Background
Lung cancer is the leading cause of cancer-related mortality in the United States, but survival has improved over the last decade, largely driven by increased screening, identification of actionable driver alterations, use of targeted therapies, and the paradigm-shifting incorporation of immunotherapy. Because more than half of patients with advanced non–small cell lung cancer (NSCLC) do not harbor a targetable alteration, they are treated instead with standard first-line therapy consisting of immunotherapy with or without chemotherapy.1–11
Despite the advances from immunotherapy clinical trials, questions remain on whether various socioeconomic and demographic characteristics influence clinical outcomes. Immunotherapy trials typically include patients that tend to be younger and healthier and have a more homogenous racial/ethnicity composition compared with clinical practice. Most patients with advanced NSCLC enrolled in these immunotherapy trials were White or Asian, with Black and Hispanic patients composing only 1% to 10% of trial participants, even though they represent 13% to 20% of the US general population.10–14
The phase III PACIFIC trial found that White patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy had improved survival compared with the White patients in the placebo arm10; however, because only 2.5% of the patients who received durvalumab were Black, no analysis was able to determine whether there was also a survival advantage in Black patients. Similarly, the phase III IMpower132 trial, consisting of patients with advanced NSCLC who received first-line atezolizumab with chemotherapy or chemotherapy alone, demonstrated improved progression-free survival (PFS) among the White and Asian patients in the immunotherapy arm; however, only 0.7% of the patients were Black, and thus no further analysis was possible for that racial group.11 Therefore, generalizability of trial data in clinical practice can pose a problem in the real-world clinical setting, and it is unknown whether other racial and ethnic groups would benefit from immunotherapy in these trials or previous immunotherapy trials.
Studies prior to the immunotherapy era examined the impact of race/ethnicity on patients with NSCLC and found that non-Hispanic Black (NHB) patients with NSCLC had worse survival outcomes compared with non-Hispanic White (NHW) patients.15,16 Interestingly, Hispanic patients have been shown to have improved survival outcomes with significant prognostic factors, including female sex and treatment type (chemotherapy, surgery, radiotherapy), but an increased risk of mortality if they are unmarried, are active or former smokers, and have comorbidities.17,18
Even after immunotherapy was approved for patients with NSCLC, disparities among different racial groups persisted, with Black patients less likely to receive immunotherapy than White patients.19 Previous studies examining race/ethnicity in patients with NSCLC treated with immunotherapy have shown mixed results regarding whether there is an association with clinical outcomes.20–25 Nonetheless, of these limited studies, none addressed other demographic or socioeconomic factors, such as insurance or income, that may also play a role in immunotherapy clinical outcomes and enrollment onto trials.
The Montefiore Einstein Comprehensive Cancer Center (MECCC) is uniquely situated to address these questions because it serves a diverse ethnic minority patient population. This real-world study provides updated information on the use of immunotherapy in the first-line setting in patients with advanced NSCLC, examining multiple clinical and sociodemographic factors that can play a role in treatment efficacy among these patients in order to help identify and predict those who may benefit and address any potential barriers.
Methods
Patients and Clinical Information
We used a retrospective cohort study of 5,920 patients diagnosed with lung cancer based on ICD-10 site codes C34.0 to C34.9 from January 1, 2013, to June 1, 2022, at MECCC. Electronic medical records (EMRs) were reviewed to identify patients who met the inclusion criteria: confirmed metastatic NSCLC, at least 2 clinical visits completed, age ≥18 years, receipt of at least 1 cycle of first-line immunotherapy and at least a follow-up of 2 weeks after the last dose of immunotherapy, and no known driver alterations in EGFR, ALK, or ROS1. This study was approved by the Institutional Review Board at Albert Einstein College of Medicine.
The clinical and demographic information was extracted from the EMRs, with self-reported race and ethnicity combined into NHB, Hispanic, and NHW groups. Other demographic variables collected were age at start of treatment, self-reported biological sex, histology based on pathology reports and registry ICD-10 coding, smoking status (former/active or never smoker), body mass index (BMI) at the start of immunotherapy, and insurance (commercial, Medicare, Medicaid, or a combination of Medicare and Medicaid). Annual household income was determined by the zip code of the patient’s address listed in the EMR, US Census Bureau data from the American Community Survey’s 2021 estimates in USD amounts, and census-based geographic data.26 The clinical status was determined by clinicians based on the patient’s ECOG performance status (PS) at the start of immunotherapy. PD-L1 expression was evaluated using immunohistochemistry staining with the Dako 22C3 antibody.
Endpoints
The primary clinical endpoint was overall survival (OS), defined as the time from first date of immunotherapy administration to the date of death or last recorded visit. Secondary outcomes included PFS and time to treatment discontinuation (TTD). PFS was defined as the time from first date of immunotherapy adminstration to the date of documented progression by imaging based on RECIST v1.1. Patients with no real-world progression were censored at their last known visit or start of a new therapy. TTD was determined from the first date of immunotherapy administration to the last date that immunotherapy was administered and discontinued. Treatment-related adverse events (TRAEs) were graded based on CTCAE v5.0.
