Pembrolizumab monotherapy survival benefits in metastatic non-small-cell lung cancer: a systematic review of real-world data

The efficacy of pembrolizumab in the treatment-naïve non-small-cell lung cancer (NSCLC) patients was proved in the KEYNOTE-024 randomized trial. The aim of this systematic literature review was to identify and summarize the real world evidence (RWE) of overall survival (OS) in previously untreated patients with NSCLC receiving pembrolizumab monotherapy. A systematic search was conducted in PubMed (MEDLINE®) and EMBASE databases. Analyses were focused on survival data (median OS and survival rates at specific time points). To explore the population comparable with the KEYNOTE-024 study, we focused on studies enrolling at least 50% of patients at stage IV of cancer and ECOG performance status 0–2. A total of 41 RWE studies covering over 7600 advanced NSCLC patients naïve to systemic treatment were identified. Overall, survival outcomes reported in those studies vary considerably (median OS range: 3.0–34.6 months). Most RWE studies reported median OS shorter to that reported in KEYNOTE-024 (26.3 months), but about half of reported OS medians were in range of 95% confidence interval for OS as reported in KEYNOTE-024 trial (18.3–40.4 months). Patients with similar characteristics of stage and performance status to those of KEYNOTE-024 trial benefited the same with pembrolizumab monotherapy as their survival outcomes (18.9–22.8 months) were consistent with those reported in the clinical trial. RWE data showed substantially worse outcomes in patients with ECOG-PS 2+ compared to ECOG-PS 0–1 patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-024-01153-3.


Introduction
Primary lung cancer is the 2nd most common malignancy after breast cancer, and leading cause of deaths due to malignancy worldwide.Lung cancer accounted for approximately 1.8 million deaths in 2020 year [1].Non-small-cell lung carcinoma (NSCLC) accounts for 80%-90% of lung cancers, and most patients with NSCLC present with advanced-stage unresectable disease (stage IIIB to IV) [2].Therefore, patients with NSCLC are at great need for effective and safe systemic therapy that can prolong their life and improve its quality.Until recently, lung cancers were considered poorly immunogenic i.e. minimal benefit have been seen in studies of vaccines or cytokine modulation [3].However, monoclonal antibodies directed against the immune-checkpoint molecules, such as programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) significantly improved NSCLC therapy outcomes.Currently, patients with locally advanced and unresectable or metastatic NSCLC with no activating genetic abnormalities (EGFR, ALK or ROS1) should be offered immunotherapy as monotherapy or combined with chemotherapy as a standard approach [2].
Pembrolizumab is a humanized monoclonal antibody against PD-1 that has increased activity in tumours which express PD-L1.Pembrolizumab is approved as monotherapy for the first-line treatment of metastatic NSCLC in adults with PD-L1 expression on at least 50% of tumour cells with no EGFR mutation or ALK fusion [4].Efficacy of pembrolizumab in the firstline treatment of patients with metastatic NSCLC and high PD-L1 expression was assessed in a randomised multicentre, open-label, controlled KEYNOTE-024 study.Patients were randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n = 154) or investigator's choice platinum-containing chemotherapy (n = 151).Among the 154 patients treated with pembrolizumab in KEYNOTE-024 (median age 64.5 years), 59.7% were male and 35.1% and 64.9% of patients had ECOG performance status 0 and 1, respectively.The majority of patients (81.2%) had non-squamous-cell carcinoma (squamous-cell carcinoma in 18.8%).Brain metastases were present at 11.7% of patients.At 5 year follow-up (median time from randomization 59.9 months), 103 patients (66.9%) in the pembrolizumab group have died.Median overall survival (OS) was 26.3 months (95% CI 18.3 to 40.4 months) and Kaplan-Meier estimate of OS at 5 years was 31.9% [5].Therefore, pembrolizumab as monotherapy has shown durable efficacy regarding OS for the first-line treatment of metastatic NSCLC in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) under controlled clinical trial.However, it is also important to analyse the real world effectiveness beyond the strictly controlled environment of clinical trial, since those studies provides data for broader populations and includes patients typically excluded or underrepresented in clinical trials.

