FDA将帕博利珠单抗高突变负荷实体瘤适应症转为正式批准：门槛由每兆碱基10个突变升至13个
美国食品药品监管局 FDA 于10月16日授予帕博利珠单抗（Keytruda）及帕博利珠单抗与 berahyaluronidase alfa-pmph 复方制剂（Keytruda Qlex）正式批准，用于经 FDA 授权检测确认肿瘤突变负荷高（TMB-H）、既往治疗后进展且无满意替代治疗方案的不可切除或转移性实体瘤成人与儿童患者。
此次批准把该适应症2020年6月获得的加速批准转为正式批准，同时修改了 TMB-H 的界定：门槛由每兆碱基至少10个突变（mut/Mb）上调至至少13个。FDA 表示，肿瘤突变负荷在10个至不足13个 mut/Mb 的患者人群中，未能证实支持正式批准的疗效。
疗效数据来自 KEYNOTE-158 研究，共纳入220名患者，其中前瞻入组的队列 M 有145人，队列 A 至 J 有75人。结果显示，客观缓解率为36%（95%置信区间30%至43%），58%的缓解患者缓解持续时间达到或超过12个月。
按 FDA 公布的用法，成人剂量为每3周200毫克或每6周400毫克、最长用药24个月；儿童剂量为每3周每公斤体重2毫克，上限200毫克。肿瘤突变负荷指肿瘤 DNA 中突变的数量，须以 FDA 授权的检测确定患者是否达到新的 TMB-H 门槛。
FDA Converts Pembrolizumab TMB-H Solid Tumor Indication to Traditional Approval, Raising Threshold to 13 Mutations per Megabase
The U.S. Food and Drug Administration (FDA) on October 16 granted traditional approval to pembrolizumab (Keytruda) and to pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
The action converts the indication's June 2020 accelerated approval to traditional approval and amends the definition of TMB-H: the threshold rises from at least 10 mutations per megabase (mut/Mb) to at least 13 mut/Mb. The FDA said efficacy to support traditional approval was not confirmed in patients whose tumors had a TMB of 10 to less than 13 mut/Mb.
Efficacy was evaluated in the KEYNOTE-158 study in 220 patients, including 145 patients in prospectively enrolled Cohort M and 75 patients in Cohorts A through J. The objective response rate was 36% (95% CI, 30%-43%), and 58% of responders had a duration of response of at least 12 months.
Under the FDA's published dosing, adults receive 200 mg every three weeks or 400 mg every six weeks for up to 24 months, and pediatric patients receive 2 mg/kg every three weeks, up to a maximum of 200 mg. Tumor mutational burden measures the number of mutations in a tumor's DNA, and an FDA-authorized test is required to determine whether a tumor meets the new TMB-H threshold.
来源：GSM·美国（原文链接）
图片来源：图：位于马里兰州 Silver Spring 的食品药品监管局 FDA White Oak 园区31号楼，局长办公室与监管事务办公室设于此楼（资料图）。美国食品药品监管局官方照片，公共领域，经维基共享资源。Photo: FDA Building 31 at the White Oak campus in Silver Spring, Maryland, home to the Office of the Commissioner and the Office of Regulatory Affairs (file photo). Official U.S. Food and Drug Administration photo, public domain, via Wikimedia Commons.
