Researchers have found that patients suffering from metastatic non-squamous non-small cell lung cancer (NSCLC) with specific mutations in the STK11 and/or KEAP1 tumor suppressor genes may have better treatment outcomes when adding the immunotherapy tremelimumab to their regimen of durvalumab combined with chemotherapy. This enhancement is particularly significant for addressing the treatment resistance commonly encountered in this patient demographic.
Researchers from The University of Texas MD Anderson Cancer Center have found that patients suffering from metastatic non-squamous non-small cell lung cancer (NSCLC) with certain mutations in the STK11 and/or KEAP1 tumor suppressor genes may see better outcomes by adding the immunotherapy tremelimumab to a combination of durvalumab and chemotherapy, particularly to counteract the treatment resistance often observed in this group of patients.
Findings published today in Nature highlight KEAP1 and STK11 as possible biomarkers to identify patients who might gain the most benefit from incorporating CTLA-4 immune checkpoint inhibitors, such as tremelimumab.
Patients with these mutations who received tremelimumab along with durvalumab and chemotherapy experienced higher overall response rates (42.9%) compared to those treated with just durvalumab and chemotherapy (30.2%) or chemotherapy on its own (28%). These results were bolstered by laboratory studies, which confirm the value of employing dual checkpoint inhibitors for patients with these specific mutations.
“Alterations in STK11 and KEAP1 are frequent among NSCLC patients and are associated with poor results with the standard first-line treatments,” explained co-lead author Ferdinandos Skoulidis, M.D., Ph.D., an associate professor in Thoracic/Head and Neck Medical Oncology. “Previous studies hinted at potential advantages from combining CTLA-4 inhibitors with PD-1 or PD-L1 inhibitors, but we lacked dependable biomarkers to determine which patients would benefit the most. This study provides compelling evidence that those with STK11 and/or KEAP1-mutated NSCLC could genuinely benefit from this dual immune checkpoint therapy.”
This research involved collaboration from 22 academic institutions across North America and Europe, along with contributions from biotech and pharmaceutical companies, and includes analyses of various clinical cohorts, patient samples, laboratory models, and data from the Phase III POSEIDON clinical trial.
Initially, observations from a clinical cohort of 871 NSCLC patients indicated that those with STK11 and/or KEAP1 mutations experienced poorer outcomes when treated with chemotherapy plus the PD-1 inhibitor pembrolizumab. Researchers then further examined the immune and genetic features of 8,592 non-squamous NSCLC tumors, discovering that mutations in the STK11 and KEAP1 genes correlated with a less favorable tumor environment, often described as a “cold” microenvironment. This environment typically had a high presence of suppressive myeloid cells and a lower number of CD8+ cytotoxic T cells, which play a crucial role in combating tumors. Interestingly, CD4+ immune cells appeared to be less affected and were still present in tumors containing STK11 and/or KEAP1 mutations.
Given these findings, the researchers proposed that utilizing dual checkpoint inhibitors, targeting both CTLA-4 and PD-1 or PD-L1, could enhance treatment results. An analysis involving 1,013 participants from the POSEIDON trial confirmed that the combination of tremelimumab with durvalumab and chemotherapy yielded improved response rates, progression-free survival, and overall survival.
To build on these results, specialists also assessed the impact of single versus dual immune checkpoint inhibition on the tumor microenvironment using several preclinical models of STK11 and/or KEAP1-mutated NSCLC. They found that dual checkpoint blockade significantly improved the tumor microenvironment by increasing the number of specific immune cells that enhance the antitumor response, potentially explaining the observed improvements.
“These results indicate that NSCLC patients with STK11 or KEAP1 mutations show relative resistance to standard treatments combining PD-(L)1 inhibitors and chemotherapy, but can experience substantial benefits when a CTLA-4 inhibitor is included in their treatment,” stated co-lead author John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Medical Oncology. “We are hopeful that these findings will encourage clinicians to consider this innovative therapeutic strategy as a preferred treatment option.”
The limitations of this study include that some analyses were conducted after the completion of the study, along with a limited sample size of patients with STK11 and/or KEAP1 mutations. Ongoing research in the Phase IIIB TRITON trial aims to prospectively compare dual checkpoint blockade using durvalumab and tremelimumab against pembrolizumab combined with chemotherapy in patients with advanced non-squamous NSCLC exhibiting STK11, KEAP1, or KRAS mutations.
This research received support from multiple sources, including the National Institutes of Health/National Cancer Institute, alongside various foundations and endowments aimed at lung cancer research.
