他汀与ICB免疫治疗的一些临床研究

他汀类药物与ICB免疫治疗临床疗效的关系，目前大都为回顾性研究；研究结果大都认为他汀类药物能改善ICB的疗效，也有一些研究认为基线他汀类药物对ICB疗效没有统计学意义上的影响。
9 N( H9 _0 O% P% O我也同意某项研究作者的观点，关键可能还是要着眼于他汀的剂量。目前回顾性研究中的他汀剂量大都是治疗高血脂的剂量，并非抗癌剂量；抗癌剂量应较抗血脂剂量提高。
现收集整理部分临床研究资料如下：
% o0 k4 e9 n: a3 n# v1、《A propensity score-matched analysis of the impact of statin therapy on the outcomes of patients with non-small-cell lung cancer receiving anti-PD-1 monotherapy: a multicenter retrospective study》
Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients' backgrounds.
, _1 `  u1 v+ a5 gResults: The Kaplan-Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome.
* C( ]$ a; a9 f+ d( l接受他汀类药物治疗的患者总生存期(OS)明显延长，但无进展生存期(PFS)却没有延长。然而，在倾向评分匹配的队列中进行的Cox回归分析显示，他汀类药物治疗不是一个独立的有利预后因素，尽管它往往与有利的预后相关。
2、《Statin treatment improves response to anti-PD1 agents in patients with malignant pleural mesothelioma and non-small cell lung cancer》
Background: After progression to standard chemotherapy, only a small proportion of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) patients (pts) benefit from anti-programmed cell death (PD-1) treatment. Combination strategies might improve response. In pre-clinical models, statins showed vaccine adjuvant activities and synergized with anti-PD1 agents. In this multi-center study, we evaluated the impact of baseline statin treatment in MPM and NSCLC pts. Methods: We separately examined MPM and NSCLC pts treated with anti-PD1 monotherapy after progression to standard chemotherapy at two European academic institutions. As control cohort, MPM pts treated with first-line chemotherapy were also examined. Pts receiving statins at start of treatment were compared with those who did not. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 287 patients were examined. Twenty-seven out of 80 (34%) MPM and 36 out of 130 (20%) NSCLC pts received statins at start of anti-PD1 treatment. The most common statins were simvastatin, atorvastatin and rosuvastatin. In MPM pts, statin use was associated with improved ORR (22% versus 5%, P = 0.05), longer PFS (median 6.7 versus 2.4 months, hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.23–0.77, P < 0.01), and longer OS (median not reached versus 6.0 months, HR 0.43, 95% CI 0.21–0.85, P = 0.01). In NSCLC pts, statin use was associated with improved ORR (40% versus 22%, P = 0.04), longer PFS (median 7.8 versus 3.6 months, HR 0.59, 95% CI 0.37–0.97.2, P = 0.03) but similar OS (median 13.1 versus 10.1 months, HR 0.79, 95% CI 0.49–1.28, P = 0.30). At multivariate analyses, after adjusting for ECOG performance status (PS) and histological subtype, the impact of statins remained significant for ORR, PFS and OS in MPM and for PFS in NSCLC. Conversely, no association between statin use and outcomes was found in 77 MPM pts treated with first-line chemotherapy. Conclusions: This study shows that statin use at start of anti-PD1 treatment improves response to anti-PD1 agents in MPM and NSCLC pts who progressed to standard chemotherapy in routine clinical practice. This association could not be found in MPM pts treated with first-line chemotherapy, thus suggesting a synergy between statins and anti-PD1 agents. Prospective studies are needed to confirm whether the combination of statin and anti-PD1 therapy could improve outcome in pts with poorly immunogenic thoracic malignancies.
6 {7 s' d, i. t. r  b4 O在MPM患者中，他汀类药物的使用与ORR改善相关(22%对5%，P= 0.05)，更长的PFS(中位数6.7比2.4个月，风险比(HR) 0.42，95%可信区间(CI)0.23–0.77，P < 0.01), and longer OS (median not reached versus 6.0 months, HR 0.43, 95% CI 0.21–0.85, P= 0.01).在非小细胞肺癌患者中，他汀类药物的使用与ORR改善相关(40%对22%，P= 0.04)，更长的PFS(中位数7.8比3.6个月，风险比0.59，95%可信区间0.37–0.97 . 2，P= 0.03)但OS相似(中位数13.1对10.1个月，风险比0.79，95%可信区间0.49-1.28，P= 0.30).在多变量分析中，调整ECOG功能状态(PS)和组织学亚型后，他汀类药物对MPM的ORR、PFS和OS以及非小细胞肺癌的PFS的影响仍然显著。相反，在接受一线化疗的77名MPM患者中，未发现他汀类药物的使用与预后之间的关联。
3、《Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events》
" |2 |' S( D4 S; F! r/ i9 a* TResults: A total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes.
