of the reference regimen resulting from the AE. Therapy hold was defined as interruption or delay of the reference regimen due to the AE. Hospitalization was defined as inpatient admission as a result of the AE. Treatment for the AE was defined as any treatment (including non-pharmacologic) that was recommended, prescribed, or administered by the clinician to treat the AE. Death resulting from the AE was also abstracted.
Analysis
Baseline patient demographics and clinical characteristics during the 6 months before and 1 month after the index date were summarized for each cohort using mean ± standard deviation (SD), median, interquartile range (IQR) for continuous variables or number (percentage) for categorical variables. The rates of AEs that occurred during 1L therapy were described for each cohort as number and proportion of patients with AEs. The exposure-adjusted AE rates were reported in cases per patient month, which were calculated as the number of patients who experienced AEs divided by the total treatment exposure time (in months). The total treatment exposure time was defined as the duration from the initiation of 1L therapy to either the initial occurrence of the AE for patients who experienced it, or the end of 1L therapy for those who did not experience the AE. Additionally, the impact of AEs was assessed for each cohort as number and percentage of patients who experienced AE-related incidents.
Results
The study population consisted of 262 patients, with 137 patients in Cohort 1 (NIVO + IPI), 46 patients in Cohort 2 (NIVO + IPI + chemotherapy), and 79 patients in Cohort 3 (other IO + chemotherapy combination therapy). The 137 patients in Cohort 1 and the 46 patients in Cohort 2 represent the entirety of the eligible patients treated with NIVO + IPI without and with chemotherapy within the Flatiron database at the time of the study. The 79 patients in Cohort 3 were randomly selected from all eligible patients receiving other approved IO + chemotherapy combination therapies as their 1L therapy.
NIVO + IPI (cohort 1)
Among the 137 patients who were treated with NIVO + IPI (Cohort 1), the median (IQR) age was 72.0 (64.0 to 80.0) years old, with 46.7% of them being female (). The majority of patients were White (72.3%), followed by Black (2.9%) and Asian (2.2%). The remaining patients belonged to other racial categories (13.1%) or were classified as unknown (9.5%). Most patients were initially diagnosed at stage IV (59.1%), exhibited an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (67.9%), and had non-squamous NSCLC (63.5%). In addition, 29.2% of patients had tumor PD-L1 expression levels of less than 1%, 38.7% of patients had tumor PD-L1 expression levels between 1 to 49%, 17.5% of patients had tumor PD-L1 expression levels of 50% or higher, and 14.6% of patients’ tumor PD-L1 expression levels were unknown. The most common comorbidities included chronic obstructive pulmonary disease (COPD; 67.2%), diabetes without organ damage (20.4%), congestive heart failure (17.5%), peripheral vascular disease (14.6%) and moderate severe renal disease (14.6%).
Table 1. Patient characteristics.
The median (IQR) treatment duration for NIVO + IPI was 3.7 (1.3 to 8.5) months. AEs occurred during this period are presented in . The most common AEs in this cohort were fatigue (67.9%), pain (66.4%), dyspnea (47.4%), weight loss (43.8%), decreased appetite (40.1%), diarrhea (38.7%), nausea/vomiting (35.8%), cough (35.0%), constipation (32.1%) and rash (29.9%). In addition, 17.5% of patients experienced lung infections during the treatment of NIVO + IPI. The treatment exposure-adjusted AE rates are presented in Supplementary Table 1.
Table 2. Adverse event rates.
A majority of patients (81.0%) received treatment to manage AEs that occurred during NIVO + IPI treatment (). In addition, 26.3% of patients experienced AEs that led to hospitalization, 24.8% required therapy hold due to AE, 4.4% experienced therapy dose or schedule changes, and 9.5% had to discontinue the treatment. The proportion of patients who received treatment for AEs that affected more than 10% of the overall population are presented in .
Table 3. Incidents related to adverse events.
Table 4. Treatment for adverse events among those affected more than 10% of the overall population.
