RB1基因状态对非小细胞肺癌免疫检查点抑制剂联合化疗反应的意义

doi:10.3877/cma.j.issn.1674-6902.2025.04.015

目的

分析晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)患者潜在基因组特征因素预测免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)联合化疗反应的临床意义。

方法

选择2021年1月至2023年2月我院收治的基线无EGFR/ALK/ROS1突变且至少接受2个周期ICIs＋化疗的晚期NSCLC患者52例，收集治疗前血浆样本，完成DNA提取和基于循环肿瘤DNA(circulating tumor DNA, ctDNA)靶向测序。抗PD-L1抗体治疗后，将治疗有反应26例分为观察组，治疗无反应26例分为对照组。随访记录患者客观缓解率(objective response rate, ORR)和无进展生存期(progression free survival, PFS)。

结果

ICIs联合化疗方案ORR为50.0%，部分缓解(partial response, PR)26例，疾病稳定(stable disease, SD) 15例，11例疾病进展(disease progression, PD)，52例中位PFS为6.27(IQR：3.05~9.40)个月。随访期间生存33例(63.46%)，死亡19例(36.54%)，死因为PD。年龄(P＝0.021)、吸烟史(P＝0.013)、一线治疗(P＝0.020)与治疗反应有关。多器官转移(HR＝2.73，95%CI：1.30~5.76，P＝0.002)、ICIs后线治疗(HR＝0.32，95%CI：0.15~0.67，P＝0.002)是影响PFS因素，基线ctDNA状态、肿瘤突变负荷(tumor mutational burden, TMB)、最大体细胞等位基因频率无相关性(P>0.05)。但是，通过单变量和多变量分析，发现RB1突变(OR＝7.15，P＝0.031)与ICIs联合化疗反应不良相关。RB1突变(vs.野生型：log rank＝4.131，P＝0.042)与PFS短相关。多变量COX分析显示，RB1突变与PFS差相关(HR＝1.95，P＝0.011)，与PD-L1表达状态、TMB、肿瘤大小和C反应蛋白水平无关。TCGA预后数据证实，与接受PD-L1联合治疗患者相比，RB1突变NSCLC患者预后差(P＝0.012)。

结论

ctDNA-RB1突变与晚期NSCLC患者ICIs联合化疗PFS差有关，ctDNA-RB1突变状态可为预测PFS的标志物。

关键词: 非小细胞肺癌, 免疫检查点抑制剂, 联合化疗, RB1突变, 循环肿瘤DNA测序

Objective

To analyze the clinical significance of potential genomic characteristic factors in predicting the response to immune checkpoint inhibitors (ICIs) combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).

Methods

A total of 52 patients with advanced NSCLC without baseline EGFR/ALK/ROS1 mutations, who received at least two cycles of ICIs and chemotherapy were enrolled in our hospital from January 2021 to February 2023. Pre-treatment plasma samples were collected for DNA extraction and circulating tumor DNA (ctDNA)-based targeted sequencing. After the first anti-PD-L1 antibody treatment, the responders 26 cases were divided into an observation group and non responders 26 cases in a control group. Patient objective response rate (ORR) and progression-free survival (PFS) were recorded during follow-up.

Results

The ORR for ICIs combined with chemotherapy was 50.0%, 26 cases of partial response (PR), 15 cases of stable disease (SD), 11 cases of disease progression (PD). The median PFS for all 52 patients was 6.27 months (IQR: 3.05~9.40). During the follow-up period, 33 cases survived (63.46%)and 19 cases died(36.54%). The cause of death was PD. Age (P=0.021), smoking history (P=0.013), and first-line treatment (P=0.020) were associated with treatment response. Multi-organ metastasis (HR=2.73, 95%CI: 1.30~5.76, P=0.002) and later-line ICIs treatment (HR=0.32, 95%CI=0.15~0.67, P=0.002) were factors affecting PFS. Baseline ctDNA status, tumor mutational burden (TMB), and maximum somatic allele frequency showed no correlation (P>0.05). However, univariate and multivariate analyses revealed that RB1 mutation (OR=7.15, P=0.031) was associated with a poor response to ICIs combined with chemotherapy. RB1 mutation (vs. wild-type: log-rank=4.131, P=0.042) was associated with shorter PFS. Multivariate COX analysis showed that RB1 mutation was associated with worse PFS (HR=1.95, P=0.011), independent of PD-L1 expression status, TMB, tumor size, and C-reactive protein levels. TCGA prognostic data confirmed that NSCLC patients with RB1 mutations had a worse prognosis compared to those receiving PD-L1 combination therapy (P=0.012).

