PO.CL01.05 · 临床研究
KRAS亚型可能改变胰腺癌对免疫治疗的不良应答：来自早期临床试验的证据
KRAS subtype may modify the poor immunotherapy response in pancreatic cancer: Evidence from early phase trials
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摘要 Abstract
中文摘要
背景：PDAC的特征是几乎普遍存在KRAS突变以及对免疫治疗应答有限。KRAS亚型间的生物学异质性可能塑造肿瘤免疫生物学和治疗耐药。
方法：我们评估了109例在早期临床试验(2014年8月至2023年8月)中接受治疗的晚期PDAC患者。估算了PFS和OS，采用cox回归模型评估生存的临床和分子预测因子。
结果：在109例患者中，64%有KRAS突变，18%为KRAS野生型，17%KRAS状态未知。中位年龄为65岁，83%有肝转移。KRAS亚型分布为G12D(46%)、G12V(31%)、G12R(13%)和其他变异(10%)。39%的患者接受了免疫调节剂，最常见于一线治疗(49%)。整个队列的mOS和PFS分别为5.65和2.73个月。KRAS突变型与KRAS野生型之间的限制性平均OS(7.54 vs 8.65，p=0.53)和PFS(3.82 vs 4.24，p=0.7)无差异。在KRAS突变型患者中，接受免疫调节治疗者的OS较未接受者更短，其中在KRAS G12D中观察到最强的关联(表1)。这一模式在KRAS野生型中未见。单变量分析显示，免疫治疗暴露、既往治疗线数和肝转移各自均与较差的OS相关。多变量分析中，免疫治疗暴露呈现出趋向较差OS的非显著趋势(HR 1.61，95% CI 0.98-2.66；p=0.06)，而其他因素仍独立地与更差的OS相关，提示免疫治疗与生存之间未经校正的关联存在混杂。
结论：我们的发现提示，在KRAS突变型PDAC——尤其是G12D——中，早期临床试验中接受免疫治疗与较短的OS相关。这可能反映潜在的生物学，或受治疗线数和疾病负荷的混杂影响，值得通过KRAS亚型知情的研究加以验证。
表1：按KRAS和免疫治疗暴露的mOS KRAS 免疫治疗(n) mOS(月) p 野生型 是(n=7) 4.47 0.08 否(n=13) 7.43 突变型 是(n=27) 2.63 0.03 否(n=43) 7.52 G12D 是(n=13) 2.07 0.04 否(n=19) 7.79 G12V 是(n=7) 4.04 0.48 否(n=15) 10.22 其他 是(n=7) 2.33 0.20 否(n=9) 5.75
查看英文原文 English abstract
Background: PDAC is characterized by a near universal presence of KRAS mutations and limited responsiveness to immunotherapy. Biologic heterogeneity among KRAS subtypes may shape tumor immunobiology and treatment resistance.
Methods: We evaluated 109 patients with advanced PDAC treated on early phase trials (08/2014 to 08/2023). PFS and OS were estimated, cox regression models assessed clinical and molecular predictors of survival.
Results: Of 109 patients, 64% had KRAS mutations, 18% were KRAS wild, and 17% had unknown KRAS status. Median age was 65 and 83% had liver metastases. KRAS subtype distribution was G12D (46%), G12V (31%), G12R (13%), and other variants (10%). Immunomodulatory agents were administered in 39% of patients, most commonly in the 1L (49%). mOS and PFS for the entire cohort were 5.65 and 2.73 months, respectively. The restricted mean OS (7.54 vs. 8.65, p=0.53) and PFS (3.82 vs. 4.24, p=0.7) did not differ between KRAS-mutant and KRAS wild. Among KRAS-mutant patients, those receiving immunomodulator therapy had shorter OS compared with those who did not, with the strongest association observed in KRAS G12D (Table 1). This pattern was not seen in the KRAS wild-type. On univariate analysis, immunotherapy exposure, number of prior treatment lines, and liver metastasis were each associated with inferior OS. On multivariate analysis, immunotherapy exposure demonstrated a non-significant trend toward inferior OS (HR 1.61, 95% Cl 0.98-2.66; p=0.06), while others remained independently associated with worse OS, suggesting confounding in the unadjusted association between immunotherapy and survival.
Conclusion: Our findings suggest that among KRAS mutant PDAC - particularly G12D - receipt of immunotherapy in early phase trials was associated with shorter OS. This may reflect underlying biology or confounding by treatment line and disease burden and warrant validation by KRAS subtype-informed studies.
Table 1: mOS by KRAS and immunotherapy exposure KRAS Immunotherapy (n) mOS (months) p wild yes (n=7) 4.47 0.08 no (n=13) 7.43 mutant yes (n=27) 2.63 0.03 no (n=43) 7.52 G12D yes (n=13) 2.07 0.04 no (n=19) 7.79 G12V yes (n=7) 4.04 0.48 no (n=15) 10.22 others yes (n=7) 2.33 0.20 no (n=9) 5.75
利益披露 Disclosure
D. Mizrak Kaya, None..
Y. Ma, None..
T. Demir, None..
A. Kalyan, None..
S. Kircher, None..
M. Mulcahy, None..
A. B. Benson III, None..
R. Chen, None..
D. Mahalingam, None.