NIVO + IPI + chemotherapy (cohort 2)
Among the 46 patients who received treatment with NIVO + IPI + chemotherapy (Cohort 2), the median (IQR) age was 70.0 (64.3 to 74.8) years old, with 39.1% being female (). The majority of these patients were White (60.9%), followed by Black (10.9%), with the remaining patients belonging to other racial categories (19.6%) or being classified as unknown (8.7%). In addition, the majority of patients were in stage IV at initial diagnosis (76.1%), exhibited an ECOG performance status of 0 or 1 (71.7%) and had non-squamous NSCLC (71.7%). In addition, 37.0% of patients had tumor PD-L1 expression levels of less than 1%, 30.4% of patients had tumor PD-L1 expression levels between 1 to 49%, 17.4% of patients had tumor PD-L1 expression levels of 50% or higher, and 15.2% of patients had unknown tumor PD-L1 expression levels. The most prevalent comorbidities included COPD (63.0%), diabetes without organ damage (21.7%), peripheral vascular disease (15.2%), congestive heart failure (10.9%) and moderate severe renal disease (8.7%). The detailed breakdown of the types of chemotherapies administered in the 1L are presented in . The most common chemotherapy combination given alongside NIVO + IPI was carboplatin and pemetrexed (50.0%), followed by carboplatin and paclitaxel (34.8%).
Table 5. First-line therapies received by patients.
The median (IQR) treatment duration of NIVO + IPI + chemotherapy was 4.1 (1.8 to 7.4) months. AEs occurred during this period are presented in . The most common AEs in this cohort were fatigue (63.0%), pain (63.0%), nausea/vomiting (58.7%), decreased appetite (54.3%), diarrhea (45.7%), dyspnea (43.5%), weight loss (41.3%), rash (41.3%), cough (32.6%) and constipation (32.6%). Additionally, 13.0% of patients experienced lung infections during the treatment of NIVO + IPI + chemotherapy. The treatment exposure-adjusted AE rates are presented in Supplementary Table 1.
The majority of patients (87.0%) received treatment to manage AEs that occurred during the treatment of NIVO + IPI + chemotherapy (). Furthermore, 26.1% of patients experienced AEs that necessitated hospitalization, 34.8% required a hold on therapy due to AE, 4.3% experienced therapy dose or schedule change, and 13.0% had to discontinue the treatment. The proportion of patients who received treatment for AEs that affected more than 10% of the overall population are presented in .
Other approved IO + chemotherapy combination therapies (cohort 3)
Among the 79 patients who underwent treatment with other approved IO + chemotherapy combination therapies (Cohort 3), the median (IQR) age was 69.0 (63.5 to 74.0) years old, with 45.6% being female (). The majority of patients were White (72.2%), followed by Black (7.6%), Asian (2.5%), with the remaining patients belonged to other race categories (8.9%) or unknown (8.9%). In addition, the majority of these patients were initially diagnosed at stage IV (70.9%), exhibited an ECOG performance status of 0 or 1 (67.1%), and had non-squamous NSCLC (72.2%). Furthermore, 35.4% of patients had tumor PD-L1 expression levels of less than 1%, 29.1% of patients had tumor PD-L1 expression levels between 1 to 49%, 13.9% of patients had tumor PD-L1 expression levels of greater than 50%, and 21.5% of patients had unknown tumor PD-L1 expression levels. The most prevalent comorbidities were COPD (60.8%), diabetes without organ damage (16.5%), peripheral vascular disease (16.5%), moderate severe renal disease (11.4%) and cerebrovascular disease (10.1%). A detailed breakdown of the types of regimens administered in the first line (1L) is provided in . The majority of patients (98.7%) received pembrolizumab as the IO therapy, and most patients (67.1%) received a combination of pembrolizumab, carboplatin and pemetrexed.
The median (IQR) treatment duration of other approved IO + chemotherapy was 3.0 (2.8 to 4.3) months. AEs occurred during this period are presented in . The most common AEs in this cohort were fatigue (77.2%), pain (60.8%), nausea/vomiting (51.9%), decreased appetite (45.6%), constipation (45.6%) weight loss (44.3%), dyspnea (43.0%), cough (43.0%), diarrhea (36.7%), rash (29.1%) and peripheral edema (29.1%; tied). In addition, 15.2% of patients experienced lung infections during the treatment of other IO + chemotherapy combination therapies. The treatment exposure-adjusted AE rates are presented in Supplementary Table 1.
