PD-1/PD-L1 Inhibitors as Monotherapy in the First-Line Treatment of Advanced Non-Small Cell Lung Cancer Patients with High PD-L1 Expression: An Expert Position Statement

Introduction: There are currently three first-line immunotherapy options used as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand 1 (PD-L1) expression (≥50%). This manuscript aims to evaluate the available data on atezolizumab (AT), cemiplimab (CEMI), and pembrolizumab (PEMBRO) and to study the results obtained during pivotal trials, especially regarding patient subgroups. Methods: Nominal group and Delphi techniques were used. Eight Spanish experts in lung cancer (the scientific committee of the project) analyzed the use of immunotherapy monotherapy as first-line treatment in patients with NSCLC and high PD-L1 expression. The expert scientific committee formulated several statements based on a scientific review and their own clinical experience. Subsequently, 17 additional Spanish lung cancer experts were selected to appraise the committee’s statements through two Delphi rounds. They completed a Delphi round via an online platform and voted according to a scale from 1 (strongly disagree) to 10 (strongly agree). The statements were approved if ≥70% of experts voted 7 or more. Results: A total of 20 statements were proposed covering the following areas: (1) general characteristics of pivotal clinical trials; (2) overall main outcomes of pivotal clinical trials; and (3) subgroup analysis. All statements reached consensus in the first round. Conclusions: AT, CEMI, and PEMBRO as monotherapy can be considered the standard of care in patients with advanced NSCLC and high PD-L1 expression (≥50%). Moreover, some differences noted among the drugs analyzed in this document might facilitate treatment decision-making, especially in clinically relevant patient subgroups, when using PD-1/PD-L1 inhibitors. The high level of agreement reached among experts supports the proposed statements.


Introduction
Lung cancer is the second-most common cancer and the deadliest type worldwide [1,2]. In 2020, the estimated age-standardized incidence rate in the United States (US) was 23.1 [2]. In the US, lung cancer is the third most frequent cancer but the leading cause of death, with approximately 127,070 deaths in 2023 [3], accounting for 18% of all cancer deaths [2].
Non-small cell lung cancer (NSCLC) represents about 80% of all lung cancers [3], and more than half of the new NSCLC cases are diagnosed with distant metastases [4]. Therefore, effective treatment in this setting is critical [5].
Immunotherapy targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1 has significantly changed NSCLC patient management. PD-L1 is expressed by tumor cells (TCs) and tumor-infiltrating immune cells (ICs) [6]. PD-L1 binding to its receptor PD-1 on activated T-cells can lower T-cell immune responses and prevent TC elimination [7]. The prevalence of PD-L1 expression in the population of patients with NSCLC ranges from 24% to 60%, even with a cutoff for positivity set at 5% [8], and it is estimated that 25 to 35% of advanced NSCLC cases test positive for PD-L1 in at least 50% of TCs. Aside from being a key element in current immunotherapy strategies, PD-L1 has also emerged as a potential prognostic factor and biomarker to predict which patients are more likely to respond to immunotherapy in NSCLC [9].
Based on the published results, we built a national consensus statement with the aim of: (1) critically analyzing and describing the best evidence available of the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy in first-line treatment of advanced NSCLC; and (2) collecting evidence and experts' opinions regarding the efficacy and safety of these drugs in several patient subgroups of clinical interest. We are confident that this document will be useful to improve NSCLC patient management.

Study Design
A qualitative study was performed. Nominal group and Delphi techniques were applied to elaborate the consensus, with a systematic literature review supporting the statements. An external methodologist, expert in the Delphi technique, guaranteed the overall quality of the process. This study was conducted following good clinical practice and the current version of the revised Declaration of Helsinki (World Medical Association Declaration of Helsinki).