Conclusion

ctDNA-RB1 mutation is associated with poor PFS in advanced NSCLC patients treated with ICIs combined with chemotherapy. The ctDNA-RB1 mutation status may serve as a biomarker for predicting PFS.

Key words: Non-small cell lung cancer, Immune checkpoint inhibitors, Combination chemotherapy, RB1 mutation, Circulating tumor DNA sequencing

表1 两组NSCLC患者临床资料比较

临床资料	观察组(n＝26)	对照组(n＝26)	t/χ²/Z	P值
既往/现在吸烟史[n(%)]	18(69.23)	9(34.62)	6.240	0.013
病理亚型[n(%)]			4.202	0.122
肺腺癌	12(46.15)	16(61.54)
肺鳞癌	8(30.77)	9(34.62)
其他	6(23.08)	1(3.85)
临床分期[n(%)]			0.923	0.337
ⅢB-ⅢC	8(30.77)	5(19.23)
Ⅳ	18(69.23)	21(80.77)
器官转移[n(%)]			4.626	0.099
0个	8(30.77)	5(19.23)
1个	14(53.85)	10(38.46)
≥2个	4(15.38)	11(42.31)
ICIs治疗线[n(%)]			5.438	0.020
一线	21(76.92)	13(50.0)
两线及以上	5(23.08)	13(50.0)
ICIs药物[n(%)]			2.511	0.643
帕博利珠单抗	10(38.46)	8(30.77)
卡瑞利珠单抗	7(26.92)	4(15.38)
信迪利单抗	6(23.08)	11(42.31)
替雷利珠单抗	2(7.69)	2(7.69)
特瑞普利单抗	1(3.85)	1(3.85)
化疗药物[n(%)]			1.460	0.692
培美曲塞	9(34.62)	6(23.08)
吉西他滨	7(26.92)	6(23.08)
紫杉醇	5(19.23)	6(23.08)
多西他赛	5(19.23)	8(30.77)
联合抗血管生成药物[n(%)]	5(19.23)	10(38.46)	2.342	0.126
PD-L1检测[n(%)]			0.962	0.618
阴性	8(30.77)	10(38.46)
阳性	8(30.77)	5(19.23)
未检测	10(38.46)	11(42.31)
CRP>ULN[n(%)]	12(46.15)	14(53.85)	0.308	0.579
LDH>ULN[n(%)]	4(15.38)	6(23.08)	0.495	0.482