Almost all the patients (96.2%) received treatment to manage AEs that occurred during the course of other IO + chemotherapy combination therapies (). In addition, 25.3% of patients experienced AEs that led to hospitalization, 30.4% required therapy hold due to AE, 12.7% experienced therapy dose or schedule change and 16.5% discontinued the treatment. The proportion of patients who received treatment for AEs that affected more than 10% of the overall population are presented in .
Discussion
This study described the real-world AE profiles of 1L IO combination therapy in patients with advanced NSCLC in the USA. While some small variations in patients’ safety experiences were observed, the rates of AEs were generally numerically similar across different IO combination regimens. In addition, a majority of patients in each cohort received treatment for AEs, and approximately one-quarter of patients required hospitalization due to AEs. Overall, the safety experiences of patients with advanced NSCLC treated with NIVO + IPI-based combination therapies appear similar to those treated with other IO + chemotherapy combination regimens.
The most common AEs across the three cohorts included fatigue, pain, dyspnea, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash. Among these, fatigue and pain affected over 60% of patients in all three cohorts, consistent with previous studies that have reported these AEs as commonly associated with cancer treatment [Citation29]. The rates of nausea/vomiting were numerically lower in Cohort 1 (NIVO + IPI; 35.8%) than in Cohort 2 (NIVO + IPI + chemotherapy; 58.7%) and Cohort 3 (other IO + chemotherapy; 51.9%). This difference is likely due to the fact that nausea and vomiting, along with other AEs such as weight or appetite loss and peripheral neuropathy, are frequently linked to chemotherapy [Citation30,Citation31].
The majority of patients in all cohorts received treatment for AEs. This indicated a high level of AE management across the cohorts. The impact of AEs on therapy hold and therapy discontinuation were relatively consistent across the cohorts. However, therapy dose or schedule changes were numerically less frequently observed in Cohort 1 (NIVO + IPI; 4.4%) and Cohort 2 (NIVO + IPI + chemotherapy; 4.3%), compared with Cohort 3 (other IO + chemotherapy; 12.7%). These differences suggest that NIVO + IPI-based regimens may be associated with a lower need for modifying the treatment dose or schedule due to AEs. This could be partially attributed to the lower number of chemotherapy cycles planned in these regimens.
The rates of hospitalization related to AEs were consistent across the cohorts (25.3–26.3%). This suggests that the occurrence of serious AEs requiring hospitalization was not influenced by the specific treatment regimens. It is worth noting that hospitalization has been identified as the key cost driver in the management of grade 3/4 AEs among patients with advanced NSCLC [Citation32]. Therefore, these findings indicate that treatment with NIVO + IPI-based regimens may result in similar clinical and economic burdens related to AEs when compared with other IO + chemotherapy combination therapies.
The most frequent AEs identified in our study closely align with those reported in pivotal trials, including symptoms such as nausea, vomiting, fatigue, constipation, diarrhea, decreased appetite, rash, cough and dyspnea. However, the present study observed numerically higher rates for most of the AEs compared with those reported in clinical trials [Citation16,Citation18,Citation33–36]. This disparity may be attributed to the greater frailty of the real-world population. For example, the median age of our study population (NIVO + IPI: 72.0 years old; NIVO + IPI + chemotherapy: 70.0; other IO + chemotherapy: 69.0) was higher than the median age of patients enrolled in clinical trials (ranging from 63.0 to 65.0 years old). Moreover, patients recruited in clinical trials exhibited an ECOG performance status of 0 or 1, while a considerable proportion of patients in our study had an ECOG performance status of 2+ (NIVO + IPI: 18.2%; NIVO + IPI + chemotherapy: 17.4%; other IO + chemotherapy: 12.7%) or unknown status (NIVO + IPI: 13.9%; NIVO + IPI + chemotherapy: 10.9%; other IO + chemotherapy: 20.3%). Despite the elevated AE rates in our real-world study relative to clinical trials, the relative rates among the three cohorts remain consistent with prior research utilizing clinical trial data. For example, in an indirect treatment comparison (ITC) of 1L NIVO + IPI + 2 cycles of chemotherapy versus pembrolizumab + chemotherapy in metastatic NSCLC, no differences in the rate of any-grade AEs between treatment arms were observed, whereas rates of nausea and colitis as well as hematologic AEs (anemia, neutropenia and thrombocytopenia) were lower with NIVO + IPI + chemotherapy [Citation37]. Another ITC of clinical trials of NIVO + IPI versus other relevant comparator regimens as 1L therapy in patients with metastatic NSCLC showed no significant differences in the risks of grade ≥3 AEs (odds ratio [OR]: 0.71, 95% CI: 0.45, 1.11) or the risks of an AE resulting in treatment discontinuation (OR: 0.58, 95% CI: 0.30, 1.11) between NIVO + IPI and pembrolizumab + chemotherapy [Citation38]. Additionally, a systematic review and network meta-analysis found that NIVO + IPI, with or without chemotherapy, was similar to other IO + chemotherapy combination therapies with respect to grade 3/4 AEs [Citation39].