Purpose of the analysis
The aim of this systematic literature review was to identify and summarize the real world evidence (RWE) of OS in previously untreated patients with NSCLC with high PD-L1 status receiving pembrolizumab monotherapy.

Methods
A systematic review of observational studies on pembrolizumab monotherapy in previously untreated NSCLC patients was performed.Systematic search was conducted in PubMed (MEDLINE®) and EMBASE databases.The search strategy included both Text Words and MeSH terms for NSCLC and pembrolizumab, coupled with queries about actual study designs regarding real world evidence and corresponding synonyms.Search strategies are presented in Tables 1 and 2 (Supplementary materials).The cut-off date was 17th June 2022.No geographic restrictions were imposed, however, the search was limited to studies published in English.Only full-text publications were reviewed, abstracts and other conference reports were excluded.
The studies were selected independently by three researchers (N.W.; K.G.; M.D.).All studies were assessed according to the eligibility criteria: 1. RWE studies-publications with the hallmarks of clinical trials, such as sample size determination, randomization etc., were excluded; 2. use of pembrolizumab as monotherapy in first-line treatment-studies in previously treated patients as well as those in which pembrolizumab was administered as part of a combination therapy were excluded; 3. presence of PD-L1 expression with a tumour proportion score (TPS) ≥ 50%; 4. performance status according to the Eastern Cooperative Oncology Group (ECOG) scale ≤ 2; 5. presence of distant metastases reported explicitly in the characteristics of the population of a given study or determined by the stage of the disease i.e. stage IV (studies in which patients with stage IV represented at least 50% of study population were allowed); 6. presented data for OS or survival rates.
We developed a standardised data extraction form in MS Excel.Key data were extracted from all studies that met the inclusion criteria for the review, including study design, patient characteristics at baseline, and efficacy endpoints    Analyses were focused on survival data (median OS and survival rates at specific time points).Although KEY-NOTE-024 trial included only stage IV and ECOG-PS 0-1, we decided to include data from studies in which at least 50% patients had IV stage of cancer and ECOG performance status 0-2.Additional explorative analyses covered data from studies which reported separately ECOG-PS 0-1 and ECOG-PS 2 patients.Wherever possible, data for population similar to KEYNOTE-024 trial (i.e.only patients at IV stage of disease and with ECOG-PS 0-1) were extracted.Correlation between median OS and ECOG was explored.
Forest plots were generated to summarize median OS for the overall study populations and subpopulation groups of interest.We did not pool estimates of median OS or survival rates since meta-analysis methods for median survival ratio are not appropriate [6].Data are summarized with median (range: min.-max.)statistics.For correlation of median OS and ECOG, brain or liver metastasis status or disease stage Spearman's correlation coefficient were used [7].We assumed correlation > 0.8 to be very strong, 0.6-0.8 to be moderately strong, 0.3-0.5 to be fair and < 0.3 to be poor [8].Hazard ratio (HR) for OS data in predefined populations recognized by ECOG, brain or liver metastasis status or cancer stage were pooled with fixed effect inverse variance approach in Review Manager (RevMan), Version 5.4.1,The Cochrane Collaboration, 2020.

