CAR-T进展：诺华CTL019 Juliet临床试验结果首次公布
来源：BioFrontier
It’s been a big week for CAR-T: Novartis, Juno, Kite, Bluebird Bio and Nanjing Legend Biotech all posted positive data for the cutting-edge experimental cancer class at ASCO, and now Novartis has revealed the long-awaited interim Juliet data for its CAR-T candidate at a Swiss conference.
这周关于CAR-T的新闻此起彼伏：诺华，Juno，凯特，Bluebird Bio和南京传奇生物都在ASCO年会上展示了它们各自在研尖端抗癌药物的正面资料。7日，在瑞士的一场学术会议上，诺华公布了其CAR-T在研药物令人期待已久的Juliet临床试验中期数据。
The FDA ‘breakthrough’ tagged Juliet data, which many have been waiting for to see how well it could stack up against rival Kite Pharma, was assessing CTL019 (a.k.a tisagenlecleucel) in 51 relapsing/refractory diffuse large B-cell lymphoma (r/r DLBCL) patients who had already received a series of treatments.
这个获得FDA“突破性疗法”认定的Juliet临床试验，在51名已接受过一系列治疗的复发难治性弥漫性大B 细胞淋巴瘤(r/r DLBCL)患者中，评定CTL019(a.k.a tisagenlecleucel)的效果。很多人都在等待这个试验结果，看看是否能与凯特制药的在研药物一较高下。
Revealed for the first time Wednesday, Novartis said the single-arm, open-label pivotal phase 2 trial hit its primary endpoint, showing a 3-month overall response rate (ORR) of 45% (23 of the 51 patients evaluated), with 37% achieving a complete response (CR) and 8% achieving a partial response (PR), respectively. In all, 141 patients were enrolled, but only 51 were evaluated.
在周三首次公布的消息中，诺华称其单组非盲关键性2期临床试验达到了其主要终点。患者3个月的总缓解率（ORR）是45%(51名患者中的23人)，其中完全缓解率（CR）37%，而且有8%的人得到了部分缓解（PR）。整个临床试验招募了141名患者，但只有51人进行了评测。
The Swiss Big Pharma said that CR also “remained stable” from 3 months through data cut-off among the patient group. And among the 51 patients with 3 months or more of follow-up or earlier discontinuation, best ORR was 59% (p<0.0001), with 43% achieving CR and 16% achieving PR.
诺华说，完全缓解的病人在3个月的试验数据采集期后，现在“仍处于稳定”。在51名患者中，考虑3个月及以上随访或提早退出的情况，最好的总缓解是59%(p<0.0001)，其中完全缓解43%，16%部分缓解。
Secondary endpoints from the study include overall survival, duration of response and progression-free survival, although Novartis tells me these are not yet mature enough to assess.
该临床试验的次要终点包括总体生存率，缓解持续时间和无进展生存期，诺华称现在还没有完整的数据来评估这些。
The new data are set to be presented at the International Conference on Malignant Lymphoma (ICML) meeting in Lugano, Switzerland.
新的数据计划在瑞士卢加诺举行的国际恶性淋巴瘤会议上公布。
This is broadly comparable to Kite Pharma’s data, which tested its rival CAR-T axicabtagene ciloleucel (a.k.a. KTE-C19) in non-Hodgkin’s lymphoma. Cohort 1 of the Zuma-1 phase 2 trial, posted last September, saw 51 patients with chemorefractory DLBCL being treated with therapy.
目前，诺华的CAR-T临床试验数据和凯特制药治疗非霍奇金淋巴瘤在研药KTE-C19(axicabtagene ciloleucel)的数据相比，整体上旗鼓相当。凯特去年9月公布了Zuma-1临床2期试验中的Cohort 1数据，51名耐药性DLBCL患者接受了该药物治疗。
At 3 months, data showed an ORR of 39% and a CR of 33%. In Februrary this year it also published longer data, in 77 DLBCL patients, that at 6 months showed a 36% ORR and 31% CR. Novartis said it would not be comparing the two, but said it was pleased with its own data.
凯特的临床试验数据显示，3个月的总缓解率是39%，其中完全缓解33%。今年2月，凯特制药公布了更长期的临床数据，在77名DLBCL患者中，6个月的总缓解率是36%，其中完全缓解是31%。诺华表示，他们对自己的临床数据很满意，而且并不会与凯特的数据做比较。
DLBCL is the most common form of lymphoma and accounts for about 30% of all non-Hodgkin lymphoma cases. Around 10 to 15% of DLBCL patients fail to respond to initial therapy or relapse within 3 months of treatment, with an additional 20% to 25% relapse after initial response to therapy.
DLBCL是最常见的淋巴瘤，占所有非霍奇金淋巴瘤的30%。一线治疗药物对大约10-15%的DLBCL患者无效，或者3个月的治疗期内就出现复发。还有20-25%的患者虽然在治疗开始时获得缓解，但不久便复发。
Novartis also said in terms of safety that 57% of all treated patients (85 in total) experienced any grade cytokine release syndrome (CRS), a known complication of CAR-T therapy, and 26% experienced grade 3/4 CRS.
诺华还宣布，在安全性方面，所有受试患者中（总共85人），57%的人出现不同程度的细胞因子释放综合症（CRS），这是一种已知的CAR-T药物副作用，其中26%的人出现3/4级的CRS。
There were however no deaths coming out of the trial from CRS or cerebral edema, and no incidents of cerebral edema were reported in the study. This is an important point, given that 5 patients died in a Juno trial of its then-leading CAR-T med JCAR015 from cerebral edema. There were 3 deaths, but the Big Pharma said these were from “disease progression within 30 days of infusion.”