Statistical Analysis
Demographic and clinical characteristics and TTD were compared between race/ethnicity groups using the Wilcoxon rank-sum or Kruskal-Wallis test for continuous variables, and the chi-square or Fisher exact test for categorical variables. PFS and OS were first compared using Kaplan-Meier survival curves along with the log-rank tests. A full comprehensive multivariate analysis with a Cox proportional hazards model was used to examine OS and PFS differences between NHW, NHB, and Hispanic patients while adjusting for clinically relevant covariates of age, sex, smoking status, histology, ECOG PS at start of immunotherapy, PD-L1 score, immunotherapy given with or without chemotherapy, and presence of brain metastasis. A proportional hazards assumption was tested using Schoenfeld residuals. In addition, reduced models were conducted for OS and PFS on significant covariates from the full models along with age, PD-L1 score, and ECOG PS among the different race/ethnicity groups. Log-transformed TTD was analyzed using a linear regression model to examine the ratios in TTD among the 3 race/ethnicity groups. All statistical analyses were conducted via SAS 9.4 (SAS Institute Inc.), and the significance level was set at P<.05 using 2-sided tests.
Results
Clinical and Socioeconomic Characteristics
Among the 248 patients with metastatic NSCLC treated with first-line immunotherapy who met the inclusion criteria (Figure 1), the median age at the start of treatment was 66 years (range, 37–91 years) (Table 1). More than half the patients were male (58.5%), and a vast majority were former or active smokers (91.9%). There was diverse mix of patients, with 39.1% self-reporting as NHB, 30.2% as Hispanic, and 30.7% as NHW. The most common NSCLC histology was adenocarcinoma (81.1%) followed by squamous cell carcinoma (18.9%). Brain metastases at the start of immunotherapy were noted in 27% of the patients, with 64.9% of patients having ECOG PS <2 at the start of immunotherapy. Most patients were positive for PD-L1 expression, with 71.8% of patients having a PD-L1 tumor proportion score (TPS) ≥1% and 39.9% having a TPS ≥50%. Age, smoking status, biological sex, histology, BMI, ECOG PS, brain metastases, immunotherapy regimens, and PD-L1 TPS were similar by racial and ethnic group (Table 1). Most patients (94.5%) were treated with a pembrolizumab-based regimen, with more than half the immunotherapy regimens combined with chemotherapy (56.1%) and the remainder being immuno-monotherapy (43.9%). In our cohort, the median duration of immunotherapy received by patients was 4.8 months. Further analysis that examined the duration of immunotherapy in mutually exclusive groups revealed that 12.1% of the study’s cohort completed only 1 cycle of immunotherapy, 10.9% were treated for 6 months, 8.9% were treated for 1 year, and 11.3% were treated for ≥2 years. Notably, there was no significant difference in the duration of immunotherapy treatment among the different racial/ethnic groups (P=.85) (Table 1).
CONSORT diagram of inclusion criteria and cohort selection.
Abbreviations: MECCC, Montefiore Einstein Comprehensive Cancer Center; NSCLC, non–small cell lung cancer.
Citation: Journal of the National Comprehensive Cancer Network 21, 12; 10.6004/jnccn.2023.7064
Patient Demographics and Clinical Factors
There were significant differences in socioeconomic characteristics among the different race/ethnicity groups by insurance (P=.02), median household income (P<.0001), and income groupings (P<.0001). Overall, 20.2% of patients had commercial insurance, 48.4% had Medicare, 23.8% had Medicaid, 6.8% had a combination of dual Medicare/Medicaid, and only 0.8% had no insurance reported. Within the race/ethnicity groups, the largest difference was between NHW and Hispanic patients, with Hispanic patients having the highest reported Medicaid enrollment (33.4%); the NHW patients had the highest commercial insurance enrollment (27.6%). Moreover, there was an income gap between NHW patients who had a median annual household income of $60,802 (range, $28,831–$193,085), with most (80.2%) earning ≥$50,000, compared with Hispanic patients, who had a median household income of $37,777 (range, $23,337–$74,889) with most (68.0%) earning <$50,000.
Clinical Outcomes
At a median follow-up of 12.0 months (range, 0.5–66.2 months), the primary OS (26.3 vs 23.5 vs 16.8 months; P=.39), PFS (8.7 vs 6.7 vs 7.6 months; P=.29), and TTD (4.5 vs 4.9 vs 4.9 months; P=.98) were similar between NHB, Hispanic, and NHW patients, respectively (supplemental eTable 1, available with this article at JNCCN.org). Kaplan-Meier estimates for OS revealed similar results by race/ethnicity (P=.39) (Figure 2A) and PFS (P=.29) (Figure 2B). Age, biological sex, smoking status, BMI, insurance, household income, histology, PD-L1 score, immunotherapy regimen, and presence of brain metastasis were not associated with OS. In terms of PFS, patients with a lower BMI of ≤24.9 kg/m2 had shorter median PFS compared with those with a BMI of ≥25 kg/m2 (P=.01). Patients with Medicare insurance had longer PFS compared with those who had commercial or Medicaid insurance (P=.008). Those with a higher PD-L1 TPS of either ≥1% or ≥50% had a longer PFS (P=.01 and P=.03, respectively). Regarding TTD, similar trends were noted for BMI: those with a lower BMI of ≤24.9 kg/m2 had a significantly shorter TTD compared with those who had a BMI of ≥25 kg/m2 (P=.02). Conversely, ECOG PS ≥2 was associated with worse OS, PFS, and TTD compared with ECOG PS <2 (P<.0001).
(A) OS and (B) PFS rates of patients with metastatic non–small cell lung cancer receiving first-line immunotherapy by race/ethnicity.
Abbreviations: NHB, non-Hispanic Black; NHW, non-Hispanic White; OS, overall survival; PFS, progression-free survival.
