Zhao Dan, Li Haiqing, Mambetsariev Isa, Mirzapoiazova Tamara, Chen Chen, Fricke Jeremy, Kulkarni Prakash, Villaflor Victoria, Arvanitis Leonidas, Hamilton Stanley, Afkhami Michelle, Pillai Raju, Armstrong Brian, Erhunmwunsee Loretta, Massarelli Erminia, Sattler Martin, Amini Arya, Salgia Ravi
Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA.
Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
Cancers (Basel). 2022 Oct 8;14(19):4933. doi: 10.3390/cancers14194933.
Background: The molecular and clinical features of KRAS-mutated lung cancer patients treated with immunotherapy have yet to be characterized, which could guide the development of therapeutics targeting KRAS with potential immuno-oncology treatment combinations. Research Question: Do KRAS-mutated patients with different subtypes and comutations have different clinical responses and overall survival (OS) to checkpoint inhibitors? Study Design and Methods: 87 patients with NSCLC at the City of Hope who received immune checkpoint inhibitors were identified and analyzed retrospectively. Tumor genomic alterations were extracted from the clinical data with next-generation sequencing using various platforms. Demographic, clinical, molecular, and pathological information was collected with the approval of the institutional review board of the City of Hope. OS was calculated if it was available at the study time point, and responses were determined according to the RECIST v1.1. Results: Among 87 patients, 32 had a KRAS G12C mutation (36.8%), 19 had G12V (21.9%), 18 had G12D (20.7%), 6 had G12A (6.9%), 3 had G12R (3.45%), and 10 had amplification (11.49%) and other uncommon mutations. G12D had a statistically significant Odds Ratio (OR) between patients who had responses and progression of the disease (OR (95% CI) = 0.31 (0.09−0.95), p < 0.05), with 5 G12D-mutated patients having responses and 11 G12D-mutated patients having progression of the disease. In the univariate analysis with OS, there was a trend of better OS in the G12D-mutated patients, with no statistically significant difference in terms of OS between the patients who had G12D mutation and the patients who had other KRAS mutations (HR (95% CI) = 0.53 (0.21−1.36), p = 0.185). The median OS was significantly worse with KRAS comutation CDKN2A/B loss (4.2 vs. 16.9 months, HR = 3.07 (1.09−8.69), p < 0.05) and MET (3.4 vs. 17 months, HR = 3.80 (1.44−10.05), p < 0.01), which were included for the multivariate analysis. The OS with other KRAS comutations was not statistically significant, including STK11 and KEAP1. Conclusion: KRAS mutation subtypes such as G12D and comutations such as CDKN2/A and MET may modulate the immunotherapy responses and outcomes in lung cancer.
接受免疫治疗的KRAS突变肺癌患者的分子和临床特征尚未明确，这可能有助于指导针对KRAS的治疗方法与潜在免疫肿瘤治疗组合的开发。研究问题：不同亚型和共突变的KRAS突变患者对检查点抑制剂是否有不同的临床反应和总生存期（OS）？研究设计与方法：对希望之城87例接受免疫检查点抑制剂治疗的非小细胞肺癌患者进行回顾性鉴定和分析。使用各种平台通过下一代测序从临床数据中提取肿瘤基因组改变。在希望之城机构审查委员会批准下收集人口统计学、临床、分子和病理信息。如果在研究时间点有可用数据，则计算OS，并根据RECIST v1.1确定反应。结果：87例患者中，32例有KRAS G12C突变（36.8%），19例有G12V突变（21.9%），18例有G12D突变（20.7%），6例有G12A突变（6.9%），3例有G12R突变（3.45%），10例有扩增（11.49%）和其他罕见突变。G12D突变患者在疾病反应和进展之间的优势比（OR）具有统计学意义（OR（95%CI）=0.31（0.09−0.95），p<0.05），5例G12D突变患者有反应，11例G12D突变患者疾病进展。在OS的单因素分析中，G12D突变患者有OS更好的趋势，G12D突变患者与其他KRAS突变患者在OS方面无统计学显著差异（HR（95%CI）=0.53（0.21−1.36），p=0.185）。KRAS共突变CDKN2A/B缺失（4.2个月对16.9个月，HR=3.07（1.09−8.69），p<0.05）和MET（3.4个月对17个月，HR=3.80（1.44−10.05），p<0.01）时，中位OS显著更差，将其纳入多因素分析。其他KRAS共突变包括STK11和KEAP1时，OS无统计学显著差异。结论：KRAS突变亚型如G12D以及共突变如CDKN2/A和MET可能调节肺癌的免疫治疗反应和结果。
