Prospective observational study of nutritional and immunological indices as predictive biomarkers of response to immune checkpoint inhibitors in non-small cell lung cancer (ICI-PREDICT study).
Authors: Shinkichi Takamori, Mototsugu Shimokawa, Masafumi Yamaguchi, Masahide Mori, Shoichi Kuyama, Masahide Oki, Yoshifumi Nishimura, Katsumi Nakatomi, Hidetoshi Yanai, Noriaki Sukoh, Nobuo Hatakeyama, Toshiyuki Kita, Keiichi Fujiwara, Kenji Chibana, Masaki Okamoto, Mitsuhiro Takenoyama
Journal: Journal of Clinical Oncology (2024)

e20524 Background: Nutritional and immunological indices, including controlling nutritional status (CONUT) score, skeletal muscle area (SMA), and neutrophil-to-lymphocyte ratio (NLR) have been reported as predictors of response to immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC). The aim of this prospective, multicenter study is to evaluate the clinical impact of pre- or early post-treatment changes in nutritional and immunological indices on treatment outcomes in patients with advanced NSCLC treated with first-line ICIs. Methods: We enrolled 301 advanced NSCLC patients treated with ICIs (monotherapy or combined with chemotherapy) as first-line therapy, without any oncogene mutations, and available data on programmed cell death-ligand 1 (PD-L1) expression (150 in training and 151 in validation cohorts) from March 2020 to November 2022. The CONUT score, SMA at the L3 level (cm 2 /m 2 ), and NLR, were evaluated before treatment initiation and at the first response evaluation. Cut-off values were determined by receiver operating characteristic curves with objective response as the outcome in the training cohort. The primary endpoint was progression-free survival (PFS). For exploratory study, serum before treatment was collected to measure 15 muscle-derived cytokines (Apelin, BDNF, CX3CL1, EPO, FABP3, FSTL1, FGF21, IL-6, IL-15, Irisin, LIF, Musclin, Myostatin, OSM, and SPARC) (n = 123). Results: The median follow-up period and PFS was 17.5 (range: 7.3-39.4) and 6.9 (range: 0.1-31.5) months, respectively. In the training cohort, men (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.30-0.90, p = 0.0183), ΔCONUT &lt; 0 (HR: 0.59, 95% CI: 0.35-0.98, p = 0.0431), and ΔSMA &gt; −0.13 (HR: 0.56, 95% CI: 0.33-0.96, p = 0.0333) were independent predictors for PFS. In the validation cohort, PD-L1 ≥ 50% (HR: 0.54, 95% CI: 0.34-0.84, p = 0.0061), NLR &lt; 3.65 (HR: 0.47, 95% CI: 0.30-0.74, p = 0.0011), and ΔSMA &gt; −0.13 (HR: 0.61, 95% CI: 0.38-0.98, p = 0.0421) were independent predictors for PFS. In the exploratory study, multivariate analysis including muscle-derived cytokines (continuous variables) revealed that performance status = 0 (HR: 0.24, 95% CI: 0.12-0.48, p &lt; 0.0001), without baseline prednisone (≥ 10 mg/day) (HR: 0.17, 95% CI: 0.05-0.58, p = 0.0213), smoking history (HR: 0.34, 95% CI: 0.14-0.81, p = 0.0269), and FSTL1 (HR: 0.97, 95% CI: 0.93-0.99, p = 0.0185) were independent predictors of PFS. Conclusions: ΔSMA was the only factor validated as an independent predictor of PFS. The underlying biological mechanisms may be related to skeletal muscle-derived FSTL1. Clinical trial information: UMIN000040450.