Limitations
Our study had several limitations that should be acknowledged. Firstly, in the present study, the evaluation of AEs was limited to those occurring during 1L therapy. However, as previous research has shown that that the majority of AEs tend to manifest in the early phase of the treatment course [Citation17], the occurrence of AEs beyond discontinuation of 1L therapy was anticipated to be relatively low. Secondly, grades of AE were not available in the data. Nevertheless, certain AE-related incidents, such as AE-related hospitalization can serve as a proxy to infer the severity of AEs. Thirdly, the sample sizes for the three cohorts were limited. Although this sample represented all of the patients within the Flatiron data treated with nivolumab + ipilimumab and nivolumab + ipilimumab + chemotherapy at the time of the study, Cohort 3 only included a random sample of all eligible patients who received 1L other IO + chemotherapy combination therapies. Future studies with larger sample sizes are needed to further confirm findings from the present study. Nevertheless, results from the present study offer a unique understanding of real-world patient experiences, filling a crucial gap in the field where data scarcity prevails. Fourthly, due to the relatively small sample sizes, this study mainly focused descriptive analyses across the three cohorts without adjusting for heterogeneities or conducting statistical comparisons. Therefore, caution should be exercised when attempting to compare safety data across these cohorts. It is worth noting that patients in Cohort 1 (NIVO + IPI) were frailer, as evidenced by their older age and higher proportions of severe comorbidities, such as COPD and congestive heart failure. Lastly, our study was constrained by the fact that it only captured the incidence of a pre-specified list of AEs from the Flatiron Spotlight data. There may exist other clinically relevant AEs that were not considered in our analysis. Notably, AEs like anemia and asthenia, which affected more than 15% of the study population in pivotal trials [Citation16,Citation18,Citation33,Citation34], were not included in our current study. In addition, hepatitis, a condition with potentially life-threatening consequences, was not captured in the current study.
Conclusion
In this study population, we found that the real-world safety experiences of patients with advanced NSCLC treated with 1L NIVO + IPI-based regimens were numerically similar to those treated with other approved IO + chemotherapy combination therapies.
Several immuno-oncology (IO) regimens have been approved as 1L treatments for advanced non-small-cell lung cancer (NSCLC). However, there are limited real-world safety data available for these regimens.
This study utilized curated Flatiron Health data (October 2021 data cut), to describe the adverse events (AEs) experienced by patients with advanced NSCLC while being treated with first-line (1L) Nivolumab + Ipilimumab (NIVO + IPI) (Cohort 1), NIVO + IPI + chemotherapy (Cohort 2), or other IO + chemotherapy combination therapies (Cohort 3).
Fatigue, pain, dyspnea, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash were the most common among patients who received 1L NIVO + IPI, NIVO + IPI + chemotherapy and other approved IO + chemotherapy combinations.
The proportions of patients experiencing AE-related therapy hold and therapy discontinuation were similar among patients received different 1L therapies, while 1L NIVO + IPI and NIVO + IPI + chemotherapy were less likely to require therapy dose or schedule change.
Results from the present study indicate that the real-world safety experiences of patients treated with 1L NIVO + IPI-based regimens are numerically similar to those treated with other approved IO + chemotherapy combination therapies.