Citation: Journal of the National Comprehensive Cancer Network 21, 12; 10.6004/jnccn.2023.7064
After accounting for potential confounding factors with a comprehensive multivariate model adjusting for race/ethnicity, age, sex, smoking status, histology, ECOG PS, PD-L1 score, chemotherapy, and brain metastasis, ECOG PS was confirmed to be associated with OS (Figure 3) and PFS (supplemental eFigure 1) (P<.0001), and PD-L1 expression was confirmed to be associated with PFS (P=.0152). A reduced multivariate model that specifically evaluated factors such as age, PD-L1 score, ECOG PS, and NHB, NHW, or Hispanic race/ethnicity again confirmed that ECOG PS was associated with OS (P<.0001) (supplemental eTable 2). When PFS was evaluated using the same covariates in the same reduced multivariate model, PD-L1 and ECOG PS were found to be associated with PFS, and Hispanic patients were found to have shorter PFS compared with NHB patients (hazard ratio [HR], 1.458; 95% CI, 1.038–2.047; P=.0296) (supplemental eTable 3). Furthermore, exploratory race/ethnicity-specific analyses revealed again that ECOG PS ≥2 was associated with worse OS among Black patients compared with non-Black patients (P<.0001) (supplemental eTable 4), and among Hispanic patients compared with non-Hispanic patients (P<.0001) (supplemental eTable 5).
Risk of death among patients with metastatic non–small cell lung cancer receiving first-line IO, adjusted for age, race/ethnicity, biological sex, smoking status, ECOG PS, histology, PD-L1 TPS, IO regimen, and presence of brain metastasis.
Abbreviations: HR, hazard ratio; IO, immunotherapy; NHB, non-Hispanic Black; NHW, non-Hispanic White; OS, overall survival; PS, performance status; TPS, tumor proportion score.
*P<.05.
Citation: Journal of the National Comprehensive Cancer Network 21, 12; 10.6004/jnccn.2023.7064
Safety Outcomes
Regarding safety, overall TRAEs were reported in 36.3% of patients, with the majority being grade <3 (57.8%). There were no significant differences in incidence of TRAEs among the different racial/ethnic groups (P=.48), or in the occurrence of grade 3 TRAEs (P=.41) (Table 1). An analysis of the subset of patients who experienced TRAEs revealed a significantly longer OS (P=.02) and PFS (P=.003) compared with those without reported TRAEs (supplemental eTable 6). However, when stratified by grade <3 or ≥3 TRAEs, the association with OS (P=.72) or PFS (P=.65) was no longer significant (supplemental eTable 6).
Discussion
Our racially and ethnically diverse cohort of patients with metastatic NSCLC treated with first-line immunotherapy regimens had similar clinical efficacy with respect to OS, PFS, and TTD. Comparably, this study revealed a range of 16.8 to 26.3 months for median OS, similar to the long-term outcomes of clinical trials with patients who had advanced NSCLC and who were treated with monotherapy pembrolizumab with a median OS ranging from 10.5 to 26.3 months.27–30 Trials with pembrolizumab and chemotherapy regimens had a median OS that ranged from 17.2 to 34.5 months, with similar incidences of TRAEs.31–33 Previous research on the efficacy of immunotherapy in NHB patients have had mixed results, with some studies showing similar efficacy and tolerability in NHB patients with advanced NSCLC versus NHW patients, with no difference in OS or PFS,20–22 whereas other studies have shown that NHB patients had a longer OS, PFS, and TTD.23,24
In regard to Hispanic patients, our analysis revealed no significant difference in OS between Hispanic and non-Hispanic patients in all 3 models, including a univariate model (supplemental eTable 1), a comprehensive multivariate model (Figure 3), and a reduced exploratory multivariate model (supplemental eTable 2 and eTable 5). However, a discrepancy emerged when examining PFS in these 3 models. Whereas both the univariate (supplemental eTable 1) and comprehensive multivariate analysis (supplemental eFigure 1) showed concurrence, indicating no significant difference in PFS among the different race/ethnicity groups, the reduced exploratory multivariate model revealed instead that Hispanic patients had a significantly worse PFS compared with NHB patients (supplemental eTable 3). Notably, a prior study that included patients with lung cancer and those with head and neck cancer found that Hispanic and NHB patients had a lower objective response rate (ORR) compared with NHW patients.25 Our study did not analyze ORR, but it is possible that a lower response to immunotherapy could lead to a lower PFS as more patients demonstrate disease progression. Nevertheless, similar in both our study and the previous report,25 OS was not significantly different. These intriguing findings require further validation in future studies.
Our research not only adds to the growing literature surrounding the use of immunotherapy in ethnic minority groups but also expands on other potentially significant predictors of immunotherapy efficacy, particularly BMI, ECOG PS, PD-L1 status, and the socioeconomic factors of insurance and annual household income.
Clinical factors such as weight changes, BMI, and the presence of cachexia have been shown in the past to be associated with outcomes in patients with NSCLC who are treated with immunotherapy.34–45 With the production of inflammatory cytokines by the immune system resulting in the multifactorial syndrome of anorexia, weight and muscle loss, and functional impairment, those with cachexia experience worse survival.42–45 This is a key understudied and poorly understood factor that is faced clinically in the real-world setting for patients with advanced NSCLC.46 Specifically, the association of BMI with clinical outcomes in immunotherapy has been studied previously, and results have shown that patients with higher BMI (ranging from ≥22 to 25 kg/m2) and obesity have been associated with improved clinical outcomes of significantly higher OS, PFS, and TTD compared with patients who are not overweight.34–41 Similarly, in this study, patients who had a higher BMI of ≥25 kg/m2 were also found to have a significantly improved PFS (P=.01) and TTD (P=.02) but not OS compared with those who had a BMI of <25 kg/m2. In preclinical studies, obesity was associated with a proinflammatory status and upregulation of PD-1 and PD-L1 expression47 and was clinically shown to increase the risk of immune-related adverse events.48–50 The presence of lower BMI and cachexia are clinical factors that need to be taken into consideration when administrating immunotherapy, as highlighted by our results and by prior studies, and that should be further investigated in future studies.
