Researchers from The University of Texas MD Anderson Cancer Center have demonstrated that patients with metastatic non-squamous non-small cell lung cancer (NSCLC) harboring specific mutations in the STK11 and/or KEAP1 tumor suppressor genes were more likely to benefit from adding the immunotherapy tremelimumab to a combination of durvalumab plus chemotherapy to overcome treatment resistance typically seen in this patient population.

Study results, published today in Nature, identify KEAP1 and STK11 as potential biomarkers to stratify patients most likely to benefit from the addition of CTLA-4 immune checkpoint inhibitors, including tremelimumab.

In these patients, adding tremelimumab to durvalumab and chemotherapy resulted in higher overall response rates (42.9%) relative to patients who received durvalumab plus chemotherapy (30.2%) or chemotherapy alone (28%). These findings were further substantiated in preclinical models, supporting the use of dual checkpoint inhibitors for patients with these mutations.

"STK11 and KEAP1 alterations are common in patients with NSCLC and are linked to poor clinical outcomes with current standard-of-care first-line treatments," said co-lead author Ferdinandos Skoulidis, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology "While prior research suggested potential benefits from adding CTLA-4 inhibitors to PD-1 or PD-L1 inhibitors, we have no reliable biomarkers to predict which patients would see the best outcomes. This study provides the strongest evidence to date that patients with STK11 and/or KEAP1-mutated NSCLC may selectively benefit from dual immune checkpoint inhibition."

This research study -- made possible by collaboration between 22 academic centers in North American and Europe as well as biotechnology and pharmaceutical companies -- combines analyses of clinical cohorts, patient samples, laboratory models and data from the Phase III POSEIDON clinical trial.

Initial observations in a clinical cohort of 871 patients with NSCLC demonstrated that patients with STK11 and/or KEAP1 alterations had poorer outcomes with chemotherapy plus the PD-1 inhibitor pembrolizumab. Researchers went on to study the immune and genetic characteristics of 8,592 non-squamous NSCLC tumors. They found that mutations in the STK11 and KEAP1 genes were linked to a less favorable tumor environment, often referred to as a "cold" microenvironment. This type of environment had many suppressive myeloid cells and fewer CD8+ cytotoxic T cells, which are important for fighting tumors. However, they noted that CD4+ immune cells were less impacted and remained present in tumors with STK11 and/or KEAP1 mutations.

Based on these observations, the researchers hypothesized that dual checkpoint inhibitors, targeting CTLA-4 in addition to PD-1 or PD-L1, may improve outcomes. In an analysis of 1,013 patients from the POSEIDON study, the researchers confirmed tremelimumab plus durvalumab and chemotherapy improved responses rates, progression-free survival and overall survival.

To further expand on these findings, experts then evaluated the effects of single and dual immune checkpoint inhibition on the tumor microenvironment in multiple preclinical models of STK11 and/or KEAP1-mutated NSCLC. Compared with PD-1 inhibition alone, dual checkpoint blockade strongly improved the tumor microenvironment by increasing the presence of specific immune cells that boost the antitumor response, providing a possible mechanism that may explain the observed benefits.

"These findings support that NSCLC patients with STK11 or KEAP1 mutations are relatively resistant to standard combinations of PD-(L)1 inhibitors and chemotherapy, but can benefit markedly when a CTLA-4 inhibitor is added to their treatment regimen," said co-lead author John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Medical Oncology. "We are optimistic that these results will prompt clinicians to consider this novel therapeutic approach as a preferred treatment option."

Limitations of this study include the fact that some of the results were analyzed after the study was completed, as well as the limited number of patients with STK11 and/or KEAP1 alterations. In the ongoing Phase IIIB TRITON trial, researchers will prospectively compare dual checkpoint blockade with durvalumab and tremelimumab versus pembrolizumab in combination with chemotherapy in patients with advanced non-squamous NSCLC with STK11, KEAP1 or KRAS alterations.