Comparative effectiveness and safety of systemic therapies for treatment-naïve, PD-L1 expression <1% advanced NSCLC: a systematic review and network meta-analysis

Introduction

Advanced non-small cell lung cancer (NSCLC) ranks among the most lethal malignancies, accounting for 1.8 million fatalities worldwide annually (1). Despite therapeutic advances that have extended survival, an estimated 40% to 50% of metastatic NSCLC cases are characterized by programmed cell death ligand 1 (PD-L1) expression <1%, and lack actionable genomic alterations, such as mutations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) (2-5). These patients are ineligible for targeted therapies and show inferior responses to single-agent immune checkpoint inhibitor (ICI) compared with those with positive PD-L1 expression (6-8). Consequently, the paucity of effective therapeutic options contributes to poor survival outcomes, underscoring the urgent need to identify optimal first-line treatment regimens for this specific population.

Historically, platinum-based chemotherapy (Chemo) has been the cornerstone of treatment in the first-line setting, but its limited efficacy in patients with PD-L1 <1% has fueled ongoing debate about the optimal treatment approaches. Pembrolizumab combined with chemotherapy (Pembro-chemo) has emerged as the most widely adopted standard of care for PD-L1 <1% advanced NSCLC. Nevertheless, uncertainty remains regarding whether Pembro-chemo represents the most effective strategy, or if alternative combinations offer superior benefits. Recent pivotal clinical trials have shown promising results with various synergistic combinations of chemotherapy, ICIs targeting and inhibiting programmed cell death 1 (PD-1), PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), antiangiogenic drugs, as well as interleukin (IL)-1β inhibitors (9-11). However, due to the absence of head-to-head trials comparing these regimens, clinicians still face challenges in selecting the most effective strategy for individual patients.

Prior meta-analyses of first-line treatments for PD-L1 negative NSCLC have been limited in scope, either focusing on specific drug combinations or categorized regimens without accounting for histologic heterogeneity (12-14). One study targeted squamous NSCLC but did not address PD-L1 negative patients (15). Other studies explored mechanistic treatment categories but failed to differentiate between inhibitors targeting PD-1 and PD-L1, potentially overlooking the potential synergies between drugs (16,17). Additionally, many analyses relied on outdated data, omitting recent long-term follow-up results. To address these limitations, we systematically conducted this study and simultaneously appraised the effectiveness and safety of both specific drug combinations and broader treatment categories by incorporating extended follow-up data. Additionally, a histologically-based subgroup analysis (non-squamous and squamous) was performed to inform personalized treatment strategies for clinicians.

We present this article in accordance with the PRISMA-network meta-analysis (NMA) reporting checklist following a predefined protocol registered in PROSPERO (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-371/rc).

Methods

Search strategy

An initial search was carried out across Ovid Medline, Embase, PubMed, and Cochrane Library utilizing the combined search terms “NSCLC”, “advanced”, “first-line”, and “randomized controlled trial”, from inception until August 15, 2025. To identify additional potential studies, a manual search was undertaken on prior meta-analyses and reference lists of the retrieved studies. The specific search strategies for each database are provided in Appendix 1.

Selection criteria

Full text or abstract publications of phase III randomized controlled trials (RCTs) that fulfilled the following criteria were deemed eligible for inclusion: (I) histologically confirmed, advanced NSCLC patients who received no previous systemic treatment, with EGFR, ALK wild type, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1, and PD-L1 status were confirmed to be <1% determined by immunohistochemistry; (II) trials comparing two or more first-line treatments; (III) and reporting at least one efficacy or safety outcome, including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (TRAEs) of grade 3 or higher. Any follow-up durations were accepted. Details of the eligibility criteria are shown in Appendix 2.

Data extraction

Using a standard template to ensure consistency in data collection, two investigators independently extracted study-level data. A third author was consulted to solve any discrepancies. The most recent publications focusing on updated and extended follow-up information were given priority, alongside a thorough examination of the supplementary materials.

