Chemoradiotherapy efficacy in patients with stage III non-small cell lung cancer (NSCLC): A prognostic clinical and biomarker-based model

Background: Chemoradiotherapy (CRT) followed by adjuvant durvalumab is the standard of care for fit patients with unresectable stage III non-small cell lung cancer (NSCLC). However, 20-25 % of the patients do not survive longer than 1 year after treatment initiation, i.e. receive futile treatment. We aimed to develop a prognostic model that can identify patients at high risk of early mortality during and after CRT. Methods: Patients with stage III NSCLC treated with CRT were included in the development- (N = 328; MAASTRO Biobank, 2004-2020, NCT01084785) and validation cohorts (N = 39; NCT02921854, NCT04432142). Both clinical parameters (age, sex, body mass index, performance status (PS), tumor stage (UICC 8), and sequence of chemotherapy administration) and peripheral immune-related biomarkers were included in the model development. Futile treatment was defined as death within one year after the first fraction of RT. Results: In the multivariable logistic regression analysis, PS >= 2 (OR = 2.89, 95 % CI 1.25-6.66, p = 0.013), stage IIIC (OR = 3.07, 95 % CI 3.07-6.9, p = 0.007), sequential chemotherapy (OR = 2.07, 95 % CI 1.19-3.62, p = 0.010), IL-6 (OR = 2.17, 95 % CI 1.27-3.70, p = 0.005), IP-10 (OR = 1.58, 95 % CI 0.92-2.73, p = 0.099), and soluble programmed death-ligand 1 (sPD-L1) (OR = 3.24, 95 % CI 1.90-5.54, p < 0.001) were identified as independent risk factors of early mortality. A nomogram was developed to calculate the risk of receiving futile treatment for each patient. The AUC of the development and validation cohort was 0.774 (95 % CI 0.716-0.832) and 0.734 (95 % CI 0.568-0.902), respectively. Patients classified as intermediate or high risk to receive futile treatment presented 23.7 % of the total cohort. Conclusions: A prognostic model was developed that can identify patients who are at high risk of early mortality during and after CRT. These patients may be included in clinical trials aiming to improve their outcome.