A new study offers hope for patients with advanced non-small cell lung cancer (NSCLC) who carry certain genetic mutations that make standard immunotherapy less effective.
Researchers have discovered that adding a second type of immunotherapy drug—called a CTLA-4 inhibitor—to existing PD-1/PD-L1 checkpoint inhibitors may overcome resistance seen in patients with mutations in the STK11 and KEAP1 genes. These two gene alterations are common in lung cancer and are linked to poorer outcomes with standard checkpoint immunotherapy.
Why it matters
Checkpoint inhibitors such as pembrolizumab (Keytruda) and durvalumab (Imfinzi) have transformed treatment for many people with advanced lung cancer. However, patients whose tumors carry STK11 or KEAP1 mutations often see little to no benefit, since these mutations create a “cold” tumor environment that blocks immune attack.
The new strategy—known as dual immune checkpoint blockade—pairs a PD-L1 inhibitor Imfinzi with a CTLA-4 inhibitor (tremelimumab). When combined with chemotherapy, this double-immunotherapy approach appeared to “reprogram” the immune environment, allowing the body’s own defenses to better recognize and attack cancer.
What the study found
- In the phase III POSEIDON clinical trial, patients with STK11 and/or KEAP1 mutations did not benefit from Imfinzi plus chemotherapy alone.
- But when tremelimumab was added to Imfinzi, these patients lived longer and had better responses.
- Lab research in mice confirmed why: dual therapy activated CD4+ helper T cells and shifted suppressive immune cells into tumor-killing states.
What this means for patients
For people with NSCLC whose tumors carry STK11 or KEAP1 mutations, current immunotherapy options may not be effective enough. This study shows that adding a CTLA-4 inhibitor to standard Imfinzi immunotherapy plus chemotherapy could offer meaningful improvement.
Next steps
The TRITON clinical trial, which is testing dual immunotherapy specifically in people with STK11 or KEAP1-mutant NSCLC is being conducted to confirm these results . If confirmed, this approach could lead to new treatment guidelines for patients whose cancers carry these challenging genetic alterations.
All patients with NSCLC should undergo molecular testing to look for STK11, KEAP1, and other mutations, talk with your oncologist about whether clinical trials of dual immunotherapy may be an option.
More Reading
Non-Small Cell Lung Cancer: What you Need to Know About ctDNA Testing
Reference:
Skoulidis F, Araujo HA, Do MT, et al. CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors. Nature. 2024 Nov;635(8038):462-471. Epub 2024 Oct 9. Erratum in: Nature. 2025 Mar;639(8054):E19. doi: 10.1038/s41586-025-08767-9.