For each trial, the following details were recorded: study population (eligibility criteria, sample size, stage, PD-L1 status, ECOG-PS, and histology); detailed treatment regimens, and number of participants for each arm; study characteristics (study design, trial name, publication year, publication sources, first author, phase status, and trial registration number); and outcomes of interest, encompassing PFS, OS as primary endpoints, ORR, and TRAEs of grade 3 or higher as secondary outcomes. PFS and OS were assessed based on hazard ratios (HRs), while ORR and safety were evaluated using odds ratios (ORs), both with corresponding 95% confidence intervals (CIs).

Risk of bias

The revised version of the Cochrane risk of bias tool (RoB 2) outlines a structured approach to evaluate the risk of bias in randomized trials, which is structured into five domains that cover all types of bias that may affect the results: (I) bias arising from the randomization process; (II) bias due to deviations from intended interventions; (III) bias due to missing outcome data; (IV) bias in measurement of the outcome; and (V) bias in the selection of the reported result (18). Two independent reviewers evaluated each trial, with discrepancies resolved by consensus or a third reviewer. For each domain, trials were classified as low, some concerns, or high risk of bias. Results of the risk of bias assessments are summarized in Figure S1.

Statistical analysis

Two separate analyses were conducted, primarily focusing on the specific drug combinations, with categorized treatments analyzed as supplementary data. Initially, pairwise meta-analyses (PWMA) in direct comparisons were performed using R software (version 4.4.1, R Foundation for Statistical Computing, Vienna, Austria) with the “meta” package, specifically utilizing metagen and metabin functions. Then, NMA were built using Bayesian modeling with the “gemtc” package, which synthesized both direct and indirect results allowing for the comparison of the effectiveness and safety of multiple interventions. This approach offers robust probabilistic estimates and facilitates indirect comparisons between interventions that lack direct head-to-head trials, thereby providing a comprehensive framework for evaluating their relative effectiveness. Deviance information criterion (DIC) was utilized to measure the goodness of model fit of global consistency and inconsistency models, where lower values correspond to preferable models and a difference of five is considered as significant. Local inconsistencies were checked by comparing direct evidence from PWMA with indirect evidence from NMA for each available comparison. I² statistic was used to assess the heterogeneity among studies, with values >50% indicating significant heterogeneity. With values ranging from 0 to 1, the treatment rankings were determined by surface under the cumulative ranking value (SUCRA). Better treatment performance and more AEs were indicated by higher SUCRA values.

Sensitivity and subgroup analyses

By omitting data from trials with median follow-up durations of less than 2, 3, and 5 years to avoid the impact of immature OS data, we ran sensitivity analyses to evaluate the robustness of results. Histologically stratified analyses were also performed.

Results

Study selection and characteristics

Of the 11,556 articles initially identified through the search, 290 were screened for eligibility, and 25 RCTs fulfilled the inclusion criteria (Figure 1). The NMA comprised 25 trials involving 5,815 participants. Fourteen of these trials were included in one prior meta-analysis (12), but data from 12 trials (9,19-30) was updated since then. Additionally, 11 trials, ORIENT-12 (31), Empower-Lung 3 part 2 (32), CHOICE-01 (33,34), GEMSTONE-302 (35,36), NEPTUNE (8), CameL-sq (37-39), AK105-302 (40), ASTRUM-004 (41), CANOPY-1 Part 2 (10), POSEIDON (42,43), JCOG2007 (44) were newly added. Table 1 presents a concise overview of the main characteristics of the included studies. The majority were judged to have a low-to-moderate risk of bias (Figure S1). Results of PWMA, utilizing chemotherapy as the reference are provided in Figures S2,S3.

Figure 1 PRISMA flow diagram of the study selection process. RCT, randomized controlled trial.