Author contributions
All named authors meet the International Committee of Medical Journal Editor criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Financial disclosure
This study was funded by Bristol Myers Squibb. The funder participated in study design, data acquisition and interpretation, and review and approval of the manuscript. KA Betts and S Gao are employees of Analysis Group, Inc., which received consulting fees from Bristol Myers Squibb to conduct this study. S Ray is an employee of and may hold stock or stock options in Bristol Myers Squibb. A Schoenfeld works as a consulting/advising role to J&J, KSQ therapeutics, BMS, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Prelude Therapeutics, Immunocore, Lyell Immunopharma, Amgen and Heat Biologics. Research funding: GSK (Inst), PACT pharma (Inst), Iovance Biotherapeutics (Inst), Achilles therapeutics (Inst), Merck (Inst), BMS (Inst), Harpoon Therapeutics (Inst) and Amgen (Inst). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Conflict of interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
Medical writing assistance was provided by Janice Imai, an employee of Analysis Group, Inc., which provided paid consulting services to Bristol Myers Squibb for the development and conduct of this study and manuscript.
Ethical conduct of research
The Flatiron Health database was used in the present study. As the data were de-identified, institutional review board approval was not required for this study.
Data sharing statement
The datasets generated and/or analyzed in the current study are not publicly available per the terms of the data use agreement between the study investigators and data vendor.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Supplementary document
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To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/fon-2023-0612
References
- Luo W , WangZ , ZhangTet al. Immunotherapy in non-small-cell lung cancer: rationale, recent advances and future perspectives. Precis Clin. Med.4(4), 258–270 (2021).
- OPDIVO (nivolumab) Prescribing Information . Bristol-Myers Squibb Company, NJ, USA (2023). (Accessed 5April2023). https://packageinserts.bms.com/pi/pi_opdivo.pdf
- KEYTRUDA (pembrolizumab) Prescribing Information . Merck Sharp & Dohme LLC, NJ, USA (2023). (Accessed 5April2023). www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
- LIBTAYO (cemiplimab) Prescribing Information . Regeneron Pharmaceuticals, NY, USA (2023). (Accessed 30May2023). www.regeneron.com/downloads/libtayo_fpi.pdf
- TECENTRIQ (atezolizumab) Prescribing Information . Genentech, CA, USA (2023). (Accessed 30May2023). www.gene.com/download/pdf/tecentriq_prescribing.pdf
- IMFINZI (durvalumab) Prescribing Information . AstraZeneca, DE, USA (2022). (Accessed 30May2023). https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/9496217c-08b3-432b-ab4f-538d795820bd/9496217c-08b3-432b-ab4f-538d795820bd_viewable_rendition__v.pdf
- YERVOY (ipilimumab) Prescribing Information . Bristol-Myers Squibb Company, NJ, USA (2023). (Accessed 5April2023). https://packageinserts.bms.com/pi/pi_yervoy.pdf
- IMJUDO (tremelimumab) Prescribing Information . AstraZeneca, DE, USA (2022). (Accessed 30May2023). https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/0102c6fd-de8a-4b43-afa3-2a2c2115d472/0102c6fd-de8a-4b43-afa3-2a2c2115d472_viewable_rendition__v.pdf
- AVASTIN (bevacizumab) Prescribing Information . Genentech, CA,USA (2023). (Accessed 5April2023). www.gene.com/download/pdf/avastin_prescribing.pdf
- Lu Y , ZhangX , NingJ , ZhangM. Immune checkpoint inhibitors as first-line therapy for non-small-cell lung cancer: a systematic evaluation and meta-analysis. Hum. Vaccin Immunother.19(1), 2169531 (2023).
- Siciliano MA , CaridàG , CilibertoDet al. Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer: a systematic review and meta-analysis. ESMO Open7(3), 100465 (2022).
- United States Food and Drug Administration . FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%) (2023). (Accessed 6April2023). www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
- United States Food and Drug Administration . FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC (2023). (Accessed 6April2023). www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc
- Vellanki PJ , MulkeyF , JaigirdarAAet al. FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic non-small-cell Lung Cancer, A Collaborative Project Orbis Review. Clin. Cancer Res.27(13), 3522–3527 (2021).
- Brahmer JR , LeeJS , CiuleanuTEet al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J. Clin. Oncol.41(6), 1200–1212 (2023).
- Hellmann MD , Paz-AresL , BernabeCaro Ret al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N. Engl. J. Med.381(21), 2020–2031 (2019).
