Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer

Simple Summary Immune checkpoint inhibitor (ICI)-based immunotherapy has dramatically improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of these patients do not benefit from this approach. Therefore, predictive biomarkers are needed. Increasing evidence demonstrates that cancer cachexia, which is often reported in patients with NSCLC, with associated chronic inflammation and related changes in body composition, metabolism, and nutritional status, may affect the immune response and impair immunotherapy efficacy. However, few prospective studies have explored the association between cachexia and the response to immunotherapy in NSCLC. We designed a prospective observational study to evaluate the prognostic and predictive role of cachexia, with its related changes in inflammatory, immunological, and nutritional parameters, on the survival and clinical response (i.e., disease control rate) to ICI in patients with advanced NSCLC. Our results suggest that cachexia can be an independent unfavorable prognostic and predictive factor. Then, the evaluation of cachexia should be strongly considered as a key parameter in the design of immunotherapy-based trials. Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (<= 6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.