As depicted in network plots, NMA included 21 drug combinations for OS, PFS, ORR and TRAEs of grade ≥3 in patients with PD-L1 <1%, advanced NSCLC (Figure 2A,2B), non-squamous (Figure 2C) and squamous NSCLC (Figure 2D), respectively. These 21 first-line treatment regimens were categorized as follows: Chemo alone; chemotherapy plus PD-1 inhibitors (aPD-1) (22,23,27-31,34,38-41) [e.g., Pembro-chemo, sintilimab (Sinti-chemo), cemiplimab (Cemip-chemo), nivolumab (Nivo-chemo), tislelizumab (Tisle-chemo), camrelizumab (Camre-chemo), penpulimab (Penpu-chemo), and toripalimab (Torip-chemo)]; chemotherapy combined with PD-L1 inhibitors (aPD-L1) (19,20,36,42,43,45,46) [e.g. sugemalimab (Sugema-chemo), atezolizumab (Atezo-chemo), and durvalumab (Durva-chemo)]; aPD-L1 monotherapy (7) (Durva); dual immunotherapy with/without chemotherapy (8,9,22,40,43-45), including nivolumab plus ipilimumab (Nivo-ipi), Nivo-ipi-chemo, durvalumab plus tremelimumab (Durva-treme), and Durva-treme-chemo; combinations utilizing anti-angiogenesis (19,25,26), including atezolizumab plus bevacizumab and chemotherapy (Atezo-beva-chemo), nivolumab plus bevacizumab and chemotherapy (Nivo-beva-chemo), and Beva-chemo; lastly, pembrolizumab plus chemotherapy and canakinumab (Pembro-chemo-canakinumab) (10). The most studied regimen is Chemo (n=1,614), followed by aPD-1/chemo (n=1,460) and aPD-L1/chemo (n=884). Despite the lack of individual patient-level data such as age and sex, transitivity assumptions were met due to comparable eligibility criteria, experimental designs, and treatment regimens across trials. Consistency was locally confirmed by consistent results between PWMA and NMA (Table S1); and generally verified by lower DIC values for consistency models (Table S2).

Figure 2 Network plots comparing efficacy and toxicity of 21 first-line drug combinations in PD-L1 <1%, advanced NSCLC based on the histological types. Comparisons used a Bayesian framework for: (A) OS, PFS, (B) ORR, and Grade ≥3 TRAEs, (C) OS and PFS in NSQ patients, and (D) OS and PFS in SQ patients. Each node represents a treatment regimen, with the size of each node proportional to the number of patients per regimen. Edge thickness reflects the number of studies per direct comparison. Atezo, atezolizumab; Beva, bevacizumab; Camre, camrelizumab; Cemip, cemiplimab; Chemo, chemotherapy; Durva, durvalumab; Ipi, ipilimumab; Nivo, nivolumab; NSCLC, non-small cell lung cancer; NSQ, non-squamous; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell death ligand 1; Pembro, pembrolizumab; Penpu, penpulimab; Sinti, sintilimab; PFS, progression-free survival; SQ, squamous; Sugema, sugemalimab; Tisle, tislelizumab; Torip, toripalimab; TRAEs, treatment related adverse events; Treme, tremelimumab.

Comparative OS, PFS, ORR, and TRAEs of drug combinations

In terms of OS (Figure 3A), Pembro-chemo-canakinumab (SUCRA =0.90, HR =0.85, 95% CI: 0.62–1.16), and Nivo-ipi (SUCRA =0.79, HR =1.00, 95% CI: 0.73–1.36) showed comparable OS benefits to Pembro-chemo (SUCRA =0.78). Notably, these three regimens (Pembro-chemo-canakinumab, Nivo-ipi, and Pembro-chemo) offered greater OS advantages than Durva-treme, Durva-chemo, Chemo, Durvalumab, and Tisle-chemo. Additionally, Nivi-ipi-chemo and Atezo-chemo showed superiority over Chemo, with HR of 0.69 (95% CI: 0.54–0.88) and 0.80 (95% CI: 0.68–0.95). Among aPD-1/chemo combinations, Pembro-chemo yielded the most favorable OS outcomes, whereas Tisle-chemo performed the worst (HR =2.35, 95% CI: 1.30–4.24 vs. Pembro-chemo).

