There is a high prevalence of type 2 diabetes mellitus in the population over 70 years old in industrial countries. This article provides recommendations for the diagnosis, prevention and treatment targets of older diabetic patients according to the current scientific evidence.
8015 Background: In AEGEAN, perioperative D + neoadj CT improved EFS and pathological complete response vs neoadj CT alone in pts with R-NSCLC. Here, we report exploratory transcriptomic analyses of the TME in tumor samples collected at baseline (BL) and surgery (Sx) to investigate the impact of neoadj D on TME features and their association with EFS. Methods: AEGEAN is a double-blind PBO-controlled study (NCT03800134). Adults with Tx-naïve R-NSCLC (stage II–IIIB[N2]) and ECOG PS 0/1 were randomized 1:1 to neoadj platinum-based CT + D or PBO IV (Q3W, 4 cycles) before Sx followed by D or PBO IV (Q4W, 12 cycles) after Sx. EFS was evaluated by BICR (RECIST v1.1) in the modified ITT (mITT) population, which excluded pts with known EGFR / ALK aberrations. Total RNA was extracted from BL and Sx tumor samples and sequenced (Illumina NovaSeq X Plus). Unsupervised hierarchical clustering of samples was conducted based on previously reported gene signatures reflective of tumor and TME components. Results: Transcriptomic data were available from 366 samples in 292 mITT pts across both arms (at BL, 257 pts; at Sx, 109 pts) whose characteristics and outcomes were broadly representative of the mITT population (74 pts with paired samples). At BL, 3 distinct phenotypic clusters (C) based on TME features were identified: an immune desert (C1, 24.9% of pts), characterized by a predominance of proliferating tumor cells; immune suppressed (C2, 39.3%), by elevated levels of suppressive myeloid cells, angiogenesis, and fibroblasts; and immune activated (C3, 35.8%), by high levels of effector T cells. A higher proportion of pts with squamous vs non-squamous tumors had phenotype C1 (37.5% vs 13.9%, respectively) while a lower proportion had C3 (22.5% vs 47.4%). The addition of perioperative D improved EFS across all BL C (C1: HR, 0.43; 95% CI, 0.19–0.94; C2: HR, 0.90; 95% CI, 0.50–1.63; C3: HR, 0.41; 95% CI, 0.20–0.81), with least improvement in C2. The same clusters were detected at Sx (C1, 32.1%; C2, 33.9%; C3, 33.9%) and pts with C1 tumors had the highest risk of progression; 36-month EFS rates (95% CI) were 27.8% (12.1–46.0), 55.7% (33.7–73.0), and 77.2% (59.3–88.0) for C1, C2, and C3, respectively. Neoadj D was associated with higher proportions of pts with C2 and C3 phenotypes at Sx, such that the proportion with poor prognosis C1 tumors at Sx was 17.9% vs 47.2% in the D vs PBO arms, respectively. Among pts with C3 tumors at Sx, EFS benefit in the D vs PBO arm was striking (HR, 0.16; 95% CI, 0.03–0.79). Conclusions: The TME before and after neoadj Tx impacts EFS in pts with R-NSCLC, with an immune suppressed phenotype associated with reduced perioperative D benefit. The TME differs between squamous and non-squamous tumors and is influenced by neoadj D, which may promote an immune-activated phenotype associated with prolonged EFS benefit with perioperative D. Clinical trial information: NCT03800134 .
In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (EFS) and pathologic complete response in patients with resectable non-small cell lung cancer (R-NSCLC), with a safety profile consistent with the individual agents. We report EFS from a second planned interim analysis, interim disease-free survival (DFS) and overall survival (OS), and safety, after all patients completed/discontinued treatment. In this phase III, double-blind, placebo-controlled study, patients with treatment-naïve R-NSCLC (stage II-IIIB [N2]) were randomly assigned (1:1) to neoadjuvant platinum-based chemotherapy plus durvalumab/placebo (once every 3 weeks, four cycles) presurgery and then adjuvant durvalumab/placebo (once every 4 weeks, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (n = 740; for DFS, its resected subpopulation), which excluded patients with documented EGFR/ALK aberrations. As of May 10, 2024 (median follow-up, 25.9 months [censored patients]), EFS benefit favoring the durvalumab arm remained consistent (hazard ratio [HR], 0.69 [95% CI, 0.55 to 0.88]). Numerical improvement in DFS (HR, 0.66 [95% CI, 0.47 to 0.92]) and OS (HR, 0.89 [95% CI, 0.70 to 1.14]) favored the durvalumab arm. Maximum grade 3/4 adverse events occurred in 15.4% and 10.6% of the durvalumab and placebo arms, respectively, during adjuvant treatment. These results further support perioperative durvalumab plus neoadjuvant chemotherapy as a new treatment option.
