FDA Approves New Cetuximab Use and KRAS Test

美国食品药品管理局(FDA)宣布已批准西妥昔单抗用于结直肠癌的新适应证，同时批准了一种遗传学检测，后者用于排除那些因携带KRAS突变而不能从治疗中获益的患者。

根据新适应证，可将西妥昔单抗(爱必妥)与三药FOLFIRI(伊立替康、5氟尿嘧啶和亚叶酸)化疗方案联用，作为表达表皮生长因子受体(EGFR)的转移性结直肠癌患者的一线治疗，EGFR是西妥昔单抗的治疗靶点。这一适应证要求患者没有KRAS突变，原因是西妥昔单抗对这类患者无效。

与此同时，FDA批准了therascreen KRAS RGQ聚合酶链反应试剂盒，后者可提供有关转移性结直肠患者是否携带KRAS突变的信息，并且“能在结肠癌患者中可靠地分辨出这些患者亚组”。这种由Qiagen生产的遗传学检测试剂盒，是一种实时聚合酶链反应检测，可从1份肿瘤标本中发现7种不同的KRAS基因突变。

FDA药物评估与研究中心肿瘤药物产品办公室主任Richard Pazdur博士指出：“批准爱必妥的这一新适应证并且同时批准遗传学检测，可指导临床医生准确地选择可能获益最大的患者。”

西妥昔单抗联合FOLFIRI方案的适应证获准是基于对3项试验中亚组患者的回顾性分析：CRYSTAL研究和2项支持性研究(CA225025和EMR 62 202-047[OPUS])。这项分析确定，西妥昔单抗的治疗收益“仅限于肿瘤中不存在7种KRAS突变中任意1种的患者”。西妥昔单抗治疗与野生型KRAS肿瘤患者的总生存率、无进展生存率和总应答率改善相关，而对于KRAS突变肿瘤患者既无益处也无潜在危害。

在CRYSTAL试验开放标记期内，表达EGFR的转移性结直肠癌患者接受FOLFIRI治疗，联用或不联用西妥昔单抗。回顾性分析显示，63%的患者为野生型KRAS肿瘤，其余37%则携带KRAS突变。在野生型KRAS患者中，西妥昔单抗+FOLFIRI组的中位总生存期达到23.5个月，而单纯FOLFIRI组仅为19.5个月，前者的中位无进展生存期也更长(9.5个月 vs. 8.1个月)。而在KRAS突变患者中，加用西妥昔单抗未能显着改善这2项指标。CA225025和OPUS试验分别在最佳支持治疗和FOLFOX方案的基础上加用西妥昔单抗。在这2项研究中，西妥昔单抗的治疗收益也仅限于野生型KRAS患者。这些研究的安全性数据符合西妥昔单抗和化疗方案的不良反应特征。

FDA建议的西妥昔单抗给药剂量和方法为，首次静脉输注400 mg/m2，在120分钟内输完，此后静脉输注250 mg/m2，至少输30分钟，每周结合方案。它说，西妥昔单抗管理应完成1小时前方案。

西妥昔单抗(爱必妥，由ImClone提交申请)于2004年获得加速审批，获准用于治疗对基于伊立替康的化疗不再有应答的晚期结直肠癌患者。2007年，FDA正式批准单剂西妥昔单抗“用于治疗基于伊立替康和基于奥沙利铂的化疗方案均失败且表达EGFR的转移性结直肠癌患者”。该药还获准用于治疗头颈癌。

本次获准的遗传学检测试剂盒是由英国曼彻斯特的Qiagen开发的。爱必妥是百时美施贵宝和礼来销售。爱必妥由百时美-施贵宝和礼来销售。

点击查看西妥昔单抗的新标签。

爱思唯尔  版权所有

By: ELIZABETH MECHCATIE,  Oncology Report Digital Network

The Food and Drug Administration has approved a new cetuximab indication in colorectal cancer along with a genetic test to rule out patients who carry a KRAS mutation and therefore would not benefit from treatment.

The new indication supports use of cetuximab (Erbitux) combined with the three-drug FOLFIRI chemotherapy regimen as a first-line treatment for patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor (EGFR) targeted by cetuximab. The indication is contingent on the patients not having a KRAS mutation, since cetuximab does not work in those patients.

Concurrently, the agency approved the therascreen KRAS RGQ PCR Kit, which provides information about KRAS mutations in patients with metastatic colorectal cancer, and "provides a reliable way to identify these subsets of patients with colon cancer," according to the FDA announcement.

The genetic assay, manufactured by Qiagen, is a real-time polymerase chain reaction assay that detects 7 different mutations of the KRAS gene in a tumor specimen, the agency said on July 6.

"The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, is quoted in the agency’s announcement.

"Clinical trial data leading to the approval of this new indication support the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations," he added.

Approval of the indication for cetuximab with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) is based on retrospective analyses of subsets of patients in three trials: the CRYSTAL study and two supportive studies (CA225025 and EMR 62 202-047 [OPUS]), which determined that the benefits of cetuximab "were limited to patients whose tumors did not have one of the seven KRAS mutations detected by the test," according to the FDA statement.

Treatment with cetuximab was associated with improvements in overall survival, progression-free survival, and overall response rates in the subset of patients with KRAS wild-type tumors, but among those with KRAS mutant tumors, "there was no benefit or potential harm." the FDA said.

In the open-label, randomized controlled CRYSTAL trial patients with EGFR-expressing metastatic colorectal cancer received FOLFIRI with or without cetuximab. A retrospective analysis found that 63% of patients had KRAS wild-type tumors, while the remaining 37% had KRAS mutations.

Overall survival reached a median of 23.5 months with cetuximab and FOLFIRI in the wild-type patients vs. 19.5 months with FOLFIRI alone. Median progression-free survival also was longer with the combination at 9.5 months vs. 8.1 months. No significant improvements were seen in patients with KRAS mutations.

The CA225025 and OPUS trials added cetuximab to best supportive care and to the FOLFOX regimen, respectively. In both studies the benefit from cetuximab was limited to patients with wild type KRAS.

Safety data in these studies was consistent with the adverse event profiles of cetuximab and the chemotherapy regimens, according to the announcement.

The FDA recommends that cetuximab be administered at 400 mg/m2 intravenously as a 120-minute infusion initially followed by 250 mg/m2 infused over 30 minutes weekly in combination with FOLFIRI. It said cetuximab administration should be completed 1 hour prior to FOLFIRI.

Cetuximab, marketed as Erbitux by ImClone, received accelerated approval in 2004 to treat late-stage colorectal cancer in patients who had stopped responding to irinotecan-based chemotherapy. In 2007, the FDA granted regular approval for single-agent cetuximab "for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens."

It also is approved in the treatment of head and neck cancers.

The genetic test kit was developed by Qiagen of Manchester, England. Erbitux is marketed by Bristol-Myers Squibb and Eli Lilly.