Figure 3 Comprehensive colleague tables comparing 21 first-line treatments in each column against treatment in each row. (A) HRs with 95% CIs for OS and PFS, (B) ORs with 95% CIs for ORR and grade ≥3 TRAEs in overall NSCLC population. Bolded values indicate statistically significant differences. HR <1 favors the column treatment for OS and PFS; OR >1 favors the column treatment for ORR, but indicates increased toxicity for TRAEs. Significance is inferred when 95% CIs exclude 1. SUCRA determined the treatment rankings, with values ranging from 0 to 1, with higher values indicating better efficacy or higher toxicity. Atezo, atezolizumab; Beva, bevacizumab; Camre, camrelizumab; Cemip, cemiplimab; Chemo, chemotherapy; CIs, confidence intervals; Durva, durvalumab; PFS, progression-free survival; HRs, hazard ratios; Ipi, ipilimumab; Nivo, nivolumab; NSCLC, non-small cell lung cancer; NSQ, non-squamous; OR, odds ratio; ORR, objective response rate; OS, overall survival; Pembro, pembrolizumab; Penpu, penpulimab; PD-L1, programmed cell death ligand 1; Sinti, sintilimab; SQ, squamous; SUCRA, surface under the cumulative ranking value; Sugema, sugemalimab; Tisle, tislelizumab; Torip, toripalimab; TRAEs, treatment related adverse events; Treme, tremelimumab.

For PFS, Nivo-beva-chemo (SUCRA =0.88, HR =0.65, 95% CI: 0.40–1.04) was the best, followed by Serplu-chemo (SUCRA =0.87, HR =0.67, 95% CI: 0.43–1.03), Torip-chemo (SUCRA =0.85, HR =0.68, 95% CI: 0.43–1.06), and Atezo-beva-chemo (SUCRA =0.81, HR =0.73, 95% CI: 0.52–1.03). Serplu-chemo provided better PFS than Nivo-chemo (HR =0.63, 95% CI: 0.40–0.99).

Regarding ORR (Figure 3B), Pembro-chemo seemed to be the optimal treatment (ORR =2.31, 95% CI: 1.28–4.21 vs. Atezo-chemo; ORR =2.37, 95% CI: 1.22–4.66 vs. Nivo-ipi), followed by Atezo-beva-chemo. Retrieving data on TRAEs for participants with PD-L1 expression <1% proved challenging; hence, safety profiles were assessed in a broader patient cohort with unselected PD-L1 expression. TRAEs of grade ≥3 were most frequent in patients receiving the following combinations: Atezo-beva-chemo (OR =2.37, 95% CI: 1.59–3.54), Nivo-beva-chemo (OR =1.80, 95% CI: 1.04–3.11), Beva-chemo (OR =1.66, 95% CI: 1.12–2.47), and Nivo-ipi-chemo (OR =1.51, 95% CI: 1.12–2.02), all of which showed higher toxicity compared to Pembro-chemo.

Subgroup analysis

In the NMA of non-squamous NSCLC, 11 studies encompassing 2,689 patients were analyzed. Data for OS and PFS were available from 11 and 8 studies, respectively. As shown in Figure 4A, none of the treatments provided better OS outcomes than Pembro-chemo, while Nivo-beva-chemo showed PFS superiority (SUCRA =0.94, HR =0.52, 95% CI: 0.30–0.92). Among the analyzed treatment regimens, Pembro-chemo demonstrated the best OS benefit with SUCRA value of 0.90, followed by Nivo-beva-chemo (SUCRA =0.82), and Nivo-ipi (SUCRA =0.66). Nivo-beva-chemo (SUCRA =0.94) emerged as the most effective regimen in terms of PFS.

