A recent analysis suggests that combining two types of immunotherapy—CTLA-4 and PD-L1 or PD-1 inhibitors—may help certain people with advanced non-small cell lung cancer (NSCLC) live longer, especially those whose tumors have specific mutations and low PD-L1 expression.
PD-L1, or programmed death-ligand 1, is a protein found on the surface of many cancer cells. It plays a crucial role in the immune system by helping cancer cells evade attacks from T-cells. Testing for PD-L1 expression is used to determine if a patient is a good candidate for immunotherapy treatments with immune checkpoint inhibitors.
How it works
- Immune suppression:
When PD-L1 on a tumor cell binds to the PD-1 protein on a T-cell, it tells the T-cell to stop attacking, effectively turning off the immune response against the cancer.
- Therapeutic target:
Drugs called “immune checkpoint inhibitors” can block this interaction. By preventing PD-L1 and PD-1 from binding, these drugs can “release the brakes” on the immune system and allow T-cells to recognize and attack cancer cells.
Understanding the Research
Immunotherapy has transformed treatment for advanced NSCLC. Most patients receive drugs that target PD-L1 or PD-1, which help the immune system attack cancer cells. In some cases, these drugs are combined with a second type of immune checkpoint inhibitor that targets CTLA-4.
CTLA-4, or Cytotoxic T-Lymphocyte-Associated Protein 4, is another protein on the surface of T-cells that acts as a “brake” on the immune system. It prevents T-cells from over-activating. By blocking the interaction between CTLA-4 and its ligands, these “checkpoint inhibitors” also prevent the T-cell “brake” from being applied.
Researchers wanted to determine whether combining CTLA-4 and PD-L1 or PD-L1 blockers improves survival compared to standard treatment with a single immunotherapy drug targeting PD-L1. To answer this question, scientists performed a systematic review and meta-analysis—a study that combines and compares results from multiple large clinical trials.
How the Study Was Done
The research team reviewed data from six randomized phase 3 trials including 2,881 people with advanced NSCLC.
- 1,282 patients received combined (dual) therapy with a CTLA-4 drug plus a PD-1 or PD-L1 inhibitor.
- 1,599 received standard treatment with a PD-1 or PD-L1 inhibitor alone.
The team analyzed long-term outcomes, specifically looking at 5-year survival and subgroups based on:
- PD-L1 expression levels on tumor cells
- Tumor type (squamous or non-squamous)
- Specific gene mutations: KRAS and STK11
What the Study Found
Overall, survival times were similar between people receiving dual therapy and those receiving a single immunotherapy drug.
However, some patient groups benefited more from the dual approach:
- Patients with low PD-L1 expression (less than 1%) lived longer with dual therapy — average survival was 15.5 months vs. 14.5 months, and 5-year survival rates were about 17% vs. 9%.
- Patients with STK11 mutations, a change in a gene that often reduces response to immunotherapy, had improved survival with dual therapy — 13.9 months vs. 7.8 months.
There was no major difference in outcomes between treatment types for people with KRAS mutations or by tumor type.
Why This Matters
These results suggest that combining CTLA-4 and PD-1 or PD-L1 checkpoint blockers may offer long-term survival benefits for people with:
- Low PD-L1 expression, or
- STK11-mutated tumors
For other patients, a single immunotherapy may still be equally effective and cause fewer side effects.
What Patients Should Know
If you or a loved one has advanced non-small cell lung cancer:
- Biomarker testing for PD-L1 and tumor gene mutations like STK11 or KRAS can help doctors choose the most effective treatment.
- Dual immunotherapy may be considered if your cancer has certain features that make it less responsive to single-agent therapy.
- Your oncologist can explain the potential benefits and side effects of combination immunotherapy and whether you might be eligible for this approach or a clinical trial.
All patients with NSCLC should have molecular biomarker testing performed on both blood and the lung cancer tissue if possible.
Additional Reading: POSEIDON Clinical Trial of Dual Checkpoint Inhibition in NSCLC
Reference
Di Federico A, Stumpo S, Mantuano F, et al. Long-term overall survival with dual CTLA-4 and PD-L1 or PD-1 blockade and biomarker-based subgroup analyses in patients with advanced non-small-cell lung cancer: a systematic review and reconstructed individual patient data meta-analysis. Lancet Oncol. 2025 Sep 29:S1470-2045(25)00429-2.