+ C3 h0 V, a0 A# a总共包括635名患者。精神药物(41%)、质子泵抑制剂(PPIs38%)、血管紧张素转换酶(ACE)抑制剂和/或血管紧张素II受体阻滞剂(ARBs32%)、糖皮质激素(26%)、抗生素(24%)、他汀类药物(21%)和吗啡(20%)是最常用的联合用药。抗生素、糖皮质激素> 10mg/天、质子泵抑制剂、精神药物、吗啡和胰岛素的基线使用与总生存期明显缩短和肿瘤反应降低有关，而他汀类药物、ACEs和/或ARB、非甾体抗炎药、阿司匹林和口服抗糖尿病药物的联合用药并不影响患者的预后。改变对ICI反应的治疗也与irAEs发生率降低相关。
3 Z. Q& _2 w) m) d9 m! d3 C8 o1 c4、《Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice》
Results: From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death.
基线他汀类药物(HR 1.60 (95% CI 1.14至2.25)，p=0.0064)，阿司匹林(HR 1.47 (95% CI 1.04至2.08，p=0.0267)和β受体阻滞剂(HR 1.76 (95% CI 1.16至2.69)，p=0.0080)被证实与客观缓解率增加独立相关。
5、《Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non-small cell lung cancer》
Given the strong association between statin and inflamed TME in silico, in vitro, and in vivo, we next examined the effect of statin use on the clinical outcome of NSCLC. We collected an in-house cohort containing 90 NSCLC patients younger than 75 receiving anti–PD-1 immunotherapy, and we evaluated the therapeutic response according to the RECIST 1.1 criteria (Figure 5A). Results indicate that statin use significantly enhanced the therapeutic response to anti–PD-1 immunotherapy and improved OS of NSCLC patients (Figure 5, B and C). Based on the inclusion and exclusion criteria (Figure 5D), 16 studies involving 63,273 participants in total were contained in our meta-analysis, in addition to our in-house cohort (Figure 5D). Overall, statin use was notably related to the improvement of OS, and further analysis indicated a possible association between statin use and improved OS in the subgroup receiving immunotherapy (Figure 5E). Sensitivity analyses were also performed and suggested the reliability of the original studies (Figure 5F). A funnel plot of included studies and Egger’s test revealed no evidence of a publication bias (Figure 5G).
! l. T) l* Q" \, _: F& k& VConsidering the limited number of NSCLC-focused studies, we performed another meta-analysis on the association between the use of statins in patients receiving ICIs and OS in all cancer types. Six studies involving 2,135 participants were contained, as was our in-house cohort (Supplemental Figure 9A). Statistical analyses suggest that the use of statins in patients with cancer receiving ICIs remarkably improved OS (Supplemental Figure 9B). Sensitivity analyses and publication bias tests were also performed. The results of sensitivity analyses indicate no obvious differences due to the removal of any studies, which suggests the credibility of the included studies (Supplemental Figure 9C), and no publication bias was revealed (Supplemental Figure 9D). Overall, such findings suggest that the use of statins is an auxiliary strategy to raise the response to anti–PD-1 immunotherapy in NSCLC.
8 p/ L- |( o7 BAs an unavoidable issue, the correlation between the doses of statin used for antitumor therapy and the safe therapeutic doses applied in patients to treat cholesterolemia should not be ignored. The dose of lovastatin used for antitumor study varies from 20 to 100 mg/kg/day (d) in the mouse, which were approximately varies from 1.62 to 8.11 mg/kg/d in the adult according to the dose conversion factor between humans and mice (51–53). In addition, the dose of lovastatin used for antitumor clinical trials varies from 0.33 mg/kg/d to 20 mg/kg/d (adult weight was regarded as 60 kg) (clinicaltrials.org; NCT00853580, NCT04297033, NCT00585052, NCT01478828, NCT00584012). The dose of lovastatin used to reduce blood fat in clinical practice varies from 0.33 to 1.33 mg/kg/d. Overall, we could observe that the dose of lovastatin used to reduce blood fat is lower than the antitumor dose. In this research, we selected 40 mg/kg/d for the in vivo assay (approximately equal to 3.24 mg/kg/d in an adult), which is about twice the maximum lipid-lowering dose but is at the median level of reported antitumor doses. Despite that a high dose of lovastatin was used in the antitumor assay, it did not cause weight loss, indicating the tolerable toxicity. Furthermore, evidence from our in-house cohort and meta-analysis suggest that statins had a sensitizing effect on anti–PD-1 therapy even at clinical lipid-lowering doses. The optimal dose of statins use for antitumor therapy needs to be further explored.
6、《Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors》
A total of 184 patients (77.7% men, mean age 66.9±9.5 years) treated with ICIs were analyzed. During follow-up, 49 (26.6%) patients developed IRAEs and 149 (81.0%) died. According to the multivariate logistic regression analysis, treatment with statins (OR:3.15; p = 0.007), previous systemic corticosteroid therapy (OR:3.99; p = 0.001), disease controlled as response to ICI (OR:5.93; p < 0.001) and higher hemoglobin values (OR:1.28; p = 0.040) were independent predictors for the development of IRAEs. Patients who developed IRAEs had significantly longer medians of PFS (41.0 vs 9.0 weeks, p < 0.001) and OS (89.0 vs 28.0 weeks; p < 0.001).
