PD-1/PD-L1 inhibitor plus chemotherapy versus bevacizumab plus chemotherapy in first-line treatment for non-squamous non-small-cell lung cancer

Anti-PD-1)/programmed cell death-ligand 1 (PD-L1) antibody plus platinum-based chemotherapy (PBC) has replaced PBC as first-line treatment for patients with non-squamous (sq) non-small cell lung cancer (NSCLC) lacking targetable driver mutations. However, few studies have directly compared immune checkpoint inhibitor (ICI) plus chemotherapy with bevacizumab plus chemotherapy (beva +chemo) in this setting. Herein, we conducted an indirect comparison for anti-PD-1/PD-L1 antibody plus chemotherapy (ICI +chemo) versus beva +chemo in non-sq NSCLC using the frequentist methods. The main outcomes analyzed include progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Data were subtracted from randomized trials comparing ICI +chemo or beva +chemo against PBC. Fourteen trials involving 6165 patients were included. Direct meta-analyses showed that both ICI +chemo (PFS: HR 0.58, OS: HR 0.73, ORR: relative risk (RR) 1.66) and beva +chemo (PFS: HR 0.74, OS: HR 0.89, ORR: RR 1.62) improved clinical outcomes compared with PBC. Indirect comparison showed that ICI +chemo reduced the risk of disease progression (HR 0.78, 95% CI 0.60 to 1.00) and death (HR 0.82, 95% CI 0.71 to 0.94) compared with beva +chemo. The PFS benefits with ICI +chemo over beva +chemo were non-significant in those with negative PD-L1 expression and non-smokers. In conclusion, ICI +chemo is superior to beva +chemo in first-line treatment for non-sq NSCLC.


INTRODUCTION
Lung cancer is the leading cause of cancerrelated mortality worldwide. 1 For decades, platinum-based chemotherapy (PBC) had been the standard-of-care first-line treatment for patients with advanced non-squamous (sq) non-small cell lung cancer (NSCLC) before the era of immune checkpoint inhibitor (ICI) therapies. The addition of bevacizumab to PBC (bevacizumab plus chemotherapy (beva +chemo)) further improved patients' survival relative to PBC in non-sq NSCLC. [2][3][4] For patients lacking sensitizing mutations, the combination of antiprogrammed cell death 1 (PD-1) or antiprogrammed cell death-ligand 1 (PD-L1) antibody with PBC (ICI +chemo) has significantly prolonged overall survival (OS) and progression-free survival (PFS) compared with PBC alone. 5 However, since the control group of these trials was PBC alone rather than beva +chemo, it remains unknown whether ICI +chemo is superior to beva +chemo for non-sq NSCLC or whether we should retain ICI as second-line treatment following beva +chemo.
Indirect treatment comparison has been demonstrated to provide useful evidence in the absence of randomized controlled trials involving a direct comparison. 6 Due to the lack of direct comparison, we conducted this indirect meta-analysis to investigate the magnitude of treatment benefit of ICI+chemo over beva +chemo in non-sq NSCLC.

Data sources and searches
PubMed, Embase, Cochrane Library, and major oncology conferences were searched for relevant studies. We used main subject terms including PD-1, PD-L1, bevacizumab, non-small cell lung carcinoma, and randomized controlled trials, etc (online supplemental additional methods).

Data extraction
The following outcomes were extracted from the included trial: PFS, OS, objective response rate (ORR) and treatment-related adverse events (AEs). Other details such as the acronym of the trial, treatment, and Open access patient characteristics were also included in the information sheet.
Assessment of study quality Trial quality was assessed by using Cochrane Risk of Bias Tool. 7

Statistical analysis
We first performed direct meta-analyses comparing ICI+chemo with chemotherapy, and beva+chemo with chemotherapy, respectively. We calculated the pooled HR for PFS and OS by applying the generic inverse-variance methods model and the pooled relative risks (RRs) for ORR and AEs by using the Mantel-Haenszel method. Heterogeneity was evaluated using Cochran's Q test; a p value of <0.1 and I 2 of >50% represented statistical heterogeneity, and a random effect model was used; otherwise, a fixed effect model was used.
Linked by arm C (chemotherapy), indirect comparisons between arm A (ICI+chemo) and arm B (beva +chemo) were further performed, applying the frequentist methods with the following formula 8 : log HR AB =log HR AC −log HR BC , and its SE for the log HR was was calculated in the same way. All statistical analyses were conducted using Stata software V.16.0. A two-sided p value of <0.05 defined statistical significance.

RESULTS
Eligible studies and patient characteristics A total of 14 studies were included (online supplemental additional figure S1), 6 of which investigated the efficacy of beva +chemo (n=1264) versus chemotherapy (n=1219), while the other 8 trials explored ICI+chemo (n=2177) versus chemotherapy (n=1505). Detailed characteristics of the included trials are summarized in table 1 and online supplemental additional table S1.

