Combination Therapies in Advanced Non-Small Cell Lung Cancer

Advanced non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide, with single-agent therapies often limited by intrinsic or acquired resistance. Combination approaches seek to exploit complementary mechanisms of action: for example, pairing immune checkpoint inhibitors with agents that normalise tumour vasculature or directly inhibit angiogenesis. By targeting both the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) axis and vascular endothelial growth factor (VEGF) pathways, these regimens remodel the tumour microenvironment to enhance T-cell infiltration, reverse immunosuppression and improve antigen presentation. Other strategies have combined cytotoxic chemotherapy with immunotherapy to increase neoantigen release, or integrated novel tyrosine kinase inhibitors with checkpoint blockade to overcome molecular drivers of resistance. Clinical trials have reported durable responses and extended progression-free survival in carefully selected patient subgroups, particularly those with high tumour mutation burden or high PD-L1 expression. As these regimens mature through randomised studies, attention to optimal sequencing, dose intensity and the balance of efficacy with toxicity will define best practice. The global impact of these advances is already reflected in new standard-of-care paradigms that promise broader, more durable clinical benefit for patients with advanced NSCLC.

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Combination Therapies in Advanced Non-Small Cell Lung Cancer publication trend

The graph below shows the total number of articles in combination therapies in advanced non-small cell lung cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Non-Small Cell Lung Cancer (NSCLC): A category of lung cancers that grow and spread more slowly than small-cell lung carcinoma, encompassing adenocarcinoma, squamous cell carcinoma and large-cell carcinoma.

Immune Checkpoint Inhibitors: Therapeutic antibodies that block inhibitory receptors or ligands on T cells or tumour cells (e.g., PD-1, PD-L1), thereby restoring antitumour immunity.

Anti-Angiogenic Agents: Drugs that inhibit the formation of new blood vessels by targeting VEGF signalling, aiming to starve tumours of oxygen and nutrients and remodel the vasculature.

PD-1/PD-L1 Axis: A key immune checkpoint pathway whereby tumour-expressed PD-L1 binds to T-cell PD-1, suppressing cytotoxic activity and facilitating immune evasion.

Vascular Endothelial Growth Factor (VEGF): A protein family that promotes angiogenesis; its overexpression in tumours contributes to abnormal vasculature and immunosuppression.

Tumour Mutation Burden (TMB): The total number of somatic mutations per coding area of a tumour genome, used as a biomarker to predict response to immunotherapy.

References

1. Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non–Small Cell Lung Cancer With High Tumor Mutation Burden. JAMA Oncology (2023).
2. Phase II study of atezolizumab with bevacizumab for non-squamous non-small cell lung cancer with high PD-L1 expression (@Be Study). Journal for ImmunoTherapy of Cancer (2022).
3. Efficacy and Safety of Anti-PD-1 Plus Anlotinib in Patients With Advanced Non–Small-Cell Lung Cancer After Previous Systemic Treatment Failure—A Retrospective Study. Frontiers in Oncology (2021).
4. The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer. Frontiers in Immunology (2021).