Retrospective evaluation of anti-angiogenic and immune checkpoint inhibitor combination therapy in SMARCA4-deficient thoracic tumors: efficacy, safety, and biomarker considerations

We sincerely appreciate the thoughtful and insightful commentary by Wu et al. on our retrospective study (1). Their analysis highlights key strengths of our findings while raising critical questions that warrant further clarification and discussion. Below, we address the major points raised in their commentary.

Immune checkpoint inhibitor (ICI)-antiangiogenic combination efficacy: advantages and constraints

We agree that the observed efficacy of combining ICIs with anti-angiogenic therapy (anlotinib) in our cohort is promising. However, as rightly noted, our small sample size (n=5) limits definitive conclusions about safety or generalizability. However, as noted in the comments, our small sample size (n=5) limits definitive conclusions regarding safety and generalizability. A previous study demonstrated that for grade ≥3 treatment-related adverse events (TRAEs), compared with placebo, anlotinib increased the risk [odds ratio (OR) =3.67; 95% confidence interval (CI): 1.12–15.77]. In contrast, neither anlotinib plus ICIs (OR =2.45; 95% CI: 0.51–11.6) nor ICIs alone (OR =1.29; 95% CI: 0.33–4.38) showed an increased risk (2). But we also believe that prospective toxicity analysis of this conclusion needs to be conducted in a larger cohort.

Choice of anti-angiogenic agent: rationale and open questions

The selection of anlotinib over VEGF-specific agents (e.g., bevacizumab) was based on its multitargeted inhibition of VEGFR, PDGFR, and FGFR, which may comprehensively disrupt tumor angiogenesis (3,4). We recognize the commentator’s valid point that bevacizumab has a more favorable toxicity profile (e.g., lower hypertension rates) (5) and encourage future studies to directly compare tyrosine kinase inhibitors (e.g., anlotinib) with monoclonal antibodies (e.g., bevacizumab) in this context.

Biomarker challenges and unresolved predictors

The absence of PD-L1 correlation (P=0.84) (6) and the unexplored impact of STK11 mutations (present in 23.6% of our cohort) (6)—a known driver of ICI resistance (7)—underscores the need for robust biomarker discovery. Due to the insufficient sample size and the problem of obtaining patient samples, this aspect cannot be further discussed. We fully support the commentator’s call for integrating advanced approaches, including tumor mutation burden (TMB), single-cell analysis, and spatial transcriptomics, to identify responders and optimize patient selection.

Clinical implications: whether it has nothing to do with histology

It is also noteworthy that there was no difference in overall survival (OS) between differentiated non-small cell lung cancer (NSCLC) and undifferentiated tumors (13.70 vs. 15.70 months, P=0.42) (6), which challenges the assumption that undifferentiated histology itself predicts a worse outcome. As discussed in our research, previous studies have shown no significant difference between the two groups in OS (8,9). The potential reason for these discrepancies may lie in the exclusion of advanced-stage tumor patients from the studies. For instance, Luo et al. found that resectable SMARCA4-deficient urothelial carcinoma patients had significantly shorter time to progression (TTP) (risk ratio =4.35, 95% CI 1.7–10.71, P=0.001) and OS (risk ratio =4.27, 95% CI 1.1–16.35, P=0.022) compared to resectable SMARCA4-deficient NSCLC patients (10). Additionally, insufficient sample size remains a key factor contributing to the divergence of research findings. These observations require further validation through prospective clinical trials.

Conclusions

While our retrospective study has limitations (e.g., small sample size, missing toxicity data), it provides foundational evidence for ICI-based combinations as a potential backbone strategy for SMARCA4-deficient thoracic tumors. We emphasize the importance of cautious clinical application with close toxicity surveillance and await results from ongoing/prospective trials. We thank the commentator for their constructive feedback, which enriches the scientific discourse on this challenging disease. Their perspectives will be acknowledged in our formal response article, and we invite further dialogue to advance this field.

Acknowledgments

The authors thank the study participants for their contribution to the research.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1136/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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