Figure 4 Forest plots of subgroup analyses in patients with different histological types, with Pembro-chemo as the reference. HRs and 95% CIs for (A) OS and (B) PFS. HR <1 indicates better survival than Pembro-chemo. aCTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; aPD-1, programmed cell death 1 inhibitor; aPD-L1, programmed cell death ligand 1 inhibitor; Atezo, atezolizumab; Beva, bevacizumab; Camre, camrelizumab; Cemip, cemiplimab; Chemo, chemotherapy; CIs, confidence intervals; Durva, durvalumab; HRs, hazard ratios; Ipi, ipilimumab; Nivo, nivolumab; NSCLC, non-small cell lung cancer; NSQ, non-squamous; ORR, objective response rate; OS, overall survival; Pembro, pembrolizumab; Penpu, penpulimab; PFS, progression-free survival; Sinti, sintilimab; SQ, squamous; SUCRA, surface under the cumulative ranking value; Sugema, sugemalimab; Tisle, tislelizumab; Torip, toripalimab; TRAEs, treatment related adverse events; Treme, tremelimumab.

For squamous NSCLC, the NMA included 10 studies involving 1,588 patients, with OS and PFS data available in seven studies. None of the treatments significantly outperformed Pembro-chemo in terms of OS and PFS (Figure 4B). Nivo-ipi-chemo (SUCRA =0.88, HR =0.60, 95% CI: 0.33–1.09) and Nivo-ipi (SUCRA =0.87, HR =0.63, 95% CI: 0.37–1.07) were the most effective strategies, suggesting possible OS advantages over Pembro-chemo. For PFS, Serplu-chemo ranked first (SUCRA =0.84), followed by Camre-chemo (SUCRA =0.78), both offering better outcomes than Atezo-chemo.

Comparative OS, PFS, ORR, and TRAEs of categorized combinations

To better understand the synergistic effects of each combination, we re-analyzed the data after categorizing all drug combinations into 12 groups based on their mechanism of action (Figure 5): Chemo, aPD-1/chemo, aPD-L1/chemo, aPD-L1, aPD-1/aCTLA-4, aPD-L1/aCTLA-4, aPD-1/aCTLA-4/chemo, aPD-L1/aCTLA-4/chemo, aPD-1/antiangio/chemo, aPD-L1/antiangio/chemo, aPD-1/chemo/aIL-1β, Antiangio/chemo. The rank probability profiles of PFS, OS, and ORR were presented in Table S3.

Figure 5 Network plots comparing 11 categorized treatments in PD-L1 <1%, advanced NSCLC, by histological subtype. Comparisons used a Bayesian framework for: (A) OS, PFS, (B) ORR, and grade ≥3 TRAEs, (C) OS and PFS in NSQ patients, and (D) OS and PFS in SQ patients. Each node represents a treatment regimen, with the size of each node proportional to the number of patients per regimen. Edge thickness reflects the number of studies per direct comparison. aCTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; aIL-1β, interleukin 1β inhibitor; Antiangio, antiangiogenesis; aPD-1, programmed cell death 1 inhibitor; aPD-L1, programmed cell death ligand 1 inhibitor; Chemo, chemotherapy; NSCLC, non-small cell lung cancer; NSQ, non-squamous; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SQ, squamous; TRAEs, treatment related adverse events.

In the OS analysis of categorized strategies (Figure 6A), the most effective strategy for OS was aPD-1/aCTLA-4, showing significant improvements over aPD-L1/aCTLA-4 (HR =0.70, 95% CI: 0.51–0.95) and aPD-L1/chemo (HR =0.76, 95% CI: 0.60–0.96); as well as potential advantages over chemo/antiangio (HR =0.73, 95% CI: 0.52–1.02) and aPD-1/chemo (HR =0.83, 95% CI: 0.68–1.02).

Figure 6 Comprehensive colleague tables comparing 11 categorized treatments in each column against treatment in each row. (A) HRs with 95% CIs for OS and PFS, (B) ORs with 95% CIs for ORR and Grade ≥3 TRAEs in overall NSCLC population. Bolded values indicate statistically significant differences. HR <1 favors the column treatment for OS and PFS; OR >1 favors the column treatment for ORR, but indicates increased toxicity for TRAEs. Significance is inferred when 95% CIs exclude 1. SUCRA determined the treatment rankings, with values ranging from 0 to 1, with higher values indicating better efficacy or higher toxicity. aCTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; aIL-1β, interleukin 1β inhibitor; Antiangio, antiangiogenesis; aPD-1, programmed cell death 1 inhibitor; aPD-L1, programmed cell death ligand 1 inhibitor; Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer; NSQ, non-squamous; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SQ, squamous; SUCRA, surface under the cumulative ranking value; TRAEs, treatment related adverse events.

