Comparative Efficacy and Safety of First-Line Immune Checkpoint Inhibitors Plus Chemotherapy with or Without Bevacizumab in Advanced Non-Squamous Non-Small Cell Lung Carcinoma

TL;DR

Adding bevacizumab to immunotherapy and chemotherapy improves progression-free survival in lung cancer but increases toxicity without improving overall survival.

Contribution

This study clarifies the role of bevacizumab in modern chemoimmunotherapy for non-squamous lung cancer through real-world data and network meta-analysis.

Findings

Bevacizumab added to chemoimmunotherapy improved progression-free survival but not overall survival.

Higher toxicity was observed with the addition of bevacizumab, including more severe adverse events and treatment discontinuations.

No patient subgroup clearly benefited from bevacizumab without increased risks.

Abstract

For patients with advanced non-squamous non-small cell lung cancer lacking EGFR or ALK mutations, initial treatment typically involves a combination of chemotherapy and immunotherapy. While adding the anti-angiogenic drug bevacizumab to chemotherapy has previously shown benefit, its role when combined with modern chemoimmunotherapy was uncertain. This study found that incorporating bevacizumab into first-line chemoimmunotherapy significantly improved progression-free survival, especially for patients with high-risk features. However, this was accompanied by significantly increased treatment-related toxicities and no overall survival benefit. Consequently, our data identified no clinical subgroup where the benefit clearly outweighs these risks, necessitating extreme caution in its clinical application.

Background: First-line chemoimmunotherapy (I + C) is the standard of care for advanced non-squamous non-small cell lung cancer (NSCLC) without oncogenic mutation. Bevacizumab has been shown to enhance the efficacy of chemotherapy in non-squamous NSCLC, yet its added value when combined with I + C (I + C + B) remains unclear. To address this gap, we conducted a real-world comparative study and a network meta-analysis to evaluate I + C + B versus I + C in this setting. Methods: This retrospective study included patients with advanced EGFR/ALK-negative non-squamous NSCLC treated with first-line I + C + B or I + C. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Efficacy endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined outcomes by PD-L1 expression, age, metastases, and chemotherapy, among other factors. In parallel, a network meta-analysis of four randomized trials (n = 2026) indirectly compared I + C + B against I + C for PFS, OS, and safety outcomes. Results: A total of 277 patients were included, with 167 (60.3%) receiving I + C + B and 110 (39.7%) receiving I + C. Before PSM, the I + C + B regimen significantly prolonged PFS versus I + C (hazard ratio [HR] = 0.69, 95% CI 0.52–0.92, p = 0.010), with this benefit maintaining post-matching (HR = 0.70, 95% CI 0.49–0.99, p = 0.045). However, OS did not differ significantly between groups in either the pre-PSM (HR = 0.93, 95% CI: 0.67–1.30; p = 0.665) or matched analyses (HR = 0.84, 95% CI: 0.54–1.29; p = 0.421). Subgroup analyses suggested greater PFS benefit from I + C + B among PD-L1-negative, older patients, those with brain metastases or multiple metastatic sites, and in patients receiving specific chemotherapy doublets. The network meta-analysis confirmed a PFS advantage for I + C + B over I + C (HR = 0.84, 95% CI: 0.71–0.98) without an OS benefit (HR = 0.95, 95% CI: 0.79–1.14). Toxicity was higher with I + C + B; rates of grade 3–5 adverse events, serious adverse events, and treatment discontinuation were all significantly increased compared to I + C. Conclusions: In the first-line treatment of advanced EGFR/ALK-negative non-squamous NSCLC, adding bevacizumab to I + C improved PFS but did not translate into an OS gain. Although PFS benefits were observed in certain subgroups, these were accompanied by significantly increased treatment-related toxicities. Our findings suggest that no clear subgroup has been identified where the benefit outweighs the risks, necessitating extreme clinical caution.

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