表1 两组NSCLC患者临床资料比较

临床资料	观察组(n＝26)	对照组(n＝26)	t/χ²/Z	P值
既往/现在吸烟史[n(%)]	18(69.23)	9(34.62)	6.240	0.013
病理亚型[n(%)]			4.202	0.122
肺腺癌	12(46.15)	16(61.54)
肺鳞癌	8(30.77)	9(34.62)
其他	6(23.08)	1(3.85)
临床分期[n(%)]			0.923	0.337
ⅢB-ⅢC	8(30.77)	5(19.23)
Ⅳ	18(69.23)	21(80.77)
器官转移[n(%)]			4.626	0.099
0个	8(30.77)	5(19.23)
1个	14(53.85)	10(38.46)
≥2个	4(15.38)	11(42.31)
ICIs治疗线[n(%)]			5.438	0.020
一线	21(76.92)	13(50.0)
两线及以上	5(23.08)	13(50.0)
ICIs药物[n(%)]			2.511	0.643
帕博利珠单抗	10(38.46)	8(30.77)
卡瑞利珠单抗	7(26.92)	4(15.38)
信迪利单抗	6(23.08)	11(42.31)
替雷利珠单抗	2(7.69)	2(7.69)
特瑞普利单抗	1(3.85)	1(3.85)
化疗药物[n(%)]			1.460	0.692
培美曲塞	9(34.62)	6(23.08)
吉西他滨	7(26.92)	6(23.08)
紫杉醇	5(19.23)	6(23.08)
多西他赛	5(19.23)	8(30.77)
联合抗血管生成药物[n(%)]	5(19.23)	10(38.46)	2.342	0.126
PD-L1检测[n(%)]			0.962	0.618
阴性	8(30.77)	10(38.46)
阳性	8(30.77)	5(19.23)
未检测	10(38.46)	11(42.31)
CRP>ULN[n(%)]	12(46.15)	14(53.85)	0.308	0.579
LDH>ULN[n(%)]	4(15.38)	6(23.08)	0.495	0.482

表2 影响NSCLC患者PFS的COX分析

影响因素	HR(95%CI)	P值
年龄(<60岁vs. ≥60岁)	0.81(0.39~1.68)	0.573
性别(女vs.男)	1.37(0.56~3.37)	0.491
吸烟史(从未vs.既往/现在)	0.86(0.39~1.66)	0.555
病理亚型(腺癌vs.鳞癌/其他)	0.73(0.34~1.57)	0.353
治疗线(一线vs.两线及以上)	2.73(1.30~5.76)	0.006
肿瘤大小(≤5 cm vs. >5 cm)	1.22(0.53~2.78)	0.645
器官转移数目(≥2个vs. 0~1个)	0.32(0.15~0.67)	0.002
PD-L1检测(阳性vs.阴性/未检测)	0.68(0.33~1.42)	0.302
ICIs药物(帕博利珠单抗vs.其他)	0.82(0.34~2.23)	0.705
化疗药物(培美曲塞vs.其他)	0.82(0.39~1.73)	0.592
联合抗血管生成药物(是vs.否)	0.18(0.07~12.58)	0.499
CRP(>ULN vs. ≤ULN)	0.55(0.26~1.14)	0.103
LDH(>ULN vs. ≤ULN)	1.51(0.69~3.3)	0.298
TMB(≥10% vs. <10%)	0.98(0.29~3.28)	0.969
MSAF(≥2% vs. <2%)	1.78(0.85~3.83)	0.122
基线ctDNA状态(阴性vs.阳性)	1.73(0.72~4.26)	0.231

表2 影响NSCLC患者PFS的COX分析

影响因素	HR(95%CI)	P值
年龄(<60岁vs. ≥60岁)	0.81(0.39~1.68)	0.573
性别(女vs.男)	1.37(0.56~3.37)	0.491
吸烟史(从未vs.既往/现在)	0.86(0.39~1.66)	0.555
病理亚型(腺癌vs.鳞癌/其他)	0.73(0.34~1.57)	0.353
治疗线(一线vs.两线及以上)	2.73(1.30~5.76)	0.006
肿瘤大小(≤5 cm vs. >5 cm)	1.22(0.53~2.78)	0.645
器官转移数目(≥2个vs. 0~1个)	0.32(0.15~0.67)	0.002
PD-L1检测(阳性vs.阴性/未检测)	0.68(0.33~1.42)	0.302
ICIs药物(帕博利珠单抗vs.其他)	0.82(0.34~2.23)	0.705
化疗药物(培美曲塞vs.其他)	0.82(0.39~1.73)	0.592
联合抗血管生成药物(是vs.否)	0.18(0.07~12.58)	0.499
CRP(>ULN vs. ≤ULN)	0.55(0.26~1.14)	0.103
LDH(>ULN vs. ≤ULN)	1.51(0.69~3.3)	0.298
TMB(≥10% vs. <10%)	0.98(0.29~3.28)	0.969
MSAF(≥2% vs. <2%)	1.78(0.85~3.83)	0.122
基线ctDNA状态(阴性vs.阳性)	1.73(0.72~4.26)	0.231