Results
Through search in PubMed and EMBASE, we identified 825 publications and based on title and abstract we selected 112 potential studies (Supplementary materials, Fig. 1).After full-text review, we identified 41 RWE studies covering 46 cohorts of advanced NSCLC patients naïve to systemic treatment (Table 1).Most patients included in those studies had ECOG-PS 0-1 (median 81.6%), were at the IV stage of the disease (median 85.8%).A minority of patients https://doi.org/10.1007/s12672-024-01153-3presented squamous-cell carcinoma (median 21.7%).Other types of NSCLC were reported inconsistently.In 13 studies, all populations were at the IV stage of the disease, and in 6 studies, all patients had ESOG 0-1.Only 3 studies [9, 18, 48-EHR cohort] reported OS in populations similar to KEYNOTE-024 i.e. all patients at IV stage of the disease and with ECOG-PS 0-1.Median age of patients treated with pembrolizumab was 69 years.Most patients were male (median = 65.7%), and current or ex-smokers (median = 90.0%).Almost fifth of all patients had brain metastases (median = 19.3%)and 13.0% had liver metastases.Most of patients with brain metastases (median = 68.8%)had undergone previous local therapy (surgery or radiotherapy).Table 2 summarize patients' characteristics in studies included in this review.Median survival times varied across studies with 3.0 months minimum and 34.6 months maximum.Most RWE studies reported median OS shorter to that reported in KEYNOTE-024; however, about half of the reported median OS were within the 95% confidence interval as reported in KN-024 trial (18.3-40.4months; Fig. 1).Expectedly, moderately strong negative correlation was seen between percentage of ECOG-PS2+ patients and OS (Spearman correlation coefficient r s = − 0.62).

Discussion
We identified substantial number of RWE studies covering over 7600 previously untreated patients with metastatic NSCLC receiving pembrolizumab monotherapy.In general, the OS results vary across all analysed studies and we believe the differences are due to high heterogeneity of population included in each study in terms of known prognostic factors (i.e.ECOG-PS, tumor stage) as well as local practice on supportive management.Approximately half of reported OS medians were in range of 95% CI OS data form KEYNOTE-024 trial.Those observations are not surprising as KEYNOTE-024 trial covered only ECOG-PS 0-1 patients, and we have shown that ECOG-PS is an important factor affecting outcome.Similar observation was reported previously for pembrolizumab in pre-treated patients with NSCLC [51].Also studies for other immune checkpoint inhibitors used for advanced NSCLC showed that patients with impaired performance status had significantly shorter survival compared to those with better performance status [52].It's worth to mention that KEYNOTE-024 trial covered only stage IV patients, while in RWE studies patients at stage III were also included.However percentage of patients with brain metastasis were overrepresented in real world data (19.6%)compared to KEYNOTE-024 trial (11.7% in pembrolizumab arm), and contrary to KEYNOTE-024 trial in real world settings not all patients received local treatment for brain metastasis.As expected, pooled HR data showed patients with brain or liver metastasis are at higher risk of death compared to patients without brain metastasis.
Review of RWE literature has shown that in real practice pembrolizumab monotherapy in patients with high PD-L1 expression may produce almost the same survival results as reported in the KEYNOTE-024 trial provided they have comparable stage and performance status.Although ESMO guidelines claim systemic therapy should be offered to all stage IV patients with PS 0-2, RWE data showed substantially worse outcomes in patients with ECOG-PS ≥ 2 compared to ECOG-PS 0-1 patients.In fact, in some countries (i.e.Poland) the use of immunotherapy is limited only to patients with ECOG-PS 0-1, what is in line with KEYNOTE-024 trial inclusion criteria.However, PePS2 trial, the only prospective phase 2 study that evaluated pembrolizumab monotherapy in patients with NSCLC and ECOG-PS 2, reported median OS of 9.8 (95%CI 7.1-14.6)months-values higher to those observed in the majority of ECOG-PS 2 RWE studies included in this review (1.5-12.8months) [53].On the other hand, RWE showed patients without distant metastases may also benefit from pembrolizumab monotherapy, but this findings has to be verify in controlled clinical study.Although a meta-analysis of clinical trials showed that pembrolizumab significantly improved overall survival in male individuals regardless of treatment line and regimen, we observed better outcomes in females [54].
Our secondary analysis has limitations, which result mainly from non-randomized settings and corresponding selection bias and many confounding variables we were unable to control for, even though the study focused on advanced NSCLC patients naïve to systemic treatment with similar characteristics of stage and performance status to those of KEYNOTE-024 trial.Many variables reflecting not only different patients' characteristics, but also clinical practice arrangements, contribute to heterogeneity and affect the generalizability of the study results.Moreover, most likely, everyday clinical practice and locally arranged patients' access to treatment not harmonized with predefined study protocol most likely could substantially affect generalizability.We focused on mortality to restrain missing data and measurement bias, but anticipated high heterogeneity, which could not be further limited with no access to individual patients data but only aggregated statistics reported in individual studies.For the same reason, our analysis focused mainly on median overall survival as most consistently reported; the only pooled statistic we could reliably provide through meta-analysis, with low heterogeneity, was the overall survival hazard ratio (HR).Certainly, general treatment efficacy claims are unjustified and were not intended as the study explored real-world outcomes in uncontrolled and pragmatic settings.We believe more RWE in the population close to that of the KEYNOTE-024 trial and specific subgroups should be collected to credibly explore pembrolizumab efficacy in real-world practice.It should not restrain from well-designed controlled trials to confirm pembrolizumab efficacy in new specific populations or clinical settings.
In conclusion, RWE studies of over 7600 advanced NSCLC patients new to systemic treatment displayed considerable variability in survival outcomes.While most studies reported a median OS shorter than that seen in the KEYNOTE-024 trial, patients with similar stage and performance status benefited equally from pembrolizumab monotherapy, with survival outcomes consistent with the clinical trial findings.
Table 3 Annual and 2-years overall survival rates OS, overall survival; N, number of all patients in the group; 95% CI, 95% confidence interval; n.d., no data (variable not reported in the source publication) *Entire study population data (no specific subgroups data available) a EHR cohort data-Velcheti et al. [48] included two patient cohorts-one with patient data obtained from electronic health records (EHR) and the other with data from the traditional Spotlight database, this cohort covers data from electronic databases b In the Alessi et al. [9] study, the results were divided into subpopulations according to the degree of patient performance determined in accordance with the ECOG-PS questionnaire-the group with a value of 0-1 and a group with a value above 1 were distinguished c Data in subpopulations by number of metastatic organs-this subpopulation is for patients with 3, 4 or 5 metastatic organs d Data read from the graph using the WebPlotDigitizer software e In Frost et al. [24] results for OS in the form of a binary value (percentage of patients with OS) are presented in subpopulations according to the presence and type of KRAS/TP53 mutation f Cohort BTS > 86 mm and BTS ≤ 86 mm-in the Bureau et al. [15] /doi.org/10.1007/s12672-024-01153-3Review (both median OS and survival rates at individual time points).The data extraction was independently verified and validated; any discrepancies between reviewers were resolved through discussion or consultation with a third reviewer if necessary.

