2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond.
2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond.
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DOI：
10.1016/j.ebiom.2015.01.011
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发表时间：
2015
期刊：
影响因子：
11.1
通讯作者：
Marincola, Francesco M.
中科院分区：
文献类型：
--
作者：
Ascierto, Paolo A.;Marincola, Francesco M.
临床肿瘤学的历史见证了几次革命性的治疗进步，显著改善了癌症护理。这些措施包括在20世纪70年代引入顺铂用于睾丸和卵巢癌，在90年代用于乳腺癌和其他实体肿瘤的紫杉烷，用于乳腺癌的抗HER2靶向治疗，以及在本世纪初用于慢性粒细胞白血病和其他癌症的c-Kit抑制剂。这些治疗方法中的每一种都彻底改变了各种癌症患者的治疗结果。今天，我们正处于癌症护理的新纪元--免疫疗法的新纪元。2010年，西普鲁塞-T被批准用于前列腺癌的治疗，2011年，ipilimumab(抗CTLA-4)被批准用于晚期黑色素瘤，这是癌症免疫疗法的第一个显著成功。在第一个检查点抑制剂(Ipilimumab)获得批准近三年后，好消息还没有结束。恰恰相反，我们只是刚刚开始，值得注意的是，这些进展不仅仅与黑色素瘤的治疗有关。免疫治疗已成为继手术、放射治疗和化疗(包括靶向治疗)之后的癌症治疗的第四支柱。这主要归因于另一组检查点抑制剂，抗PD-1/PD-L1药物，对各种恶性肿瘤的治疗产生的影响。与抗CTLA-4一样，抗PD-1/PD-L1的故事始于黑色素瘤。来自pembrolizumab(Robert等人，2014a，b)的大型I期研究的数据导致其在2014年9月获得美国食品和药物管理局(FDA)的批准，用于治疗无法切除或转移的黑色素瘤患者，以及ipilimumab之后的疾病进展，如果BRAF V600突变呈阳性，则使用BRAF抑制剂。这项对411名患者的研究表明，培溴利珠单抗的总有效率(ORR)为34%，中位无进展生存期(PFS)为5.5个月，1年总生存率(OS)为69%，18个月总生存率(OS)为62%。此外，一项使用两种不同剂量(每三周2 mg/kg或10 mg/kg)的pembrolizumab治疗对先前的ipilimumab治疗无效的晚期黑色素瘤的随机II期试验表明，与研究者选择的化疗相比，这两种剂量都改善了pFS(Ribas等人，2014年)。结果显示，培溴利珠单抗2 mg/kg、10 mg/kg和化疗组6个月有效率分别为34%、38%和16%，9个月有效率分别为24%、29%和8%。这三组的ORR分别为21%、25%和4%。最近，2014年12月，另一种抗PD-1的nivolumab被FDA批准用于与Pembrolizumab相同适应症的晚期黑色素瘤患者。使用nivolumab的一项大型I期试验的数据显示，ORR为32%，1年、2年、3年和4年的OS率分别为63%、48%、42%和32%。此外，先前接受ipilimumab治疗的转移性黑色素瘤患者的III期研究数据显示，nivolumab的ORR为32%，而化疗对照组的ORR为11%(D‘Angelo等人，2014年)。在另一项随机的III期试验中，未经治疗的晚期BRAF野生型黑色素瘤患者接受尼伏鲁单抗或达卡巴津治疗，并将其与化疗进行了比较。尼伏卢单抗组ORR为40.0%，达卡巴肼组ORR为13.9%。一年后，尼伏卢单抗组的OS为73.0%，而达卡巴津组为42.1%。尼伏鲁单抗组的中位PFS为5.1个月，而达卡巴津组为2.2个月(Robert等，2014a，b)。
The history of clinical oncology has witnessed several revolutionary therapeutic advances that have significantly improved cancer care. These have included the introduction of cisplatin in the 1970s for testicular and ovarian cancers, the taxanes in the 1990s for breast and other solid tumors, targeted therapy with anti-HER2 for breast cancer and c-Kit inhibitors for chronic myeloid leukemia and other cancers at the start of this millennium. Each of these treatments has revolutionized outcomes for patients with various types of cancer. Today, we are at the start of a new era in cancer care—that of immunotherapy. The approval of sipuleucel-T for the treatment of prostate cancer in 2010 and ipilimumab (anti-CTLA-4) for advanced melanoma in 2011 was the first notable success in the immunotherapy of cancer. After almost three years from the approval of the first checkpoint inhibitor (ipilimumab), the good news is not over. Quite the contrary, we are only at the beginning and, notably, these advances do not relate just to the treatment of melanoma. Immunotherapy has become the fourth pillar of cancer treatment alongside surgery, radiotherapy and chemotherapy (including targeted therapy). This can be attributed primarily to the impact that another group of checkpoint inhibitors, the anti-PD-1/PD-L1 agents, is having on the treatment of various malignancies. As with anti-CTLA-4, the anti-PD-1/PD-L1 story starts with melanoma. Data from a large phase I study with pembrolizumab (Robert et al., 2014a, b) led to its approval by the US Food and Drug Administration (FDA) in September 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This study of 411 patients showed that pembrolizumab resulted in an overall response rate (ORR) of 34%, a median progression-free survival (PFS) of 5.5 months, and overall survival (OS) rates of 69% at one year and 62% at 18 months. Moreover, a randomized phase II trial with pembrolizumab at two different dosages (2 mg/kg or 10 mg/kg every three weeks) in advanced melanoma refractory to previous ipilimumab therapy showed that both doses improved PFS compared with investigator choice chemotherapy (Ribas et al., 2014). In fact, the 6-month PFS was 34% with pembrolizumab 2 mg/kg, 38% with pembrolizumab 10 mg/kg and 16% with chemotherapy, while the 9-month PFS was 24%, 29% and 8% respectively. The ORR in the three groups was 21%, 25% and 4%, respectively.More recently, in December 2014, another anti-PD-1, nivolumab, was approved by the FDA for patients with advanced melanoma with the same indication as pembrolizumab. Data from a large phase I trial with nivolumab showed an ORR of 32% and 1, 2, 3, and 4-year OS rates of 63%, 48%, 42%, and 32%, respectively. In addition, data from a phase III study in patients with metastatic melanoma previously treated with ipilimumab reported that nivolumab had an ORR of 32% compared with 11% with the chemotherapy control arm (D'Angelo et al., 2014). Nivolumab was also compared to chemotherapy in another randomized phase III trial in which untreated patients with advanced BRAF wildtype melanoma received either nivolumab or dacarbazine. The ORR was 40.0% in the nivolumab group versus 13.9% in the dacarbazine group. At 1 year, the OS was 73.0% in the nivolumab group compared with 42.1% in the dacarbazine group. Median PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (Robert et al., 2014a, b).
影响因子：
168.9
作者：
Robert, Caroline;Ribas, Antoni;Daud, Adil
通讯作者：
Daud, Adil
影响因子：
64.8
作者：
Powles, Thomas;Eder, Joseph Paul;Vogelzang, Nicholas J.
通讯作者：
Vogelzang, Nicholas J.