A new hope for aggressive thoracic cancers: foundational efficacy of frontline immunotherapy in SMARCA4-deficient tumors

The retrospective analysis by Liu et al. (1) provides compelling evidence supporting that immune checkpoint inhibitors (ICIs) significantly improve survival in advanced SMARCA4-deficient thoracic tumors, with first-line ICI-based therapy extending median overall survival (OS) to 21.67 months versus 8.80 months for non-immunotherapy approaches (P=0.003). The most striking finding is the unprecedented efficacy of combining ICIs with anti-angiogenic agents (anlotinib), demonstrating a median progression-free survival (PFS) of 20.43 months and unreached median OS—significantly surpassing chemotherapy-ICI combinations (1). Three patients [2 with undifferentiated tumors (dUT)] receiving this regimen achieved durable responses >12 months, including two exceeding 36 months (1). This suggests potential synergy between vascular normalization and immune reactivation in these historically treatment-resistant tumors. The synergy observed aligns with preclinical evidence that anti-angiogenics normalize tumor vasculature, enhancing T-cell infiltration and reversing immunosuppressive microenvironments (2).

However, three critical considerations warrant caution. First, the 5-patient cohort for ICI-anlotinib therapy precludes definitive safety conclusions, particularly given known anlotinib adverse effects (11.9–46.3% ≥ grade 3) (3,4). Second, the choice of anlotinib over vascular endothelial growth factor (VEGF)-specific agents like bevacizumab lacks robust justification. While bevacizumab increases ≥ grade 3 hypertension versus chemotherapy (7% vs. <1%) (5), its toxicity profile remains favorable compared to multi-target tyrosine kinase inhibitors (TKIs). Third, biomarker discordances—including the lack of programmed death-ligand 1 (PD-L1) correlation (P=0.84) (1) and unexplored impact of STK11 mutations (23.6%) (1) known to drive ICI resistance (6)—highlight unresolved predictive challenges.

Clinically, this study provides two transformative insights: first-line immunotherapy significantly prolonged progression-free survival compared to delayed administration (13.93 vs. 6.95 months), though this difference did not reach statistical significance (P=0.27) (1). Furthermore, no significant difference in overall survival was observed between deficient non-small cell lung cancer (dNSCLC) and dUT (13.70 vs. 15.70 months, P=0.42), indicating a histology-independent treatment benefit and challenging prior assumptions regarding the poorer prognosis of undifferentiated malignancies (7).

For future research, we recommend prospective validation of ICI combined with anlotinib alongside powered safety analyses, direct comparisons between anti-angiogenic agent classes (e.g., TKIs vs. monoclonal antibodies), and integrated biomarker studies incorporating tumor mutation burden (TMB) (8), single-cell analysis and spatial transcriptomics (9). While this retrospective analysis has limitations—including missing toxicity data and small sample sizes—the findings underscore ICI-based combinations as a promising foundational strategy for these aggressive cancers. Clinicians should consider this approach while maintaining vigilant toxicity monitoring and awaiting confirmation from prospective trials.

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