Lung cancer is predominantly diagnosed in elderly patients; the data in this study reconfirmed this, given that 58% of the patients with metastatic NSCLC started immunotherapy at age ≥65 years and additionally 35% had an ECOG PS ≥2. Although this aligns with previous reported estimates of up to 35% to 50% of patients with lung cancer having an ECOG PS ≥2 and aged ≥65 years, clinical trials often exclude this population, thus resulting in no specific guidelines for this older and frailer population.51–53 Reviews of the limited number of immunotherapy trials that included patients with advanced/metastatic NSCLC aged ≥65 years have shown no difference in OS compared with younger patients.54,55 A meta-analysis examined the association of a patient’s ECOG PS and their clinical outcomes of 18 trials that involved various malignancies, including lung cancer, that were treated with immunotherapy. Findings showed that patients with an ECOG PS of 0 had similar OS as those with an ECOG PS 1–2.56 However, only 54 of the 11,354 patients examined in the analysis had an ECOG PS of ≥2 and no definitive conclusions could be drawn for those with higher ECOG PS. Prospective studies such as ELDERS57 and PePS258 and have attempted to address this group of older patients with advanced NSCLC and ECOG PS ≥2 and have found no significant difference in response, OS, and toxicities compared with patients aged <70 years or who had an ECOG PS of 0 to 1, respectively.57,58 In contrast, retrospective studies and reviews revealed that patients with a ECOG PS ≥2 have significantly worse survival and response rates than those with a PS <2.34,35,59,60 Another retrospective study that examined patients with NSCLC and ECOG PS ≥2 treated with immunotherapy with or without chemotherapy showed a survival benefit compared with no treatment,61 indicating that there could still be a clinical benefit of treatment. Thus, chronological age should not be the main selection for treatment, and it should be noted that elderly patients are a heterogeneous group. The clinical approach for how to choose management may depend more on functional status, such as ECOG PS, in the real-world setting, which is highlighted in the results of this study with ECOG PS being significant in both univariate and multivariate analysis of OS, PFS, and TTD.
Another group of patients who are often underrepresented and excluded from clinical trials are those diagnosed with brain metastases.62 To reflect the real-world clinical setting, the inclusion criteria in this analysis encompassed patients with either symptomatic or asymptomatic brain metastasis. Examination of the study cohort revealed that 27% of the patients were diagnosed with brain metastasis at the onset of immunotherapy, which aligns with prior studies that report brain metastases occurring in up to 10% to 40% of patients with metastatic lung cancer either at diagnosis or during their clinical course.63–66 Moreover, prognosis for patients with NSCLC who have brain metastasis has been shown to be poor in previous studies.66–69 To our knowledge, this study is one of the first real-world investigations reporting similar incidences of brain metastases among racial/ethnic groups, with no significant difference in OS or PFS (Figure 3; supplemental eTable 1 and eFigure 1). Furthermore, 2 pooled analyses of the KEYNOTE-001, -010, -024, and -04270 and KEYNOTE-021, -189, and -407 clinical trials,71 which included patients with metastatic NSCLC with baseline stable and previously treated brain metastasis treated subsequently with pembrolizumab with or without chemotherapy, yielded comparable results to our study. Median OS was 19.7 months in the pooled analysis of KEYNOTE-001, -010, -024, and -042,70 and 18.8 months in the pooled analysis of KEYNOTE-024, -189, and -407,71 similar to our study’s reported OS of 18.7 months in the overall patient subset (supplemental eTable 1). These findings may be attributed to improvements in earlier detection and more effective management of central nervous system metastases through advances in neurosurgery and radiotherapy with stereotactic radiosurgery and whole-brain radiation therapy.65,72–74 Therefore, these results highlight the continued importance of proper staging and imaging in this patient population and emphasize the need for further research.
Although there are limitations to PD-L1 expression as a predictive biomarker, it currently remains the primary biomarker used to determine immunotherapy regimen selection for patients with NSCLC.75 Our study revealed longer PFS in patients with PD-L1 TPS ≥1%, but with no difference in OS or TTD. Notably, most patients (71.8%) in our cohort exhibited PD-L1 TPS ≥1%, and 39.9% demonstrated PD-L1 TPS ≥50%, with no significant difference observed among the different racial/ethnic groups. Consistent with prior studies, NHB patients were found to have PD-L1 expression similar to that of NHW patients.76–78 Interestingly, Hispanic patients have been shown to have less PD-L1 positivity compared with non-Hispanic patients (P=.016).78 However, it is worth noting that these previous studies were conducted between 2014 and 2017, which was before the widespread adoption of immunotherapy in the first-line setting, and they were limited to only 92 patients with PD-L1 test results. Consequently, further research is warranted to explore the role of PD-L1 expression as a prognostic and predictive factor in patients with NSCLC treated in the real-world setting, with careful consideration of race/ethnicity.
The association of clinical efficacy of immunotherapy and TRAEs has previously been reported, with patients who experience TRAEs demonstrating significantly higher OS and PFS.79–83 Our study showed similar results in terms of OS and PFS, but this association was not significant when patients with TRAEs were stratified by either grade <3 or ≥3 based on CTCAE v5.0 (supplemental eTable 6). These findings suggest that the presence of TRAEs may be associated with clinical outcomes, but the grading of the TRAE itself may not be the main determining factor.
