给ICB免疫减毒增效的 药物（十九）--肌苷、β-葡聚糖

第一部分 肌苷

. s* z0 [& X$ P% E+ m& k) o' P
《Inosine enhances the efficacy of immune-checkpoint inhibitors in advanced solid tumors: A randomized, controlled, Phase 2 study》 一文介绍了一项前瞻性随机对照二期临床试验：
3 \  k& n9 c5 b
; y  \0 @; F' P: H, \' h2 _1、入组患者：172名晚期实体瘤患者，分为 ICB免疫治疗+肌苷组和 ICB免疫治疗组不联合肌苷（该组部分患者联合了化疗或者靶向）两组，每组86名患者。

0 [1 g( {* T* Y0 |2、肌苷用法：口服肌苷片，每天三次，每次0.2克。
* b. J; K8 R* q  z9 a% m' x
# f8 V* L6 p" b, \3、试验结果：肌苷组和非肌苷组中位PFS (95% CI)分别为7.00(5.31-8.69)和4.40(3.10-5.70)个月(风险比[HR]0.63；95%置信区间为0.44–0.90，p= 0.011)，肌苷组PFS提高有统计学意义。ORR分别为26.7%和15.1%(p= 0.061)，肌苷组ORR有改善。非肌苷组中位OS为29.67个月(95% CI 17.40–41.94)，肌苷组中位OS尚未达到。
  b$ r' ^2 p* R0 f
肌苷组和非肌苷组分别有25名(29%)和31名(36%)患者出现3级和4级不良反应，肌苷组的不良反应趋于减少。


# ~3 I- R, N: b$ I! c( x0 i4 E  C& q
第二部分 β-葡聚糖


/ \! \2 d) {! {$ ]9 J8 X2 s; J《β-glucan combined with Envafolimab and Endostar as immune rechallenge for metastatic non-small cell lung cancer》一文介绍了一项前瞻性随机对照二期临床试验，β-葡聚糖+pd-1i 恩沃利 + 抗血管生成药物治疗先前pd-1i治疗失败的非小细胞肺癌。

1、入组患者：23名晚期非小细胞肺癌患者，这些患者之前用pd-1i治疗都已经失败。
- B  D" P- U$ n; w
2、β-葡聚糖用法：每天两次，每次500毫克。

3、试验结果：ORR 21.7%，DCR 73.9%.，PFS 4.3个月，OS 8.9个月。PD-L1阳性和阴性亚组之间的mPFS有显著差异(6.3个月对2.3个月，p = 0.002)。
- ~7 b: X3 T$ Z7 Y
, s7 O) }* `& c8 U5 Q52.2%的患者发生了治疗相关的不良事件。最常见的原因是甲状腺功能减退(26.1%)和疲劳(26.1%)。报告了2例(8.7%)3级不良事件。未观察到与死亡相关的不良反应。
; m) z0 |+ a8 \3 U) m6 H
8 E' f, h7 n, N! O0 g) D蛋白质组学分析显示CASP-8、ARG1、MMP12、CD28和CXCL5的水平与对治疗的抗性相关，而CD40-L和EGF的水平与有利的反应相关。
. h! w+ m" A8 N$ j. l) P. i; ^: B
: l7 ], ?4 s) [3 g, y! i6 S- ?（因为患者都是之前用pd-1i都已经失败的患者，所以ORR 21.7%，DCR 73.9% 还是很不错的）
3 V# G" \( x( {2 [7 ]9 q
' I+ x$ r% v4 t- T& R% B. ^
I 《Inosine enhances the efficacy of immune-checkpoint inhibitors in advanced solid tumors: A randomized, controlled, Phase 2 study》
! [) k0 U% V8 J8 o  n; ^' B
Background: This study aimed to evaluate whether inosine enhances the efficacy of immune-checkpoint inhibitors in human malignant solid tumors.

Methods: This single-center, prospective, randomized, open-label study was conducted, from January 2021 to December 2022, in Beijing Friendship Hospital, Capital Medical University, and participants were randomly assigned (1:1) to either the inosine (trial) or non-inosine (control) group that received inosine (dosage: 0.2 g, three times/day) + PD-1/PD-L1 inhibitor or only PD-1/PD-L1 inhibitor ± targeted ± chemotherapy, respectively. Efficacy was assessed every 6 weeks (i.e., after every two-three treatment cycles). The primary endpoint was the objective response rate (ORR); the secondary endpoints were disease control rate, overall survival (OS), and progression-free survival (PFS). The trial was registered at ClinicalTrials.gov (NCT05809336).

! [7 h: q% V, z$ R% tResults: Among the 172 participants with advanced malignant solid tumors, 86 each were assigned to the inosine and non-inosine groups, wherein the median PFS (95% CI) was 7.00 (5.31-8.69) and 4.40 (3.10-5.70) months, respectively (hazard ratio [HR] 0.63; 95% CI 0.44-0.90, p = 0.011), and the ORR was 26.7% and 15.1%, respectively (p = 0.061). In the inosine and non-inosine groups, the median OS was not reached and was 29.67 (95% CI 17.40-41.94) months, respectively (HR 1.05 [95% CI 0.59-1.84], p = 0.874). Compared with the non-inosine group, the median PFS and ORR of the inosine group were significantly prolonged and improved in the multiple exploratory subgroup analyses. The safety analysis showed that Grades 3 and 4 adverse reactions occurred in 25 (29%) and 31 (36%) patients in the inosine and non-inosine groups, respectively, and tended to decrease in the inosine group compared with the non-inosine group.
7 ~( P7 k3 R0 J
4 T4 n$ e/ M% m# t1 N, T$ yConclusion: Inosine had a tendency to enhance the efficacy of immune-checkpoint inhibitors and reduced immunotherapy-related adverse reactions.



; R# Y0 X& Z& y0 [: mII 《β-glucan combined with Envafolimab and Endostar as immune rechallenge for metastatic non-small cell lung cancer》
2 Q; x6 o3 K8 {8 J& r
0 l6 m0 J; s2 p- U# c0 v" G" L- ABackground: Immune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). β-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received β-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis.

Results: Twenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0-6.6] and 9.8 months [95% CI: 7.2-12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response.

Conclusion: β-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.