表3 Logistic回归分析基线时ctDNA突变与ICIs联合化疗反应关系

基因	基因状态(n)		单变量分析		多变量分析
基因	野生型(WT)	突变型(Mut)	OR(95%CI)	P值	OR(95%CI)	P值
TP53	12	26	1.17(0.51~2.72)	0.726	－	－
EGFR	29	9	1.35(0.56~3.28)	0.506	－	－
RB1	30	8	9.15(1.01~83.97)	0.048	7.15(1.03~70.72)	0.031
KEAP1	31	7	7.29(0.78~67.90)	0.081	6.26(0.91~58.32)	0.067
FANCM	32	6	0.39(0.11~1.34)	0.124	－	－
NFE2L2	32	6	0.62(0.21~1.86)	0.394	－	－
SPTA1	32	6	1.51(0.44~5.19)	0.504	－	－
ERBB4	33	5	1.72(0.38~7.83)	0.477	－	－
MYC扩增	33	5	3.7(1.31~10.45)	0.008	1.84(0.24~14.27)	0.561
FLT1	33	5	0.6(0.14~2.56)	0.487	－	－
KMT2C	33	5	1.48(0.43~5.11)	0.533	－	－
KMT2D	33	5	0.8(0.23~2.76)	0.726	－	－
BRINP3	34	4	1.2(0.27~5.24)	0.808	－	－
KRAS	34	4	3.39(1.12~10.32)	0.021	3.53(0.33~37.92)	0.297
ROS1	34	4	3.37(1.11~10.24)	0.022	1.58(0.09~28.38)	0.757
STK11	35	3	2.53(0.71~9.04)	0.148	－	－

表3 Logistic回归分析基线时ctDNA突变与ICIs联合化疗反应关系

基因	基因状态(n)		单变量分析		多变量分析
基因	野生型(WT)	突变型(Mut)	OR(95%CI)	P值	OR(95%CI)	P值
TP53	12	26	1.17(0.51~2.72)	0.726	－	－
EGFR	29	9	1.35(0.56~3.28)	0.506	－	－
RB1	30	8	9.15(1.01~83.97)	0.048	7.15(1.03~70.72)	0.031
KEAP1	31	7	7.29(0.78~67.90)	0.081	6.26(0.91~58.32)	0.067
FANCM	32	6	0.39(0.11~1.34)	0.124	－	－
NFE2L2	32	6	0.62(0.21~1.86)	0.394	－	－
SPTA1	32	6	1.51(0.44~5.19)	0.504	－	－
ERBB4	33	5	1.72(0.38~7.83)	0.477	－	－
MYC扩增	33	5	3.7(1.31~10.45)	0.008	1.84(0.24~14.27)	0.561
FLT1	33	5	0.6(0.14~2.56)	0.487	－	－
KMT2C	33	5	1.48(0.43~5.11)	0.533	－	－
KMT2D	33	5	0.8(0.23~2.76)	0.726	－	－
BRINP3	34	4	1.2(0.27~5.24)	0.808	－	－
KRAS	34	4	3.39(1.12~10.32)	0.021	3.53(0.33~37.92)	0.297
ROS1	34	4	3.37(1.11~10.24)	0.022	1.58(0.09~28.38)	0.757
STK11	35	3	2.53(0.71~9.04)	0.148	－	－

图1 RB1突变分别与PD-L1、基线肿瘤大小、CRP水平和TMB相关注：PD-L1为程序性死亡配体1；CRP为C反应蛋白；TMB为肿瘤突变负荷

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Clinical significance of RB1 gene status predicting the response to immune checkpoint inhibitor combined with chemotherapy in patients with non-small cell lung cancer

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Clinical significance of RB1 gene status predicting the response to immune checkpoint inhibitor combined with chemotherapy in patients with non-small cell lung cancer