Expert Panel Selection and Clinical Statement Generation
A scientific committee of eight experts on lung cancer was established as a first step. They were responsible for (1) selecting the expert panel involved in the Delphi process, (2) identifying current relevant clinical questions/controversies in the management of advanced NSCLC with PD-1/PD-L1 inhibitors, and (3) generating statements regarding the evidence and use of PD-1/PD-L1 inhibitors in clinical practice. These statements were organized into three main sections: (a) main characteristics of AT, CEMI, and PEMBRO pivotal trials; (b) main results of AT, CEMI, and PEMBRO pivotal trials; and (c) outcomes of AT, CEMI, and PEMBRO in predefined patient subgroups including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, histological subtypes, presence of brain metastases, patients with unresectable locally advanced NSCLC, and PD-L1 levels. Along with the methodologists, the steering committee also defined the consensus level of agreement, and they analyzed and interpreted the results of the Delphi study.
The expert panel invited to participate in the Delphi procedure comprised 25 experts that were selected according to the following criteria: they had to be (1) medical oncologists and (2) specialized in NSCLC with proven clinical expertise. In the selection process, a balanced territorial representation of Spain was considered.

Systematic Literature Review
With the help of expert documentalists, a systematic literature review in Medline, Cochrane (CENTRAL), and Clinicaltrials.gov up to July 2022 was performed. The objective was to analyze the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy in firstline advanced NSCLC treatment. We used MeSH (Medical Subject Headings) terms (e.g., "carcinoma, non-small cell lung") but also free text terms like "cemiplimab". The inclusion criteria were: (1) adult patients with non-squamous or squamous NSCLC, measurable by response evaluation criteria in solid tumors (RECIST), version 1.1, and high PD-L1 expression (in ≥50% tumor cells); (2) treated with AT, CEMI, or PEMBRO as monotherapy in first-line treatment; (3) no restrictions were applied regarding the comparator; (4) articles should report outcomes like OS, PFS, objective response rate (ORR), or safety; (5) types of studies-meta-analysis, systematic literature reviews, and randomized controlled clinical trials-were accepted. Two reviewers independently selected the articles by reading the title and abstract, then thoroughly reading the whole article and collecting the data. The quality of the studies was analyzed using the Jadad score. Evidence and result tables were generated.

Delphi Process
The expert panel completed a Delphi round through an online platform. In the first round, the experts voted according to a scale from 1 (totally disagree) to 10 (totally agree). The statement was approved if more than 70% of participants voted ≥7. Statements with an agreement level <70% were analyzed, and if required, these statements were re-edited and voted on during a second round.

Edition of the Document
The steering committee wrote the position statement document, supported by the narrative review results.

Results
A total of 20 statements were generated. In the first Delphi round, all of them reached the required level of agreement. Delphi results are listed in Table 1.

20
The magnitude of the clinical benefit observed with CEMI were incrementally associated with PD-L1 expression levels. There are no corresponding data for AT and PEMBRO

Main Characteristics of Pivotal Trials
Tables 2-4 and Figure 1 depict the main characteristics of AT, CEMI, and PEMBRO pivotal trials [17][18][19]. Corresponding statements are presented in Table 1 (statements 1 to  7), with a high grade of consensus observed.