In terms of PFS (Figure 6A), the top-ranking regimen for PFS was aPD-1/chemo/antiangio, followed by aPD-L1/chemo/antiangio and aPD-1/chemo. However, regimens containing antiangiogenic drugs seemed to be associated with more Grade ≥3 TRAEs, with aPD-L1/antiangio/chemo had the highest toxicity (SUCRA =0.98). The use of antiangiogenic agents was associated with a significantly higher toxicity than aPD-1/chemo, aPD-(L)1/aCTLA-4, chemotherapy, or aPD-L1 monotherapy. Importantly, the toxicity of aPD-1/aCTLA-4/chemo was greater than aPD-1/aCTLA-4 (OR =1.67, 95% CI: 1.2–2.33). Results of NMA for categorized treatments based on histological types are shown in Figure S4. Regarding ORR and safety (Figure 6B), aPD-L1/chemo/antiangio was the optimal treatment, albeit with the highest toxicity.

Sensitivity analysis

The results of sensitivity analyses are summarized in Table 2 (as detailed in Figures S5-S7), showing the HRs and their 95% CI for OS of each treatment regimen compared to Pembro-chemo. The results of Nivo-ipi and Nivo-ipi-chemo were highly consistent across varying follow-up durations, with robust OS benefits comparable to Pembro-chemo. Conversely, some treatment regimens, such as Pembro-chemo-canakinumab and Sugema-chemo, showed potential benefits only in short-term follow-up. However, the durability of their efficacy remains uncertain due to the lack of long-term follow-up data.

Discussion

This study summarized the latest evidence and filled a critical literature gap by offering a comprehensive overview of the comparative effectiveness and safety of all first-line treatments for treatment-naïve advanced NSCLC with PD-L1 <1% and no actionable mutations. The general recommendations that emerged from this study are as follows: (I) for overall population, Nivo-ipi and Nivo-ipi-chemo provided long-term survival benefits comparable to Pembro-chemo. However, Nivo-ipi-chemo was associated with higher toxicity. Nivo-beva-chemo emerged as the most effective regimen in terms of PFS. (II) For non-squamous NSCLC, Nivo-chemo-beva stood out as the most effective strategy for PFS, albeit with increased toxicity. Pembro-chemo remained the most effective regimen for OS. (III) For squamous patients, Serplu-chemo provided the best PFS benefits, and Nivo-ipi with or without chemotherapy was optimal for OS. (IV) Pembro-chemo-canakinumab, and some emerging aPD-(L)1/chemo combinations, such as Sugema-chemo, Penpu-chemo, and Camre-chemo showed promising short-term OS improvements comparable to Pembro-chemo. However, further validation for these regimens is needed in the long-term. (V) When it comes to mechanism-based combinations, aPD-1/aCTLA-4 potentially outperformed aPD-1/chemo. Additionally, the survival outcomes of regimens containing aPD-1 were potentially more favorable than that of combinations containing PD-L1 inhibitors, especially in combination with CTLA-4 inhibitors.