试验中没有发生因CRS或脑水肿导致的死亡，并且报告中也未见脑水肿病例。这是一个重要的试验结果，而之前领先别家的Juno，它的CAR-T在研药物JCAR015的临床试验中发生5起病人死亡事件。
Novartis adds that 13% of patients had grade 3/4 neurologic adverse events, but said these “were managed with supportive care.”
诺华还透露13%的患者发生了3/4级的神经系统副作用，但这些都经过支持治疗得到了控制。
“The overall response rate seen in this early analysis is impressive for these heavily pretreated patients with relapsed/refractory DLBCL, who have limited treatment options,” said Juliet lead investigator, Stephen Schuster, M.D., Professor of hematology/oncology in the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center.
“对于已经经过彻底治疗、当下治疗手段非常有限的复发/难治性弥漫性大B细胞淋巴瘤的治疗，从这个临床试验数据初步分析得到的总缓解率令人印象深刻”，Juliet临床试验的首席科学家、宾夕法尼亚大学医学院和宾夕法尼亚大学Abramson癌症中心血液学/肿瘤学教授，Stephen Schuster博士说道，
“The goal for these patients is achieving durable response. The most promising aspect of these data is that, at the time of this interim analysis, all patients with complete response at three months have remained in complete response.”
“试验的目的是让这些病人获得持续缓解。试验最有希望的一点是，目前我们只得到了的中期数据分析结果，但所有经过3个月治疗获得完全缓解的患者仍处于完全缓解阶段”。
On the safety side for Kite, from its non-Hodgkin lymphoma trial data from February, the most common grade 3 or higher adverse events included anemia (43%) and neutropenia (39%).
在凯特制药的安全性方面，2月份它的非霍奇金淋巴瘤临床试验显示，最常见的3级或以上副作用包括贫血（43%）和嗜中性白血球减少症（39%）。
The grade 3 or higher CRS was 13% and neurologic events 28%, but it initially said it had no cases of cerebral edema. There were 3 deaths not due to disease progression in the study, with Kite saying 2 events, one hemophagocytic lymphohistiocytosis and one cardiac arrest in the setting of CRS, “were deemed related to axicabtagene ciloleucel”. The third case, a pulmonary embolism, was deemed unrelated.
3级或以上细胞因子释放综合症（CRS）占13%，神经系统副作用占28%，起初凯特表示没有脑水肿的病例。试验中，有3起非疾病进展导致的死亡，凯特表示，1人死于嗜血细胞性淋巴组织细胞增多症；另1人有CRS，死于心搏停止。这两起都“认为与CAR-T药物，axicabtagene ciloleucel有关”。第三人死于肺栓塞与CAR-T药物无关。
But in May, the biotech revealed that a month before there had in fact been the death of a patient from cerebral edema in the non-Hodgkin’s lymphoma test. At the time, the company told FierceBiotech: “This was a singular event and as you know, Grade 5 events [i.e., deaths] are not unexpected in studies involving patients who are suffering from rapidly progressing cancer that is refractory to treatments. The Safety Expansion Cohort was initiated after the close of the registrational trial.”
但在5月，凯特披露了，在之前一个月，一名受试非霍奇金淋巴瘤患者死于脑水肿。当时，该公司告诉FierceBiotech：“这是一个单独事件，而且你知道，在一个受试者都是罹患耐药且恶化迅速的癌症患者的临床试验中，5级事件（死亡）并非意料之外的事。安全性扩展组的试验将在临床试验登记完成后启动。”
Novartis, which has developed its med with Penn University and has U.K. biotech Oxford BioMedica manufacturing the lentiviral vector expressing CTL019, said the full rundown of the Juliet will be posted later this year, with it being used as the basis for its submissions to the FDA and the EMA.
诺华的CAR-T药物由诺华和宾夕法尼亚大学共同研发，表达CTL019的慢病毒载体由英国牛津BioMedica公司生产。诺华表示，这个Juliet试验完整的纲要将在今年下半年公布。也会基于这个试验的结果来申请FDA和EMA的药物评审。
In May, Kite was given an FDA priority review for its med in aggressive non-Hodgkin lymphoma, with a PDUFA date of November 29, based on its Zuma-1 phase 2 data.
5月，凯特得到FDA对于其药物治疗恶性非霍奇金淋巴瘤的优先评审资格。对其Zuma-1临床2期试验结果的PDUFA（处方药使用者法案，评审结果日期）是11月29日。
Novartis will clearly be behind Kite in that indication, but looks on course to be the first to gain a CAR-T approval, as it also said this week that there will be an AdComm with the FDA on 12 July for CTL019 and its proposed indication for the treatment of r/r pediatric and young adult patients with B-cell acute lymphoblastic leukemia (a smaller patient population than r/r DLBCL). Should things go well, this indication could get approval by September.
在这个适应症上，诺华将明显迟于凯特制药。但放眼在争夺成为第一个获批CAR-T药物的路上，诺华本周透露，7月12日FDA咨询委员会（AdComm）将与FDA决定CTL019治疗幼儿和青年患者复发难治性急性B细胞淋巴细胞白血病（病人基数少于复发难治性弥漫性大B 细胞淋巴瘤,r/r DLBCL）的申请。如果一切顺利，该适应症最早会在9月通过评审。
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