Main Characteristics of Pivotal Trials
Tables 2-4 and Figure 1 depict the main characteristics of AT, CEMI, and PEMBRO pivotal trials [17][18][19]. Corresponding statements are presented in Table 1 (statements 1 to  7), with a high grade of consensus observed. The AT, CEMI, and PEMBRO trials shared many characteristics but also presented several differences [17][18][19]. All were phase III randomized controlled trials in which the experimental drug was compared with platinum doublet chemotherapy ( Table 2). However, in cases of disease progression, crossover was allowed in the CEMI and PEMBRO trials [17,18], but not in the AT trial [19]. In the CEMI trial, the continuation of immunotherapy after disease progression combined with chemotherapy was allowed [18].
Regarding inclusion and exclusion criteria, the three trials included patients with metastatic disease and a PS score of 0 or 1 [17][18][19]. In the CEMI study, locally advanced NSCLC patients who were not candidates for radical chemoradiotherapy were also allowed [18]. Smokers and former smokers were represented in all the trials, but the CEMI study did not include never smokers. Nevertheless, the CEMI trial considered patients with controlled hepatitis B virus (HVB), hepatitis C virus (HVC), and HIV infection [18]. Patients presenting baseline brain metastases (AT trial), untreated brain metastases (CEMI and PEMBRO trials), and those with any prior adjuvant or neoadjuvant treatment (AT and PEMBRO trials) were excluded.
OS was the primary endpoint in the AT study [19], the PEMBRO study mainly focused on PFS [17], and the CEMI trial examined OS and PFS [18] (Table 2). The AT, CEMI, and PEMBRO trials shared many characteristics but also presented several differences [17][18][19]. All were phase III randomized controlled trials in which the experimental drug was compared with platinum doublet chemotherapy ( Table 2). However, in cases of disease progression, crossover was allowed in the CEMI and PEMBRO trials [17,18], but not in the AT trial [19]. In the CEMI trial, the continuation of immunotherapy after disease progression combined with chemotherapy was allowed [18].
Regarding inclusion and exclusion criteria, the three trials included patients with metastatic disease and a PS score of 0 or 1 [17][18][19]. In the CEMI study, locally advanced NSCLC patients who were not candidates for radical chemoradiotherapy were also allowed [18]. Smokers and former smokers were represented in all the trials, but the CEMI study did not include never smokers. Nevertheless, the CEMI trial considered patients with controlled hepatitis B virus (HVB), hepatitis C virus (HVC), and HIV infection [18]. Patients presenting baseline brain metastases (AT trial), untreated brain metastases (CEMI and PEMBRO trials), and those with any prior adjuvant or neoadjuvant treatment (AT and PEMBRO trials) were excluded.
OS was the primary endpoint in the AT study [19], the PEMBRO study mainly focused on PFS [17], and the CEMI trial examined OS and PFS [18] (Table 2).  Baseline characteristics of the patients are shown in Table 3. The AT pivotal trial included 554 patients with a PD-L1 level >1%, of whom 205 had a PD-L1 expression ≥50% [19]. All patients in the CEMI and PEMBRO trials presented a PD-L1 expression ≥50% [18]. Globally, the pivotal trials analyzed patients with similar median ages [17][18][19]. The amount of male patients was slightly lower in the PEMBRO trial [17] (Table 3), while the rate of non-squamous cancers was higher [17] (slightly more than 80% in the control and treatment arms). The percentage of patients with brain metastases in the experimental arm was similar in the CEMI and PEMBRO trials [18]. Nevertheless, the number of patients with baseline brain metastases in the control arms was slightly lower in the PEMBRO trial than in the CEMI trial (6.6% vs. 12%) [18].
Based on these data, all the experts agreed that in NSCLC patients with high PD-L1 expression (≥50%) and PS score ≤ 1, first-line treatment with AT, CEMI, or PEMBRO should be considered (statement 7, Table 1).

Main Results of Pivotal Trials
Primary and secondary endpoint results of each pivotal trial are listed in Table 4 (see  also Table 1, statements 8-13). Once again, it is important to highlight that a high grade of consensus was achieved by the expert panel.
Among all the patients evaluated for safety, treatment-related adverse events occurred in 60.5% of cases with AT [19], 57% with CEMI [18], and 87.2% with PEMBRO [25]. The rates of grade 3 and 4 adverse events were 30.1% and 28% for patients treated with AT and CEMI [18,19], respectively. Grade 3 and 4 treatment-related adverse events occurred in 15.4% of patients treated with PEMBRO [25] (no grade 5 events occurred in the PEMBRO trial).