Our findings substantiated the use of aPD-1/aCTLA-4 (Nivo-ipi) combination as providing substantial long-term OS benefits. This combination leverages the complementary mechanisms of action of two different ICI, aPD-1 and aCTLA-4. PD-1 inhibitor works by blocking the PD-1 receptor on T cells, hindering its interaction with PD-L1 and PD-L2, thus reinvigorating T-cell activity and augmenting the immune response to defense and eliminate cancer cells (50,51). On the other hand, antibodies against CTLA-4 (e.g., tremelimumab and ipilimumab) are designed to block the interaction between B7 molecules and CTLA-4 receptor, which serves as an inhibitory regulator of T-cell activation, thereby promoting an effective immune response against tumor cells. As of now, aPD-1/aCTLA-4 has currently received approval for the treatment of several advanced solid tumors, including melanoma, hepatocellular carcinoma, renal cell carcinoma, and NSCLC. In addition to Nivo-ipi, several other aPD-1/aCTLA-4 combinations are under investigation in clinical trials, some of these include sintilimab combined with IBI310 (NCT05118334), as well as bifunctional PD-1/CTLA-4 dual blocker (e.g., cadonilimab and QL1706) (52,53). However, the comparative efficacy between Nivo-ipi-chemo and Pembro-chemo remains a matter of debate. A real-world study reported that Nivo-ipi/chemo led to better OS than Pembro-chemo in PD-L1 negative patients. Differently, our evidence based on direct and indirect comparisons showed that Nivo-ipi/chemo, provided substantial survival benefits comparable to those of Pembro-chemo (54). Moreover, the first head-to-head trial, JCOG2007, directly comparing Pembro-chemo with Nivo-ipi/chemo, revealed no OS difference between groups. Given that the potential for immature data in the final OS analysis with a median follow-up duration of only 15.3 months, extended follow-up data deserves close attention to further validate the comparative efficacy. In summary, given the comparable efficacy to Pembro-chemo and its potential cost-saving benefits (55,56), Nivo-ipi with or without chemotherapy offers a promising treatment alternative, especially for patients with heavy economic burdens.

Furthermore, in addition to dual ICI regimens, canakinumab selectively targeting IL-1β has also been explored in advanced NSCLC when combined with Pembro-chemo in one recent published trial (CANOPY-1) (10). Although this study failed to achieve its endpoints in the general population the subgroup analyses revealed some evidence suggesting that canakinumab may potentially reduce the risk of death compared to Pembro-chemo, particularly in patients with PD-L1 expression <1%. This potential benefit may be attributed to the immunomodulatory effects of IL-1β inhibitors and chemoimmunotherapy, indicating a need for further exploration of its role in cancer treatment. Given the relatively short follow-up duration of <2 years, it is crucial to closely monitor subsequent updates in OS data.

Notably, an intriguing and highly clinically relevant finding from our analysis was that aPD-1/antiangio/chemo (Nivo-beva-chemo) regimens offer PFS advantages but lack OS benefits for untreated, PD-L1 negative advanced NSCLC without actionable alterations. Currently, pembrolizumab as a partner for chemotherapy has been recommended as the preferred initial systemic treatment by guidelines (57-59). However, an advantageous PFS of aPD-1/antiangio/chemo over aPD-1/chemo was observed, and our drug-specific analyses indicated that Nivo-beva-chemo led to a significantly longer PFS than Pembro-chemo. The observed improvement in PFS can be explained by the synergistic effects between PD-1 inhibitors and antiangiogenic agents on the tumor microenvironment (TME) by normalizing the vascular structure, blocking the various immunosuppressive effects induced by vascular endothelial growth factor on the TME, promoting infiltration of immune cells, increasing intratumoral blood perfusion and flow, and establishing an immune-supportive TME (60). Additionally, in hypoxic circumstances, PD-L1 expression mediated by interferon-γ is upregulated by antiangiogenic therapy in order to enhance the efficacy of immunotherapy. However, despite its promising short-term effects, the underlying mechanisms of immune escape, tumor evolution, and resistance may counteract its long-term impact, limiting the durability of treatment effects. Additionally, subsequent lines of therapy often employed once progression occurs, should be fully taken into consideration, which may potentially obscure the long-term benefits of the initial regimen. Although aPD-1/antiangio/chemo provides promising PFS benefits, additional studies are warranted to evaluate its impact on long-term survival and to develop effective sequential treatment strategies that could optimize survival outcomes in the clinical setting.

