给免疫治疗“减毒增效”的辅助药物（九）--PCSK9抑制剂

PCSK9是治疗高血脂症的一个靶点。意大利的一项前瞻性研究和中国的两项回顾性研究表明，无论是血液还是病灶组织中PCSK9表达低，ICB疗效更好。
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; Q4 v3 ?- P" P2 R! [1、《Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study》

% F) D4 G* F, |“Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.”

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2 r# ?- U6 E3 n" g# H2、《Low baseline plasma PCSK9 level is associated with good clinical outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer》
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3 a* N9 H& J# U( Z. N“A total of 55 patients were enrolled in the study. The median progression-free survival (PFS) following treatment with ICIs in all patients was 9.9 months. The optimal threshold of baseline plasma PCSK9 was 232.2 ng/ml. Patients with low baseline plasma PCSK9 had a longer PFS (NR vs. 7.37 months, p = 0.017, HR = 0.207, 95% CI: 0.086-0.498) and a better response (ORR 71.4% vs. 43.9%, p = 0.075, DCR 100% vs. 80.5%, p = 0.098) to ICIs. Younger patients (≤66 years) with a lower PCSK9 had a significantly longer PFS and higher treatment response than those with a high baseline level of PCSK9 (NR vs. 5.83 months, p = 0.021, HR = 0.134, 95% CI: 0.044-0.409; ORR 66.7% vs. 30.0%, p = 0.106, DCR 100% vs. 75%, p = 0.153). The situation was similar in patients who received first-line therapy (NR vs. 8.97 months, p = 0.022, HR = 0.138, 95% CI: 0.047-0.400; ORR 63.6% vs. 46.4%, p = 0.480, DCR 100% vs. 89.3%, p = 0.545). Multivariate analysis showed that low PCSK9 concentration was independently associated with PFS (p = 0.032, HR = 0.201).”

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3、《PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer》
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) p) a4 ?: W) c" Q“One hundred fifteen advanced NSCLC patients who received anti-PD-1 immunotherapy were retrospectively studied with PCSK9 expression in baseline NSCLC tissues detected by immunohistochemistry (IHC). The mPFS of the PCSK9lo group was significantly longer than that of the PCSK9hi group [8.1 vs. 3.6 months, hazard ratio (HR): 3.450; 95% confidence interval (CI), 2.166-5.496]. A higher objective response rate (ORR) and a higher disease control rate (DCR) were observed in the PCSK9lo group than in the PCSK9hi group (54.4% vs. 34.5%, 94.7% vs. 65.5%).”
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