DISCUSSION
In this indirect meta-analysis, ICI +chemo was found to prolong both PFS and OS without increasing toxicity when compared with beva +chemo in the first-line treatment for advanced non-sq NSCLC. The PFS benefit was more obvious in patients with PD-L1 TPS of ≥50%. These findings consolidate the role of ICI in front-line treatment of patients with NSCLC, especially for those with high PD-L1 expression.
In updated analysis from IMpower150 study, atezolizumab plus carboplatin plus paclitaxel failed to prolong PFS (HR 0.91, 95% CI 0.78 to 1.06) or OS (HR 0.85, 95% CI 0.71 to 1.03) compared with bevacizumab plus carboplatin plus paclitaxel. 9 This raised growing concern about whether ICI should be placed in first-line setting. This concern is relevant because few studies have used beva+chemo as control arm despite the fact that this regimen is more efficacious than chemotherapy alone. In our study with more patients analyzed, ICI +chemo and beva +chemo yielded similar ORR (RR 1.02, 95% CI 0.79 to 1.33). However, ICI +chemo was associated with a 22% reduction in the risk of disease progression or death (HR 0.78, 95% CI 0.60 to 1.00) and a 18% reduction in the risk of death (HR 0.82, 95% CI 0.71 to 0.94) compared with beva +chemo. One important reason for the discrepancies among ORR, PFS and OS benefit was the longer duration of response for patients treated with ICI +chemo than with beva +chemo (median 8.4-36.3 months vs 6.1-8.0 months, table 1). Another important finding was that the magnitude of survival benefit with ICI +chemo was reduced when the control group shifted from   Open access chemotherapy to beva +chemo (our previous pooled analysis showed that ICI +chemo was associated with 38% and 32% reduction in the risk of disease progression/death and death compared with chemotherapy alone, respectively 5 ). This implied that the delayed application of bevacizumab in most ICI +chemo trials may be detrimental for patients in the control group. One open question is whether combing ICI, bevacizumab and chemotherapy together in a first-line setting will further improve survival benefit. This is partially addressed in the IMpower150 9 and LUN 17-139 10 studies, both of which showed that ICI plus beva+chemo (ICI +beva+chemo) prolongs PFS compared with beva +chemo, but at the expense of more toxicities. However, whether ICI +beva+chemo outperforms ICI +chemo remains a question to be answered with randomized studies in the future. Interestingly, subgroup analysis from IMpower150 indicates that ICI +beva+chemo may provide survival benefit in patients who are less likely to respond to ICI, such as those with liver metastasis or epidermal growth factor receptor (EGFR) mutation. 9 The PD-L1 expression was an established biomarker for anti-PD-1/PD-L1 monotherapy in NSCLC and remains a suitable biomarker to predict the PFS benefit with ICI+chemo versus beva +chemo in this study. PD-L1 TPS of ≥50% was associated with significantly longer PFS (HR 0.51, 95% CI 0.37 to 0.70) with ICI+chemo versus beva +chemo, while patients with PD-L1 of less than 1% had comparable PFS when treated with ICI+chemo or beva +chemo (HR 0.92, 95% CI 0.69 to 1.23). ICI+chemo also did not produce PFS benefit in non-smokers. Further studies were warranted to explore predictive biomarker to differentiate beneficiary from ICI+chemo versus beva +chemo.
In terms of toxicity, ICI +chemo and beva +chemo were comparable for AEs of ≥grade 3 (HR 0.82, 95% CI 0.55 to 1.22), but the risk of AEs leading to death was significantly lower with ICI +chemo versus beva +chemo (HR 0.56, 95% CI 0.32 to 0.97). However, since the profiles of AEs for ICI and bevacizumab were different, the risk of AEs should be assessed individually. For example, patients with hypertension or high bleeding risk might suffer greater risk from bevacizumab, while patients with autoimmune disease might suffer greater risk from ICI. 11 Based on our observation, we cautiously postulate the following recommendations: for patients with PD-L1 TPS of at least 50% and without contraindications for immunotherapy, ICI+chemo should be preferred compared with beva+chemo; for patients with PD-L1 TPS of less than 50%, ICI+chemo is recommended, but beva+chemo could serve as an alternative, especially for those with PD-L1 TPS of less than 1% or/and with high risk of developing immune-related AEs or hyperprogression disease. 11 The high quality of the enrolled trials and the low heterogeneity between trials make this analysis reliable. Nevertheless, several limitations should be noted. First, this is an indirect analysis and due to the different inclusion and exclusion criteria between the ICI+chemo trials and beva+chemo trials, the patients' characteristics might not be well balanced between the two groups. Thus, the result should be interpreted with extra caution. However, considering that a prospective trial that compares ICI+chemo with beva+chemo is unlikely to be conducted, this analysis would meet current clinical needs. Second, the results regarding OS should be further investigated in prospective trials, since patients who received beva+chemo in this study did not cross over to immunotherapy in later-line treatments.
In conclusion, ICI+chemo was associated with significantly longer PFS and OS and comparable risk of AEs compared with beva +chemo. PD-L1 expression might be a predictive biomarker of PFS benefit with ICI+chemo versus beva +chemo.