Main Results in Predefined Patient Subgroups in the Pivotal Trials
Several exploratory subgroup analyses have been reported with the use of first-line AT, CEMI, and PEMBRO monotherapies. A summary of these analyses is exposed in Tables 5 and 6 (see also statements 14 to 20 of Table 1), and Figure 1. A consensus was reached by the expert panel, especially for statements 16 and 17. In this setting, AT, CEMI, and PEMBRO have shown global efficacy, irrespective of age or sex [18,20,21,26] (Table 5). Interestingly, the clinical benefit obtained in men was significantly higher than chemotherapy in all pivotal trials and outcomes (OS, PFS) [18,20,21] [20].
Regarding PS score (Table 5), AT, CEMI, and PEMBRO demonstrated efficacy (or a tendency) in improving OS compared with chemotherapy in patients with PS scores of 0 or 1 [18,20,21]. CEMI also showed positive results when analyzing PFS in patients with PS 0 and 1 [18].
On the other hand, post hoc subgroup analysis in locally advanced NSCLC patients from the CEMI pivotal trial (Table 5) demonstrated improved OS and PFS with first-line CEMI compared with chemotherapy [28]. Therefore, the experts encourage clinicians to consider CEMI in unresectable, locally advanced NSCLC patients who are not candidates for radical chemoradiotherapy.
Finally, exploratory analysis of the CEMI pivotal trial showed that the magnitude of clinical benefits observed with CEMI was superior to chemotherapy and higher as PD-L1 expression increased (Table 6) [30]. This sub-analysis is currently not available for AT and PEMRBO. A consensus has been acquired considering these data (statement 20 of Table 1). Table 6. Clinical benefits of first-line cemiplimab monotherapy by PD-L1 expression levels [18,30].

