Effects of immediate elevation of inflammatory cytokines after platinum, pemetrexed, and pembrolizumab on antitumor efficacy in advanced non-squamous, non-small cell lung cancer.

Abstract

8525 Background: Inflammatory cytokines play a crucial role in the tumor microenvironment and may serve as potential biomarkers for the sustained efficacy of PD-1/L1 inhibitors combined with chemotherapy. Numerous studies have been conducted on cytokines to date; however, studies on cytokine fluctuations immediately after administration remain notably limited. Methods: A prospective observational study at Wakayama Medical University enrolled 110 patients with thoracic malignancies receiving PD-1/L1 inhibitors as first line therapy from Oct 2019 to Nov 2023. We analyzed 41 patients with advanced or recurrent non-squamous, non-small cell lung cancer treated with platinum, pemetrexed, and pembrolizumab (CPP). Peripheral blood samples were collected at baseline, day 3(±1), day 7(±1), and day 42. 40 serum proteins were quantified using a Luminex 200 analyzer and a Milliplex MAP system. The association between cytokine increase and progression-free survival (PFS) was statistically analyzed. Results: Patient characteristics were as follows: median age (range), 71 (46-84) years; male/female, 33/8; adenocarcinoma/other, 36/5; performance status (PS) 0/1, 8/33; stage IV/recurrence, 31/10; cisplatin/carboplatin, 16/25; PD-L1 tumor proportional score (TPS) <1/1-49/≥50, 14/12/15. The dose of dexamethasone at the first treatment was 6.6 mg (3.3-9.9 mg). Among the 40 measured cytokines, 10 showed an average increase of ≥50% from baseline to Day 3, of which 7 were inflammatory or immune-stimulatory (IL-1α, G-CSF, CXCL10, CXCL13, IL-6, IL-15, MCP-1). Five of them decreased by Day 7. Eight cytokines showed an increase of ≥50% from baseline to Day 7, of which 4 were inflammatory, and all of them were among those ≥50% elevated at Day 3 (IL-1α, G-CSF, IL-6, MCP-1). A univariate Cox proportional hazard analysis revealed that an increase in IL-6 or MCP-1 at day 3 (Day 3/0 ratio >1) was significantly associated with longer PFS [IL-6: HR 0.41 (95%CI 0.17-0.97), p=0.049; MCP-1: HR 0.43 (95% CI 0.19-0.97), p=0.042]. After adjustment for age, PS, and PD-L1 TPS in the multivariate analysis, MCP-1 remained a significant predictive factor (HR 0.36, 95% CI 0.13-0.97, p=0.043). PFS curves were significantly different between MCP-1 increased and decreased cases (median PFS 463 vs. 201 days, p=0.036), with 12-month PFS rates of 60% and 31%, and 25-month PFS rates of 50% and 8%, respectively. Conclusions: This study demonstrated that inflammatory cytokines increased immediately after CPP, despite the concomitant use of dexamethasone for antiemesis. Furthermore, the immediate increase in MCP-1 after treatment was associated with prolonged PFS, suggesting its potential as a predictor of treatment efficacy and providing insights into the mechanisms of chemo-immunotherapy.