Surprising Results with Dual Immunotherapy in STK11- and KEAP1-Mutant Lung Cancer

Since 2010, immunotherapies have revolutionized lung cancer treatment, offering new hope to patients at all stages. However, not all patients benefit equally. Among the groups with limited responses are patients with NSCLC (non-small cell lung cancer) carrying STK11 and KEAP1 mutations . These mutations cause tumors to develop an immunosuppressive microenvironment , which can reduce or completely negate the effectiveness of immunotherapy. Approximately 20-25% of NSCLC patients carry an STK11 mutation, while the proportion carrying a KEAP1 mutation ranges from 15-20% . These mutations can complicate treatment by limiting the response to immunotherapy. 

An STK11 mutation affects a tumor suppressor gene that regulates cell growth and survival, while a KEAP1 mutation weakens cellular defenses against oxidative stress, helping cancer evade the immune system. These features limit the success of immunotherapy and increase the likelihood of resistance. In this context, comprehensive genetic testing has become even more important for NSCLC treatment decisions, opening the door to patient-specific treatment strategies.

Immune checkpoints are proteins that regulate excessive immune responses and help the body respond to abnormalities such as infection or cancer without harming its own tissues. However, cancer cells can evade the immune system by disabling these checkpoints. Drugs known as immune checkpoint inhibitors (such as PD-1, PD-L1 and CTLA-4 inhibitors) block these proteins, enabling immune cells to recognize and destroy cancer cells and producing a revolutionary effect in cancer treatment.

Dual Immune Checkpoint Blockade in NSCLC

New evidence suggests that dual immune checkpoint blockade may be effective in NSCLC, particularly in patients carrying STK11 and/or KEAP1 mutations. A study led by Dr. Ferdinandos Skoulidis, published on October 9, 2024, in Nature , presents important findings from a retrospective analysis of phase 3 POSEIDON data. By revealing biological mechanisms that improve treatment outcomes, the analysis has the potential to reshape treatment decisions.

What Were the Original POSEIDON Findings?

Based on the POSEIDON results, the dual immunotherapy combination of tremelimumab (Imjudo, AstraZeneca) and durvalumab (Imfinzi, AstraZeneca), together with platinum-based chemotherapy, received FDA (US Food and Drug Administration) approval on November 10, 2022.

The study included patients with metastatic NSCLC, totaling 1013 patients.

The study compared

1. chemotherapy alone,
2. chemotherapy plus the PD-L1 inhibitor durvalumab, and
3. chemotherapy plus durvalumab and the CTLA-4 inhibitor tremelimumab.

The initial results showed that adding durvalumab to chemotherapy improved progression-free survival (PFS) but did not significantly affect overall survival. However, dual checkpoint blockade with tremelimumab produced substantial improvements in both PFS and overall survival.

Further Analysis and the Role of STK11/KEAP1 Mutations

Skoulidis and colleagues' further analysis of POSEIDON data aimed to confirm the effectiveness of dual checkpoint blockade, particularly in patients carrying STK11 and KEAP1 mutations . These mutations are thought to create an immunosuppressive tumor microenvironment that confers resistance to PD-L1 inhibition. In patients carrying STK11/KEAP1 mutations, adding durvalumab to chemotherapy provided limited benefit, whereas adding tremelimumab produced a substantial improvement in outcomes.

These findings were particularly notable in response rates : The response rate was 42.9% in patients receiving chemotherapy plus dual checkpoint blockade, compared with 30.2% with single checkpoint blockade and 28% with chemotherapy alone. Overall survival showed a similar trend, with median overall survival of 15.8 months in the dual-blockade group.

How Do These Findings Relate to Previous NSCLC Research?

These findings are consistent with previous research such as CheckMate 9LA . The study confirms that patients carrying STK11 and KEAP1 mutations benefit more from dual blockade in PD-L1-negative tumors. PD-L1-negative NSCLC patients have also shown greater and more durable long-term survival benefits with dual blockade in previous clinical trials.

Molecular Mechanisms of Dual Checkpoint Blockade

The significance of this study goes beyond clinical data; it is supported by mechanistic findings showing how STK11 and KEAP1 mutations shape the tumor microenvironment. In mouse models and cell lines, Skoulidis and colleagues observed an immunosuppressive microenvironment with increased suppressive myeloid cells and reduced CD8+ T cells. This limits the effectiveness of PD-1 blockade. Dual checkpoint blockade was shown to reprogram the microenvironment, increase antitumor responses and extend survival.

Despite these promising findings, more evidence may be needed before dual checkpoint blockade is adopted as standard first-line treatment. Results from ongoing phase 3 trials such as TRITON may settle this debate.

The Importance of Genetic Profiling: New Opportunities for the Future

This study again highlights the importance of comprehensive tumor profiling and integrating genetic analyses into clinical decisions. Such data help clarify how genetic changes such as STK11 and KEAP1 affect treatment response and support patient-centered treatment strategies.