Vitrakvi真的是抗癌神药?

有某海外华人资讯的刷屏文章称：近日美国“FDA上市”“第一款（实为第二个）与肿瘤类型无关‘广谱抗癌药物’，”“治愈率高达75%”，“对于肿瘤无法切除，获已经转移的患者有奇效”等等，引起了不小轰动。

其实，这些说法有失偏颇。应答率（有效率）有完全应答和部分应答之分，即便是完全应答率也不等同于治愈率，而且持续应答时间尚没有结论，停止应答即意味着复发。该肿瘤药用于有某种基因突变，和多个前置条件的患者，并非普遍适用。本文根据FDA官方网站发布的信息和相关的专题报告择要整理而成，对该药作客观介绍。

11月26日，美国FDA通过加速审批程序批准Vitrakvi（larotrectinib，拉洛替尼）——一种治疗携带特定遗传特征（生物标志物）的成人和儿童癌症患者。

这是该机构基于不同类型肿瘤中共同的生物标志物批准的第二个癌症治疗药[第一个为默沙东的Keytruda（pembrolizumab，派姆单抗]，而无关乎身体的原发肿瘤部位[获准用于黑色素瘤、非小细胞肺癌、头颈癌、经典型霍奇金淋巴瘤、尿路上皮癌、微卫星不稳定性高恶性肿瘤（Microsatellite Instability-High Cancer）、胃癌、宫颈癌]。该批准是“组织不可知（tissue agnostic）”的抗癌药开发的新范例。

Vitrakvi用于治疗TRK融合癌——一种携带神经营养性受体酪氨酸激酶（neurotrophic receptor tyrosine kinase，NTRK）基因融合而无已知的获得性抗性突变，转移性的或手术切除可能导致严重病状，目前没有满意的替代治疗或治疗后可能恶化的实体肿瘤成人和儿童患者。其成功意义重大。

FDA掌门人Scott Gottlieb博士指出：这项批准标志着基于肿瘤基因而非体内部位治疗癌症的重要转变迈出的新的一步。这个新药并不是专门针对在身体特定器官中发生的癌症，例如乳腺癌或结肠癌，即与肿瘤位点无关。这项批准反映了使用生物标志物指导药物开发以及更能靶向传输的药物开发方面取得的重要进展。日后，合适的患者有可能在正确的时间得到正确的治疗。

这类药物的开发需招募患有不同肿瘤而有共同基因突变的患者。在十年前，由于人们对这种癌症基因突变知之甚少，显然这是不可能实现的。

研究表明，编码TRK蛋白的NTRK基因可以异常地与其它基因融合，从而产生支持肿瘤生长的信号。NTRK融合很罕见，但存在于身体许多部位出现的癌瘤中。在Vitrakvi获准之前，对于表达这种突变的癌症，例如乳腺类似物分泌癌、细胞或混合先天性中胚层肾瘤和婴儿纤维肉瘤都没有治疗手段。

在三项临床试验中对larotrectinib的疗效进行了研究，参与者中包括55名患有实体肿瘤的儿科和成人患者，这些患者携带已确定而没有抗性突变的NTRK基因融合，并且他们的肿瘤是转移性的，或者手术切除可能导致严重病状。这些患者迄今没有满意的替代治疗办法或治疗后会迅速恶化。

在不同类型的实体瘤中larotrectinib显示出75％的总体应答率（22%完全应答，53%部分应答）。这些应答是持久的，其中有73％至少持续6个月，在结果分析时有39％已经持续1年或更长时间。对larotrectinib产生应答的携带NTRK融合的肿瘤类型包括软组织肉瘤、唾液腺癌、婴儿纤维肉瘤、甲状腺癌和肺癌等多种实体瘤。

在临床试验中接受Vitrakvi的患者报告的常见副作用包括疲劳、恶心、咳嗽、便秘、腹泻、头晕、呕吐以及肝脏中AST（谷草转氨酶）和ALT（谷丙转氨酶）水平升高。医务人员应该在治疗的第一个月内每两周监测患者的ALT和AST肝脏检查数据，随后每月和根据临床需要进行监测。孕妇或哺乳期妇女不应服用Vitrakvi，因为它可能对正在发育的胎儿或新生儿造成伤害。患者应报告神经系统反应的征兆，如头晕等。

该药被FDA认定为突破性新药并给予优先审批，这是对精准肿瘤药物创新以及更有针对性的有效治疗药物开发的有力支持，在儿科癌症治疗方面尤显得重要。FDA表示将继续推进更加现代化的临床试验设计框架，支持基于对癌症等疾病的生物学知识的深入了解，对跨疾病类型治疗更有针对性的创新。Vitrakvi还被归为罕见病药。Vitrakvi通过加速审批程序获准的，从而可被及时用于可能获得临床益处患者，但还需要进一步的临床试验进行确认，这类研究正在进行或计划中。这项批准授予Loxo Oncology。

关于TRK融合癌

TRK融合癌（TRK fusion cancer）发生在一种NTRK基因与另一种不相关的基因融合，产生一种改变的TRK蛋白。该改变的蛋白或TRK融合蛋白变成组成型活化或过表达，引发信号级联，TRK融合蛋白是致癌驱动因子，促进细胞生长和存活，导致TRK融合癌，可出现在身体各个部位，而不局限于某些组织，包括肺癌、甲状腺癌、胃肠癌（结肠癌，胆管癌，胰腺癌和阑尾癌）、肉瘤、中枢神经系统癌（胶质瘤和胶质母细胞瘤）、唾液腺癌（乳腺类似物分泌癌）和儿科癌症（婴儿）、纤维肉瘤和软组织肉瘤，患者不限年龄。

FDA approves first cancer treatment for any solid tumor with a specific genetic feature

Release

The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.

Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

“This is an important first for the cancer community,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Keytruda works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Keytruda may help the body’s immune system fight the cancer cells. The FDA previously approved Keytruda for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Keytruda was approved for this new indication using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of Keytruda, and the sponsor is currently conducting these studies in additional patients with MSI-H or dMMR tumors.

The safety and efficacy of Keytruda for this indication were studied in patients with MSI-H or dMMR solid tumors enrolled in one of five uncontrolled, single-arm clinical trials. In some trials, patients were required to have MSI-H or dMMR cancers, while in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began. A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial and other gastrointestinal cancers. The review of Keytruda for this indication was based on the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and for how long (durability of response). Of the 149 patients who received Keytruda in the trials, 39.6 percent had a complete or partial response. For 78 percent of those patients, the response lasted for six months or more.

Common side effects of Keytruda include fatigue, itchy skin (pruritus), diarrhea, decreased appetite, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), musculoskeletal pain, constipation and nausea. Keytruda can cause serious conditions known as immune-mediated side effects, including inflammation of healthy organs such as the lungs (pneumonitis), colon (colitis), liver (hepatitis), endocrine glands (endocrinopathies) and kidneys (nephritis). Complications or death related to allogeneic hematopoietic stem cell transplantation after using Keytruda has occurred.

Patients who experience severe or life-threatening infusion-related reactions should stop taking Keytruda. Women who are pregnant or breastfeeding should not take Keytruda because it may cause harm to a developing fetus or newborn baby. The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

The FDA granted this application Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted accelerated approval of Keytruda to Merck & Co.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.