Regan Memmott

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy—a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that—together with CD4+ and CD8+ T cells—contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations. Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Introduction: Mesothelioma is a rare but aggressive cancer primarily caused by asbestos exposure. In March 2024, the Environmental Protection Agency banned asbestos in the United States, but its use will take years to phase out. Therefore, asbestos remains a threat, and incidence may remain stable or slowly decrease due to the long latency between exposure and diagnosis. This study investigates mesothelioma mortality trends in the United States from 1999 to 2020, focusing on demographic and geographic variations. Methods: Data on mesothelioma-related deaths from 1999 to 2020 were extracted from the Centers for Disease Control and Prevention database. Variables including race/ethnicity, sex, geographic density, and mesothelioma subtype were assessed. Age-adjusted mortality rates were calculated per 1 million individuals and standardized to the 2000 United States population. Joinpoint regression identified statistically significant changes in mortality trends over time. Results: From 1999 to 2020, there were 54,905 mesothelioma-related deaths in the United States (age-adjusted mortality rate = 7.5). Pleural mesothelioma accounted for 8.1% of deaths, peritoneal for 4.6%, pericardial for 0.01%, other sites for 10.9%, and unspecified sites for 76.3%. Most deaths (81.3%) occurred in individuals aged over 65 years. Overall mortality decreased from 8.5 in 1999 to 5.7 in 2020 at -1.9% annually. Non-Hispanic Whites had the highest mortality, and male individuals experienced higher mortality than female individuals. Suburban and rural populations had the highest mortality rates. Conclusions: The study highlights significant declines in mesothelioma mortality in the United States from 1999 to 2020, with variations across demographic and geographic groups. Continued monitoring and targeted interventions are necessary to address disparities and further reduce mesothelioma mortality.