Further, the synergistic effects of PD-(L)1 inhibitors and chemotherapy observed in our study align with finds from earlier meta-analyses (16). Chemotherapy has been proved to possess immunostimulatory properties (61,62) through upregulating PD-L1 expression and modulating the TME, even though it has traditionally been assumed to be immunosuppressive because of its cytotoxic effects,. Interestingly, our analysis further revealed the potential superiority of regimens containing aPD-1 over aPD-L1-based combinations, which aligns with a recent research (63) evaluating survival outcomes across various cancer types, suggesting that aPD-1 therapies are associated with more favorable prognosis and a comparable safety profile relative to aPD-L1 therapies. We validated this finding specifically in subpopulations with confirmed advanced NSCLC, PD-L1 expression <1% and no targetable gene mutations.

Ongoing advancements in cancer immunotherapy are exploring new avenues for the treatment of advanced NSCLC. One promising candidate under evaluation is SKB264, an antibody-drug conjugate (ADC) that targets trophoblast cell surface antigen 2 (TROP2), a protein that commonly overexpressed in solid tumors correlated with tumor progression, aggressiveness and worse prognosis. SKB264 is being investigated as a potential treatment for NSCLC (64), when combined with pembrolizumab. Another exciting direction in immunotherapy is the development of next-generation ICI targeting novel molecules such as T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing 3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) (65). These molecules represent novel targets for cancer immunotherapy and are being actively investigated in clinical trials. For instance, an ongoing study named SKYSCRAPER-06 investigated the effectiveness an TIGIT antibody as a partner for Atezo-chemo to treat NSCLC in the first-line setting. Although the trial failed to achieve its primary endpoint, subsequent research is needed to explore the potential benefits of these next-generation immunotherapies. The benefits of these treatments either alone or in combination with existing medications, should be further assessed in upcoming studies to confirm their clinical value.

However, several limitations of this work should be acknowledged. First, while the study reported the occurrence of TRAEs (66), it failed to provide stratified data specific to PD-L1 negative patients. This omission limits the precision of toxicity management for personalized treatment strategies. Future research should provide such detailed subgroup analyses to balance efficacy and safety more effectively. Second, the results targeting PD-L1 negative patients stemmed from a subgroup analysis of clinical trials, which are inherently subject to potential bias and should be carefully taken into interpretation. Third, data sparsity was notable for certain regimens. For example, findings on aPD-1/chemo/aIL-1β combinations are based on a single trial, and conclusions on antiangiogenesis combination therapies rely on only two trials. The limited evidence reduces the reliability of our conclusions and fails to comprehensively reflect the true efficacy of these regimens. Additionally, several treatment comparisons were noticeably indirect given paucity of head-to-head research, particularly combinations like aPD-(L)1/antiangio/chemo, and aPD-(L)1/aCTLA-4 with or without chemotherapy. The long-term survival benefits of certain therapies, such as Pembro-chemo-canakinumab, Nivo/chemo/beva remained to be validated, which limits the comprehensive evaluation of these regimen’s durability. Finally, economic analyses, such as cost-effectiveness evaluations, are essential for clinical decision-making, especially when comparing complex treatment regimens. However, this study does not address this aspect, which diminishes its practical applicability, particularly in resource-limited settings. Further clinical trials are essential to address these limitations, generating more comprehensive efficacy and safety data, and directly comparing regimens to validate their long-term benefits.

Conclusions

In conclusion, this meta-analysis provides insights based on the most up-to-data evidence into the long-term benefits and harms of various promising first-line systemic therapies for previously untreated PD-L1 negative advance NSCLC, as well as introducing evidence-based recommendations for histology-based subpopulations. Pembro-chemo and Nivo-beva-chemo combinations are recommended as the optimal first-line options for non-squamous patients, and Nivo-ipi-chemo for squamous patients. However, caution is advised when using regimens containing antiangiogenic agents due to the increased toxicity. The long-term benefits of adding aIL-1β to Pembro-chemo deserves further exploration.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-NMA reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-371/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-371/prf

Funding: This study was financed by the Beijing Municipal Natural Science Foundation (No. L222151), National High-Level Hospital Clinical Research Funding (State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University), and Beijing Xisike Clinical Oncology Research Foundation (No. Y-HS202202-0073). The funders of the study had no involvement in designing, collecting, analyzing, and interpreting data, or writing the manuscript.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-371/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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