Studies from the era before immunotherapy that examined socioeconomic characteristics in patients with NSCLC have shown an association of insurance and income with low-dose CT screening,84,85 staging,86,87 chemotherapy access,88 and survival.89 However, studies that examined the socioeconomic factors of patients treated with immunotherapy are scarce, and only one study has specifically examined income.19 That study revealed that after FDA approval of immunotherapy, lower median household income (<$63,000) was associated with lower receipt of immunotherapy compared with a median household income of ≥$63,000.19 Our study is one of the first to incorporate insurance, income, and clinical outcomes. We observed that annual household income was not associated with OS, PFS, or TTD, although there was a trend toward higher OS, PFS, and TTD in patients with a household income of ≥$100,000 compared with those earning <$100,000. Another finding was that although on average it takes Medicare 17 months after FDA approval to cover novel treatments with requirements for prior authorization,90,91 patients with Medicare had a higher PFS compared with those who had commercial insurance or Medicaid. Further studies evaluating income and insurance are needed as financial toxicity and burden grows with increasing costs, and to confirm the findings in this study.
Despite the important findings in this study, there are several limitations. This study is a retrospective analysis of data from a healthcare system comprising multiple hospitals. Despite efforts to control confounding factors, the inability to capture all variables limits the provision of more specific patient data. In particular, socioeconomic details such as individual income data were unavailable, and estimations were based on annual household income from US census data derived from the patient’s zip code. In addition, 13 patients (5.2%) with missing PD-L1 scores were excluded from the analyses involving PD-L1 scores as covariates. Another aspect not accounted for in this cohort was the examination of comorbidity scores; instead, ECOG PS at the start of immunotherapy, as determined by clinical providers, was analyzed. At the same time, most of the patients in this cohort received all of their therapy at our institution, and with extensive records available, the overall extent of missing data was not substantial. Furthermore, no discernible trends related to missing data were observed, indicating that no major bias was associated with missing data.
Another important limitation in this real-world study pertains to the evaluation of TRAEs. The TRAEs were extracted from medical record reviews based on detailed documentation by providers. The analysis and interpretation were then determined by CTCAE v5.0 as accurately as possible. However, the study did not differentiate between TRAEs resulting from immunotherapy and those occurring in conjunction with chemotherapy. In addition, the presence of immortal time bias and survivor bias could introduce confounding effects, because the occurrence of TRAEs during a patient’s clinical course may not only indicate clinical efficacy but may also suggest that the patient survived long enough for an AE to manifest itself.83,92 Moreover, previous research has demonstrated that the timing of TRAEs, whether early- or late-onset, can influence OS. Thus, in future studies examining TRAEs in patients treated with immunotherapy, considering specific time points for evaluation may prove crucial in assessing clinical efficacy.83,92 Although this study lacks a landmark timepoint, and the reported TRAEs encompass any events occurring during the course of immunotherapy, it indicates the need for further analysis to better understand the implications of TRAEs on treatment outcomes.
Similar to the limitations in the pooled analyses of the KEYNOTE trials, in our study, prior local therapy was not analyzed, and no distinction was made regarding whether the brain metastases were symptomatic or not and if patients required possible steroids. Additionally, this study did not address other metastatic sites that can also potentially contribute to differential treatment responses and clinical outcomes and the number of additional sites.93 Thus, further studies are warranted given the increasing amount of data on the efficacy and safety of immunotherapy and radiotherapy and on the optimal sequencing of treatments,94–96 as well as to investigate expanding the inclusion criteria to include patients with either active or asymptomatic brain metastases.
Nonetheless, the limitations of this study are also its strengths, because this study provides valuable insights into an unmet need for detailing the clinical efficacy of immunotherapy in a real-world setting comprising a diverse patient population that is rarely reported in either clinical trials or in retrospective studies. Although these patients were included in this analysis to emulate the real world, results from this study are similar to those from the 5-year updates of the KEYNOTE trials. Thus, the results from our study can help determine patient selection factors for future treatment, and illustrate the need for larger studies to examine clinical and socioeconomic factors that can influence patient care and lead to inclusion of a more diverse group of patients in future trials. Our data add to the growing body of literature on the impact of race/ethnicity on first-line immunotherapy in patients with NSCLC.
Conclusions
Despite the advances in immunotherapy for patients with NSCLC, the lack of inclusion of a more diverse group of patients in clinical trials has created a gap in knowledge about the impact of healthcare disparities and race/ethnicity. This study is one of the first that incorporates ethnic minorities as the majority of the patient population and demonstrates that despite significant differences in socioeconomic factors such as income and insurance, race/ethnicity may not impact the benefits of immunotherapy. However, factors such as ECOG PS do significantly impact OS, and BMI and PD-L1 expression are significantly associated with PFS and TTD. These findings help identify potential factors that can be addressed to optimize outcomes and care while patients are undergoing immunotherapy, and they highlight the need for randomized trials evaluating the efficacy of immunotherapy in high-risk patients such as those with poor ECOG PS. This real-world study provides insightful analysis of these understudied factors that warrant further study to improve clinical care and create more inclusive trials.
Acknowledgments
The authors acknowledge the Montefiore Einstein Cancer Center for the support of this research, especially the Montefiore Einstein Cancer Center Price Family Foundation Health Equity Pilot Award (to H. Cheng).
References
- 1.↑
Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016;387:1415–1426.
- 2.↑
Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov 2017;7:596–609.
- 3.↑
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018–2028.
- 4.↑
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540–1550.
- 5.↑
Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–1833.
- 6.↑
Mok TS, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819–1830.
- 7.↑
Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497–1508.
- 8.↑
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078–2092.
- 9.↑
Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379:2040–2051.
- 10.↑
Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342–2350.