Fig. 1
Fig. 1 Median survival in RWE studies (all included trials)

Fig. 4
Fig.4 Pooled overall survival HR in patients subgroups: males vs females (A), never smokers vs current/ever smokers (B) patients with and without brain metastases (C) and patients with and without liver metastases (D)

Table 1
Characteristics of the studies included in the analysis Study

Table 1 (
| https://doi.org/10.1007/s12672-024-01153-3Note the table includes studies, in which IV stadium of the disease had at least 50% of patients ECOG-PS, Eastern Cooperative Oncology Group Performance Status; stage, tumor stage according to TNM classification, range from I to IV; n.d., no data (variable not reported in the source publication) a ECOG-PS 0-2/ECOG-PS 2 b BTS > 86 mm and BTS ≤ 86 mm cohorts-in Bureau et al. [15] study cohorts were distinguished due to baseline tumour size (BTS)-the data given are for the cohort with BTS > 86 mm and the cohort with BTS ≤ 86 mm separately ^c Mean d EHR and spotlight cohorts-in Velcheti et al. [48] two patient cohorts were included-one of patient data collected with electronic health records (EHR), and the second one containing data from the traditional Spotlight database e BM cohort-in Wakuda et al. [49] study the cohort of patients with brain metastases (BM) and the cohort of patients with no brain metastases (non-BM) were included

Table 2
Pooled patients characteristics included in the analysisa Surgery or radiotherapy-data presented based on assumption that only patients with diagnosed brain metastases received treatment study, cohorts were distinguished according to the baseline tumor sizethe data provided for the cohort with BTS > 86 mm and the cohort with BTS < 86 mm separately | https://doi.org/10.1007/s12672-024-01153-3