Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, Leuven, Belgium B-3000.
J Clin Oncol. 2012 Oct 10;30(29):3570-7. doi: 10.1200/JCO.2012.42.2592. Epub 2012 Jun 25.
We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D-mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment.
Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed.
Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D-mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies.
The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.
我们在前瞻性研究中首次发现，化疗联合西妥昔单抗治疗对化疗抵抗的 KRAS G13D 突变转移性结直肠癌（mCRC）患者有益。
CRYSTAL 和 OPUS 研究共纳入了 1378 例可评估患者的数据，我们对其中肿瘤 KRAS 突变状态（野生型、G13D、G12V 或其他突变）与无进展生存期（PFS）、总生存期（OS）和缓解率的相关性进行了分析。多变量分析中对基线预后因素进行了校正。
533 例（39%）KRAS 突变患者中，83 例（16%）为 G13D 突变，125 例（23%）为 G12V 突变，325 例（61%）为其他突变。G13D 突变患者的肿瘤缓解率（P =.005）和 PFS（P =.046）与其他突变（包括 G12V）相比存在显著差异。在 KRAS 突变亚组中，西妥昔单抗联合化疗与单纯化疗相比，可显著改善 PFS（中位值 7.4 个月比 6.0 个月；风险比 [HR]，0.47；P =.039）和肿瘤缓解率（40.5%比 22.0%；比值比 [OR]，3.38；P =.042），但对 OS（中位值 15.4 个月比 14.7 个月；HR，0.89；P =.68）没有影响。G12V 和其他突变患者不能从这种联合治疗中获益。仅接受化疗的 G13D 突变患者的结局更差（缓解率，22.0%比 43.2%；OR，0.40；P =.032），与其他突变患者相比。CRYSTAL 和 OPUS 研究中也观察到相似的结果。
化疗联合西妥昔单抗似乎对 KRAS G13D 突变型肿瘤患者有益。相对治疗效果与 KRAS 野生型肿瘤患者相似，但绝对效果值较低。