- 11.↑
Nishio M, Barlesi F, West H, et al. Atezolizumab plus chemotherapy for first-line treatment of nonsquamous NSCLC: results from the randomized phase 3 IMpower132 trial. J Thorac Oncol 2021;16:653–664.
- 12.↑
Patel K, Alpert N, Tuminello S, et al. Association of personal characteristics and effectiveness of immunotherapy in late-stage non-small cell lung cancer: a systematic review. JNCI Cancer Spectr 2022;6:pkac015.
- 13.↑
Booth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer 2014;110:551–555.
- 14.↑
Katkade VB, Sanders KN, Zou KH. Real world data: an opportunity to supplement existing evidence for the use of long-established medicines in health care decision making. J Multidiscip Healthc 2018;11:295–304.
- 15.↑
Aizer AA, Wilhite TJ, Chen MH, et al. Lack of reduction in racial disparities in cancer-specific mortality over a 20-year period. Cancer 2014;120:1532–1539.
- 16.↑
Albain KS, Unger JM, Crowley JJ, et al. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J Natl Cancer Inst 2009;101:984–992.
- 17.↑
Saeed AM, Toonkel R, Glassberg MK, et al. The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival: an analysis of the Survival, Epidemiology, and End Results database. Cancer 2012;118:4495–4501.
- 18.↑
Klugman M, Xue X, Hosgood HD III. Race/ethnicity and lung cancer survival in the United States: a meta-analysis. Cancer Causes Control 2019;30:1231–1241.
- 19.↑
Ermer T, Canavan ME, Maduka RC, et al. Association between Food and Drug Administration approval and disparities in immunotherapy use among patients with cancer in the US. JAMA Netw Open 2022;5:e2219535.
- 20.↑
Butaney M, Satkunasivam R, Goldberg H, et al. Analysis of heterogeneity in survival benefit of immunotherapy in oncology according to patient demographics and performance status: a systematic review and meta-analysis of overall survival data. Am J Clin Oncol 2020;43:193–202.
- 21.↑
Nazha B, Goyal S, Chen Z, et al. Efficacy and safety of immune checkpoint blockade in self-identified Black patients with advanced non-small cell lung cancer. Cancer 2020;126:5040–5049.
- 22.↑
Peravali M, Ahn J, Chen K, et al. Safety and efficacy of first-line pembrolizumab in Black patients with metastatic non-small cell lung cancer. Oncologist 2021;26:694–700.
- 23.↑
Ayers KL, Mullaney T, Zhou X, et al. Analysis of real-world data to investigate the impact of race and ethnicity on response to programmed cell death-1 and programmed cell death-ligand 1 inhibitors in advanced non-small cell lung cancers. Oncologist 2021;26:e1226–1239.
- 24.↑
Tiu AC, Potdar R, Djibo DA, et al. Clinical outcomes of African American patients with advanced or metastatic non-small cell lung cancer on nivolumab in a single community-based cancer center. Med Oncol 2018;35:109.
- 25.↑
Florez MA, Kemnade JO, Chen N, et al. Persistent ethnicity-associated disparity in anti-tumor effectiveness of immune checkpoint inhibitors despite equal access. Cancer Res Commun 2022;2022:806–813.
- 26.↑
United States Census Bureau. American community survey data. Accessed July 1, 2023. Available at: https://www.census.gov/programs-surveys/acs/data.html
- 27.↑
Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 2019;37:2518–2527.
- 28.↑
Herbst RS, Garon EB, Kim DW, et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non‒small-cell lung cancer in the KEYNOTE-010 study. J Clin Oncol 2020;38:1580–1590.
- 29.↑
Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol 2021;39:2339–2349.
- 30.↑
de Castro G, Kudaba I, Wu YL, et al. KEYNOTE-042 5-year survival update: pembrolizumab versus chemotherapy in patients with previously untreated, PD-L1–positive, locally advanced or metastatic non–small-cell lung cancer. J Immunother Cancer 2021;9(Suppl 2):Abstract 363.
- 31.↑
Awad MM, Gadgeel SM, Borghaei H, et al. Long-term overall survival from KEYNOTE-021 cohort G: pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous NSCLC. J Thorac Oncol 2021;16:162–168.
- 32.↑
Gray J, Rodríguez-Abreu D, Powell SF, et al. Pembrolizumab + pemetrexed-platinum vs pemetrexed-platinum for metastatic NSCLC: 4-year follow-up from KEYNOTE-189. J Thorac Oncol 2021;16(Suppl):Abstract FP13.02.
- 33.↑
Robinson A, Vicente Baz D, Tafreshi A, et al. First-line pembrolizumab plus chemotherapy for patients with advanced squamous NSCLC: 3-year follow-up from KEYNOTE-407. J Thorac Oncol 2021;16(Suppl):Abstract 960.
- 34.↑
Zhang S, Pease DF, Kulkarni AA, et al. Real-world outcomes and clinical predictors of immune checkpoint inhibitor monotherapy in advanced lung cancer. Clin Med Insights Oncol 2021;15:11795549211004489.
- 35.↑
Grosjean HAI, Dolter S, Meyers DE, et al. Effectiveness and safety of first-line pembrolizumab in older adults with PD-L1 positive non-small cell lung cancer: a retrospective cohort study of the Alberta Immunotherapy Database. Curr Oncol 2021;28:4213–4222.
- 36.↑
An Y, Wu Z, Wang N, et al. Association between body mass index and survival outcomes for cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. J Transl Med 2020;18:235.
- 37.↑
Gelibter A, Occhipinti M, Pisegna S, et al. Status of correlation between BMI and response to immunocheck-point inhibitor in advanced non-small-cell lung cancer. Lung Cancer Manag 2020;9:LMT26.
