Department of Radiation Oncology, UCLA, Los Angeles, California.
NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
Cancer Res Commun. 2023 Oct 11;3(10):2074-2081. doi: 10.1158/2767-9764.CRC-23-0084.
RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617.
From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant.
A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients-while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13-10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11-0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11-2.28, P = 0.012).
CONCLUSIONS/DISCUSSION: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy.
The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.
RTOG 0617 是一项针对无法切除的 IIIA/IIIB 期非小细胞肺癌患者的 III 期随机试验，比较了标准剂量（60Gy）与高剂量（74Gy）放疗和化疗加或不加西妥昔单抗。尽管该研究结果为阴性，但基于先前的证据表明，携带 KRAS 变异（一种遗传性种系突变）的患者从西妥昔单抗中获益，我们在 RTOG 0617 中评估了 KRAS 变异患者。
从 RTOG 0617 中，496 名患者中有 328 名（66%）被纳入本分析。对于生存时间的结果，采用分层对数秩检验和多变量 Cox 回归模型。对于二分类结果，采用 Cochran-Mantel-Haenzel 检验和多变量逻辑回归模型。所有统计检验均为双侧，P 值<0.05 被认为具有统计学意义。
共有 17.1%（56/328）的患者存在 KRAS 变异，KRAS 变异和非变异患者的总生存率相似。然而，仅在 KRAS 变异患者中观察到西妥昔单抗的时间依赖性效应——在治疗后的第一年，西妥昔单抗治疗患者的死亡风险更高[风险比（HR）=3.37，95%置信区间（CI）：1.13-10.10，P=0.030]，从第 1 年到第 4 年，死亡风险降低（HR=0.33，95%CI：0.11-0.97，P=0.043）。相比之下，在非变异患者中，加用西妥昔单抗显著增加了局部失败（HR=1.59，95%CI：1.11-2.28，P=0.012）。
结论/讨论：尽管 KRAS 变异患者未获得总生存优势，但西妥昔单抗可能对这一遗传亚组患者具有潜在影响。相比之下，西妥昔单抗似乎对非变异患者有害。这些发现进一步支持了在研究全身性药物联合放疗的试验中，基于遗传选择患者的重要性。
KRAS 变异是首次在癌症中发现的功能性、遗传性 miRNA 破坏变异。我们的发现支持西妥昔单抗对接受放疗的 KRAS 变异患者具有潜在的有益影响。该研究证实了先前的证据，即 KRAS 变异患者是对放疗特别敏感的亚组。这些发现进一步支持了此类变异作为真正的治疗个体化的潜力，同时考虑到反应和毒性等同样重要的终点。