Discussion
Immunotherapy has emerged in recent years as a breakthrough therapy for NSCLC. The development of antibodies against PD-1 and its ligand, PD-L1, has dramatically transformed the therapeutic scenario for NSCLC patients. In advanced disease, the results of several randomized clinical trials have led to the approval of PD-L1 inhibitors in the first or subsequent treatment lines [31].
In this project, we have critically reviewed and analyzed the best evidence available regarding the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy in the first-line treatment of advanced NSCLC and in several patient subgroups of clinical interest. Based on the review, a set of related statements was proposed and voted on by an expert panel in a Delphi process. A high consensus grade was achieved by the expert panel in the first Delphi round as the required agreement level was reached in all the statements, thus reinforcing their value. This is the most relevant and noteworthy outcome of this project. Figure 1 summarizes the different patient profiles and the indicated treatments for them.
One of the main conclusions of our work is that, according to the experts and the reviewed literature, first-line PD-1/PD-L1 inhibitors as monotherapy can be considered the standard of care in advanced NSCLC patients with PD-L1 expression ≥50% without targetable mutations, in line with current clinical guidelines [5]. Significant benefits were observed regarding efficacy with PEMBRO [20] and CEMI [18], even when crossover was carried out, and benefits were particularly high with CEMI. We have also discussed the role of PD-L1 inhibitors as monotherapy in first-line treatment based on patient subgroups and their differences.
It is important to note that in the CEMI trial [18], controlled HVB, HVC, and HIV infections were allowed, as were unresectable locally advanced NSCLC patients who were not candidates for radical chemoradiotherapy.
Many lung cancer diagnoses occur in elderly patients, who are quite underrepresented in clinical trials. It is estimated that more than half of lung cancers are diagnosed in patients aged 65 or older [32]. Mortality is also higher with increasing age [32]. Therefore, this subgroup of patients deserves special consideration in clinical practice. Exploratory data from AT, CEMI, and PEMBRO pivotal trials have shown that elderly patients seem to obtain the same OS benefit as younger patients without additional toxicity [18,20,21,26]. Thus, age is not a limiting factor regarding AT, CEMI, and PEMBRO treatments.
Sex should also be considered since there are genetic, hormonal, and behavioral/lifestyle differences between males and females that might influence the response to immunotherapy [33,34]. We found that although AT, CEMI, and PEMBRO demonstrated efficacy regardless of sex [17][18][19][20][21]26], the clinical benefits (OS, PFS) obtained in men were more marked. Different meta-analyses have depicted quite similar results, suggesting sex-related differences in the response to immunotherapy [33]. The inherent strong immune response in females might explain, at least partly, why therapies enhancing the immune response are less effective in them compared to males. In contrast, the combination of immunotherapy and chemotherapy, or therapy enhancing the antigenicity of tumor cells, would be more effective in females than males [33]. However, the role of sex in cancer immunotherapy should be further explored. In the meantime, both male and female patients with advanced NSCLC are candidates for PD-1/PD-L1 inhibitors in first-line treatment as monotherapy.
ECOG PS score assessment is critical to oncologists treatment decision-making. In addition, the impact of the ECOG PS score on immunotherapy efficacy is already well known [35]. A recent metanalysis of real-world data showed that ECOG PS at treatment initiation represents a prognostic factor in patients with immunotherapy, with worse outcomes determined for those with poorer clinical conditions [36]. The three pivotal trials included patients with ECOG PS scores of 0 or 1. Since no differences were observed between the two groups, the experts stated that these drugs can be used independently of the ECOG PS score of 0 or 1 in clinical practice.
The other subgroup analyses were made according to histological types of cancer (squamous and non-squamous) in patients treated with AT, CEMI, and PEMBRO [18][19][20]. The frequency and efficacy results were higher for squamous cell carcinoma with CEMI. Overall, the results led the experts to consider the three immunotherapy options in both histologies.
Brain metastases in lung cancer patients are very common. They are present in approximately 20 to 40% of cases and are potentially devastating complications in advanced lung cancer, leading to a decreased quality of life and an extremely poor prognosis [37,38]. Despite changes in NSCLC treatment options with the emergence of immunotherapy, there is still a degree of caution about using these new drugs for the treatment of lung cancer patients with brain metastases. In the past, an absent lymphatic system and bloodbrain barrier were considered responsible for poor brain immunogenicity [39]. The CEMI and PEMBRO trials included patients with treated and clinically stable brain metastases, accounting for approximately 10% of the enrolled patients [17,18]. CEMI was significantly superior to chemotherapy in OS and ORR [18,27], while PEMBRO only demonstrated a positive tendency over chemotherapy regarding OS [17,20]. However, these results should be interpreted with caution due to the small sample size. The experts finally concluded that CEMI or PEMBRO should be considered in patients with brain metastases, but also noted that current data are more relevant for CEMI.
Approximately one-third of NSCLC diagnoses are classified as locally advanced, resectable, or unresectable [40]. The CEMI trial included a notable proportion of unresectable locally advanced NSCLC patients who were not candidates for definitive chemoradiation (15% in the PD-L1 ≥50% population and 16% in the intention-to-treat population) [18]. In a post-hoc analysis, first line CEMI monotherapy demonstrated improved survival benefits compared with chemotherapy [28]. Considering these data, the expert panel supports the inclusion of unresectable, locally advanced NSCLC patients who are not candidates for radical chemoradiotherapy for CEMI treatment.
Finally, the effect of PD-L1 expression level on treatment response was assessed only in patients treated with CEMI. We have shown that the benefits (OS, PFS, and ORR) with CEMI [30] were superior to chemotherapy and incrementally associated with PD-L1 expression levels. Thus, baseline PD-L1 expression levels may be used to identify advanced NSCLC patients who will likely benefit the most from first-line treatment with CEMI.
One of the main limitations of this project was the lack of direct cross-comparison studies or comparisons between trials. In addition, several differences in the trial design might explain differences in the baseline characteristics of the included patients, limiting their comparability. For example, randomization stratification, previous chemotherapy, and smoking status. It is worth mentioning gender disparities across trials. The pivotal CEMI trial [18] had far fewer women (84 in both groups) than men (479 in both groups), compared to the PEMBRO trial [17] (118 women vs. 187 men in both groups) and the AT trial [19] (62 women vs. 143 men in both groups). More research is needed to clarify the impact of these differences in treatment response. This is why we conducted this Delphi project: to obtain expert opinions to deliver statements trying to resolve uncertainties. In this regard, the strength of this study lies in the high level of agreement achieved among a broad group of expert oncologists. On the other hand, we included many subgroup analyses, which are still considered exploratory and require further confirmation. Nevertheless, they provide provisional and relevant data for treatment decision-making. In addition, some non-significant results are likely due to a lack of statistical power (low sample size, etc.). It is important to note that we performed a comprehensive literature review that was critically interpreted by a broad committee of clinical oncologists, providing a balanced view of the diseases and treatments.
In summary, PD-1/PD-L1 inhibitors as first-line monotherapy can be considered the standard of care in patients with advanced NSCLC and PD-L1 expression ≥50% without targetable mutations. We expect that this work will improve treatment decision-making, especially in clinically relevant patient subgroups displaying differences when treated with PD-1/PD-L1 inhibitors. The remarkably high agreement level reached among experts supports the proposed statements.