- 38.↑
Kichenadasse G, Miners JO, Mangoni AA, et al. Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer. JAMA Oncol 2020;6:512–518.
- 39.↑
Ichihara E, Harada D, Inoue K, et al. The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer. Lung Cancer 2020;139:140–145.
- 40.↑
Cortellini A, Ricciuti B, Tiseo M, et al. Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation. J Immunother Cancer 2020;8:e001403.
- 41.↑
Cortellini A, Bersanelli M, Buti S, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. J Immunother Cancer 2019;7:57.
- 42.↑
Morimoto K, Uchino J, Yokoi T, et al. Impact of cancer cachexia on the therapeutic outcome of combined chemoimmunotherapy in patients with non-small cell lung cancer: a retrospective study. Oncoimmunology 2021;10:1950411.
- 43.↑
Degens JHRJ, Dingemans AC, Willemsen ACH, et al. The prognostic value of weight and body composition changes in patients with non-small-cell lung cancer treated with nivolumab. J Cachexia Sarcopenia Muscle 2021;12:657–664.
- 44.↑
Roch B, Coffy A, Jean-Baptiste S, et al. Cachexia - sarcopenia as a determinant of disease control rate and survival in non-small lung cancer patients receiving immune-checkpoint inhibitors. Lung Cancer 2020;143:19–26.
- 45.↑
Rounis K, Makrakis D, Tsigkas AP, et al. Cancer cachexia syndrome and clinical outcome in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: results from a prospective, observational study. Transl Lung Cancer Res 2021;10:3538–3549.
- 46.↑
Morita-Tanaka S, Yamada T, Takayama K. The landscape of cancer cachexia in advanced non-small cell lung cancer: a narrative review. Transl Lung Cancer Res 2023;12:168–180.
- 47.↑
Wang Z, Aguilar EG, Luna JI, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 2019;25:141–151.
- 48.↑
Guzman-Prado Y, Ben Shimol J, Samson O. Body mass index and immune-related adverse events in patients on immune checkpoint inhibitor therapies: a systematic review and meta-analysis. Cancer Immunol Immunother 2021;70:89–100.
- 49.↑
Gülave B, Hew MN, de Groot JS, et al. High body mass index and pre-existing autoimmune disease are associated with an increased risk of immune-related adverse events in cancer patients treated with PD-(L)1 inhibitors across different solid tumors. ESMO Open 2021;6:100107.
- 50.↑
McQuade JL, Hammers H, Furberg H, et al. Association of body mass index with the safety profile of nivolumab with or without ipilimumab. JAMA Oncol 2023;9:102–111.
- 51.↑
Lilenbaum RC, Cashy J, Hensing TA, et al. Prevalence of poor performance status in lung cancer patients: implications for research. J Thorac Oncol 2008;3:125–129.
- 52.↑
Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 2001;92:2639–2647.
- 53.↑
Tagliamento M, Frelaut M, Baldini C, et al. The use of immunotherapy in older patients with advanced non-small cell lung cancer. Cancer Treat Rev 2022;106:102394.
- 54.↑
Marur S, Singh H, Mishra-Kalyani P, et al. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies. Semin Oncol 2018;45:220–225.
- 55.↑
Carmichael JA, Wing-San Mak D, O’Brien M. A review of recent advances in the treatment of elderly and poor performance NSCLC. Cancers (Basel) 2018;10:236.
- 56.↑
Bersanelli M, Brighenti M, Buti S, et al. Patient performance status and cancer immunotherapy efficacy: a meta-analysis. Med Oncol 2018;35:132.
- 57.↑
Gomes F, Woolley S, Califano R, et al. Elderly lung cancer patients on immunotherapy: preliminary results from the ELDERS study. J Thorac Oncol 2017;12(Suppl 2):Abstract MA 10.07.
- 58.↑
Middleton G, Brock K, Savage J, et al. Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. Lancet Respir Med 2020;8:895–904.
- 59.↑
Choi MG, Choi CM, Lee DH, et al. Impact of gender on response to immune checkpoint inhibitors in patients with non-small cell lung cancer undergoing second- or later-line treatment. Transl Lung Cancer Res 2022;11:1866–1876.
- 60.↑
Facchinetti F, Di Maio M, Perrone F, et al. First-line immunotherapy in non-small cell lung cancer patients with poor performance status: a systematic review and meta-analysis. Transl Lung Cancer Res 2021;10:2917–2936.
- 61.↑
Veluswamy R, Hu L, Smith C, et al. Immunotherapy outcomes in individuals with non-small cell lung cancer and poor performance status. JNCI Cancer Spectr 2022;6:pkac013.
- 62.↑
El Rassy E, Botticella A, Kattan J, et al. Non-small cell lung cancer brain metastases and the immune system: from brain metastases development to treatment. Cancer Treat Rev 2018;68:69–79.
- 64.↑
Villano JL, Durbin EB, Normandeau C, et al. Incidence of brain metastasis at initial presentation of lung cancer. Neuro Oncol 2015;17:122–128.
- 65.↑
Myall NJ, Yu H, Soltys SG, et al. Management of brain metastases in lung cancer: evolving roles for radiation and systemic treatment in the era of targeted and immune therapies. Neurooncol Adv 2021;3(Suppl 5):v52–62.
- 66.↑
Waqar SN, Samson PP, Robinson CG, et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin Lung Cancer 2018;19:e373–379.
- 67.↑
Sperduto PW, Mesko S, Li J, et al. Survival in patients with brain metastases: summary report on the updated diagnosis-specific graded prognostic assessment and definition of the eligibility quotient. J Clin Oncol 2020;38:3773–3784.