根据多变量logistic回归分析，他汀类药物治疗(OR:3.15；p = 0.007)，既往全身皮质类固醇治疗(OR:3.99；p = 0.001)，疾病控制作为对ICI的反应(OR:5.93；p < 0.001)和较高的血红蛋白值(OR:1.28；p = 0.040)是IRAEs发展的独立预测因子。发生IRAEs的患者PFS (41.0比9.0周，p < 0.001)和OS (89.0比28.0周；p < 0.001)。
5 x6 I( L7 d" l7、《Statin use improves the efficacy of nivolumab in patients with advanced renal cell carcinoma》
0 g" w6 W6 y/ c& A. J) sA total of 219 patients with mRCC receiving nivolumab between January 2016 and September 2021 were eligible for inclusion in this study; 59 (27%) were statin users. The median OS (34.4 versus 18.6 months, p = 0.017) and PFS (11.7 versus 4.6 months, p = 0.013) resulted apparently longer in statin users. Stratified by age, longer median OS and PFS were associated with statin exposure in both patients aged ≥70 y (median OS: 21.4 versus 10.1 months, p = 0.047; median PFS: 16.4 versus 4.6 months, p = 0.022) and <70 y (median OS: 34.4 versus 21.4 months, p = 0.043; median PFS: 10.3 versus 4.6 months, p = 0.042). Overall clinical benefit resulted higher in statin users than non-users (71% versus 54%, p = 0.030).
他汀类药物使用者的中位OS (34.4对18.6个月，p = 0.017)和PFS (11.7对4.6个月，p = 0.013)明显延长。按年龄分层，在年龄≥70岁的患者中，较长的中位OS和PFS与他汀类药物暴露相关(中位OS: 21.4对10.1个月，p = 0.047中位PFS: 16.4对4.6个月，p = 0.022)和& lt70岁(中位OS: 34.4对21.4个月，p = 0.043中位PFS: 10.3个月对4.6个月，p = 0.042)。他汀类药物使用者的总体临床获益高于非使用者(71%比54%，p = 0.030)。
9 D' K1 d  D: n" v% E) u: p* I8 ^8、《Statins improve survival in patients previously treated with nivolumab for advanced non-small cell lung cancer: An observational study》
There are a number of suggested predictive factors of nivolumab for non-small cell lung cancer (NSCLC), however, there is not enough evidence to determine a single factor that can predict the efficacy of nivolumab. As the progress of biomarkers for cancer treatment is improving, it has been speculated that certain clinical factors serve an important role when predicting the outcome of chemotherapy. A total of 67 patients treated with nivolumab for NSCLC from 2016-2017 were prospectively investigated. Age, sex, the Eastern Cooperative Oncology Group Performance Status, histology, epidermal growth factor receptor (EGFR) mutation, history of chemotherapy, smoking status, use of statins, use of fibrates, use of dipeptidyl peptidase-4 (DPP-4) inhibitors, and use of metformin were examined as clinical factors. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for risk factors and the tumor response of 67 patients was assessed. The patients had a median age of 67 years (range, 36-87 years), and 46 males and 21 females were enrolled; performance status 0/1 was 59. Cases were categorized as adenocarcinoma (n=41), squamous cell carcinoma (n=17) and other (n=9). A total of 13 patients (19.4%) had EGFR mutations. These clinical factors were not statistically significant in overall survival (OS). Clinical laboratory findings, complications and use of medical agents including antidiabetes mellitus or lipidemia were also analyzed. Statins exhibited statistical significance for response (P=0.02). Time-to-treatment failure (TTF) in statin-use group was not reached [95% confidence interval (CI): 1.9-not reached] and was 4.0 months (95% CI: 2.0-5.4) in the non-statin group (P=0.039). The median OS in statin-use group was not reached (95% CI: 8.7-not reached) and was 16.5 months (95% CI: 7.5-not reached) in the non-statin group (P=0.058). NSCLC patients previously treated with nivolumab who were administered statins exhibited an increased response rate and longer TTF. This response was not statistically significant in OS.
他汀类药物对反应具有统计学意义(P=0.02)。他汀类药物使用组的治疗失败时间(TTF)未达到[95%可信区间(CI):1.9-未达到]，而非他汀类药物组为4.0个月(95% CI:2.0-5.4)(P = 0.039)。他汀类药物使用组的中位OS未达到(95% CI:8.7-未达到)，而非他汀类药物组的中位OS为16.5个月(95% CI:7.5-未达到)(P=0.058)之前接受尼伐单抗治疗的非小细胞肺癌患者在接受他汀类药物治疗后，反应率增加，TTF延长。这种反应在OS中没有统计学意义。
3 q% n# D; @+ M5 M3 r9、《Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study》
We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries。A total of 802 patients were eligible for this retrospective study。The use of statins or metformin was not associated with response or survival.
他汀类药物或二甲双胍的使用与反应或存活无关。
10、《Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy》
950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort.
# R& m3 m% e  k基线他汀类药物、阿司匹林、β-受体阻滞剂和二甲双胍，在彭布罗利珠单抗队列中未发现与临床结果相关。