- Paz-Ares LG , RamalingamSS , CiuleanuTEet al. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J. Thorac. Oncol.17(2), 289–308 (2022).
- Paz-Ares L , CiuleanuTE , CoboMet al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol.22(2), 198–211 (2021).
- Paz-Ares LG , CiuleanuT-E , CoboMet al. First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations. Journal of Thoracic Oncology18(2), 204–222 (2023).
- Reck M , CiuleanuTE , CoboMet al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: checkMate 9LA 2-year update. ESMO Open6(5), 100273 (2021).
- Reck M , BorghaeiH , O’byrneKJ. Nivolumab plus ipilimumab in non-small-cell lung cancer. Future Oncol.15(19), 2287–2302 (2019).
- Wei SC , AnangNaS , SharmaRet al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc. Natl Acad. Sci. USA116(45), 22699–22709 (2019).
- Park R , LopesL , CristanchoCR , RianoIM , SaeedA. Treatment-related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis. Frontiers in Oncology10, 258 (2020).
- Melero I , BermanDM , AznarMA , KormanAJ , PérezGracia JL , HaanenJ. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer15(8), 457–472 (2015).
- Liu SV , RaiP , WangD , HuX , SchwarzenbergerPO. First-Line Pembrolizumab Plus Chemotherapy for Advanced Squamous NSCLC: Real-World Outcomes at U.S. Oncology Practices. JTO Clin. Res. Rep.4(2), 100444 (2023).
- Velcheti V , HuX , YangL , PietanzaMC , BurkeT. Long-Term Real-World Outcomes of First-Line Pembrolizumab Monotherapy for Metastatic non-small-cell Lung Cancer With ≥50% Expression of Programmed Cell Death-Ligand 1. Front Oncol.12, 834761 (2022).
- Waterhouse D , LamJ , BettsKAet al. Real-world outcomes of immunotherapy-based regimens in first-line advanced non-small-cell lung cancer. Lung Cancer156, 41–49 (2021).
- Nguyen-Duc T , MulliganN , MannuGS , Bettencourt-SilvaJH. Deep EHR Spotlight: a Framework and Mechanism to Highlight Events in Electronic Health Records for Explainable Predictions. AMIA Jt Summits Transl. Sci. Proc.2021, 475–484 (2021).
- National Institutes of Health – National Cancer Institute . Side Effects of Cancer Treatment. (Accessed7 April 2023). www.cancer.gov/about-cancer/treatment/side-effects
- American Cancer Society . Chemotherapy for non-small-cell Lung Cancer (2020). (Accessed 7April2023). www.cancer.org/cancer/lung-cancer/treating-non-small-cell/chemotherapy.html
- Nurgali K , JagoeRT , AbaloR. Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae?Front Pharmacol.9, 245 (2018).
- Banz K , BischoffH , BrunnerMet al. Comparison of treatment costs of grade 3/4 adverse events associated with erlotinib or pemetrexed maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) in Germany, France, Italy, and Spain. Lung Cancer74(3), 529–534 (2011).
- Gandhi L , Rodríguez-AbreuD , GadgeelSet al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med.378(22), 2078–2092 (2018).
- Paz-Ares L , LuftA , VicenteDet al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N. Engl. J. Med.379(21), 2040–2051 (2018).
- West H , MccleodM , HusseinMet al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. The Lancet Oncology20(7), 924–937 (2019).
- Socinski MA , JotteRM , CappuzzoFet al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med.378(24), 2288–2301 (2018).
- Jiang P , MaoZ , WangQet al. An Indirect Comparison Between Nivolumab + Ipilimumab + Two Cycles of Chemotherapy vs. Pembrolizumab + Chemotherapy as First-Line Treatment for Metastatic non-small-cell Lung Cancer. Front Oncol.11, 698199 (2021).
- O’byrne K , PopoffE , BadinFet al. Long-term comparative efficacy and safety of nivolumab plus ipilimumab relative to other first-line therapies for advanced non-small-cell lung cancer: a systematic literature review and network meta-analysis. Lung Cancer177, 11–20 (2023).
- Pang LL , GanJD , HuangYHet al. Role of antiangiogenic agents in first-line treatment for advanced NSCLC in the era of immunotherapy. BMC Cancer23(1), 72 (2023).