- 68.↑
Peters S, Bexelius C, Munk V, et al. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev 2016;45:139–162.
- 69.↑
Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol 2017;19:1511–1521.
- 70.↑
Mansfield AS, Herbst RS, de Castro G Jr, et al. Outcomes with pembrolizumab monotherapy in patients with programmed death-ligand 1-positive NSCLC with brain metastases: pooled analysis of KEYNOTE-001, 010, 024, and 042. JTO Clin Res Rep 2021;2:100205.
- 71.↑
Powell SF, Rodríguez-Abreu D, Langer CJ, et al. Outcomes with pembrolizumab plus platinum-based chemotherapy for patients with NSCLC and stable brain metastases: pooled analysis of KEYNOTE-021, -189, and -407. J Thorac Oncol 2021;16:1883–1892.
- 72.↑
Jablonska PA, Bosch-Barrera J, Serrano D, et al. Challenges and novel opportunities of radiation therapy for brain metastases in non-small cell lung cancer. Cancers (Basel) 2021;13:2141.
- 73.↑
Mizuno T, Takada K, Hasegawa T, et al. Comparison between stereotactic radiosurgery and whole-brain radiotherapy for 10-20 brain metastases from non-small cell lung cancer. Mol Clin Oncol 2019;10:560–566.
- 74.↑
Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol 2022;40:492–516.
- 75.↑
Bhalla S, Doroshow DB, Hirsch FR. Predictive biomarkers for immune checkpoint inhibitors in advanced non-small cell lung cancer: current status and future directions. Cancer J 2020;26:507–516.
- 76.↑
Mitchell KA, Zingone A, Toulabi L, et al. Comparative transcriptome profiling reveals coding and noncoding RNA differences in NSCLC from African Americans and European Americans. Clin Cancer Res 2017;23:7412–7425.
- 77.↑
Choudhury NJ, Eghtesad M, Kadri S, et al. Fewer actionable mutations but higher tumor mutational burden characterizes NSCLC in Black patients at an urban academic medical center. Oncotarget 2019;10:5817–5823.
- 78.↑
Shum E, Su C, Zhu C, et al. PD-L1 expression analysis in African American (AA) and Hispanic lung cancer patients at a minority-based academic cancer center. J Thorac Oncol 2017;12(Suppl 2):Abstract P1.07-027.
- 79.↑
Shankar B, Zhang J, Naqash AR, et al. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol 2020;6:1952–1956.
- 80.↑
Sato K, Akamatsu H, Murakami E, et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer 2018;115:71–74.
- 81.↑
Sung M, Zer A, Walia P, et al. Correlation of immune-related adverse events and response from immune checkpoint inhibitors in patients with advanced non-small cell lung cancer. J Thorac Dis 2020;12:2706–2712.
- 82.↑
Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018;4:374–378.
- 83.↑
Dall’Olio FG, Rizzo A, Mollica V, et al. Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: a meta-analysis. Immunotherapy 2021;13:257–270.
- 84.↑
Li CC, Matthews AK, Kao YH, et al. Examination of the association between access to care and lung cancer screening among high-risk smokers. Front Public Health 2021;9:684558.
- 85.↑
Shin D, Fishman MDC, Ngo M, et al. The impact of social determinants of health on lung cancer screening utilization. J Am Coll Radiol 2022;19:122–130.
- 86.↑
Aghdam N, McGunigal M, Wang H, et al. Ethnicity and insurance status predict metastatic disease presentation in prostate, breast, and non-small cell lung cancer. Cancer Med 2020;9:5362–5380.
- 87.↑
Gupta A, Omeogu CH, Islam JY, et al. Association of area-level socioeconomic status and non-small cell lung cancer stage by race/ethnicity and health care-level factors: analysis of the National Cancer Database. Cancer 2022;128:3099–3108.
- 88.↑
Toubat O, Atay SM, Kim AW, et al. Disparities in guideline-concordant treatment for pathologic N1 non-small cell lung cancer. Ann Thorac Surg 2020;109:1512–1520.
- 89.↑
Lin JQ, Li SQ, Pezzi TA, et al. Veterans Affairs insurance disparities for metastatic lung cancer in the Hawaiian Islands. JTO Clin Res Rep 2020;1:100003.
- 90.↑
Shaw DL, Dhruva SS, Ross JS. Coverage of novel therapeutic agents by Medicare prescription drug plans following FDA approval. J Manag Care Spec Pharm 2018;24:1230–1238.
- 91.↑
Roginiel AC, Dhruva SS, Ross JS. Evidence supporting FDA approval and CMS national coverage determinations for novel medical products, 2005 through 2016: a cross-sectional study. Medicine (Baltimore) 2018;97:e12715.
- 92.↑
Hsiehchen D, Naqash AR, Espinoza M, et al. Association between immune-related adverse event timing and treatment outcomes. Oncoimmunology 2022;11:2017162.
- 93.↑
Gibson AJW, Li H, D’Silva A, et al. Impact of number versus location of metastases on survival in stage IV M1b non-small cell lung cancer. Med Oncol 2018;35:117.
- 94.↑
Lehrer EJ, Peterson J, Brown PD, et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother Oncol 2019;130:104–112.
- 95.↑
Kotecha R, Kim JM, Miller JA, et al. The impact of sequencing PD-1/ PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol 2019;21:1060–1068.
- 96.↑
Schapira E, Hubbeling H, Yeap BY, et al. Improved overall survival and locoregional disease control with concurrent PD-1 pathway inhibitors and stereotactic radiosurgery for lung cancer patients with brain metastases. Int J Radiat Oncol Biol Phys 2018;101:624–629.
