检查点抑制剂可持续缓解转移性肾细胞癌

芝加哥——美国临床肿瘤学会（ASCO）年会上公布的一项I期研究显示，联合使用易普利单抗（Yervoy）和nivolumab这两种免疫检查点抑制剂可使转移性肾细胞癌（mRCC）患者获得持续缓解。

在这项由约翰霍普金斯大学Sidney Kimmel综合癌症中心的Hans J. Hammers医生及其同事进行的研究中，既往未接受过治疗或接受过治疗的具有透明细胞组织学表现的mRCC患者被随机分入nivolumab 3 mg/kg+易普利单抗1 mg/kg静脉诱导治疗组（下称N3/I1组）和nivolumab 1 mg/kg +易普利单抗3 mg/kg静脉诱导治疗组（N1/I3组），每3周治疗1次，治疗4个周期。患者在每次诱导治疗期间接受2次输注，先输注nivolumab，然后在nivolumab输注完成后至少30 min开始输注易普利单抗。在诱导治疗后，所有患者继续接受nivolumab 3 mg/kg维持治疗，每2周1次，直至出现疾病进展。

结果显示，N3/I1组21例患者中有16例（76.2%）发生治疗相关不良事件（主要终点），N1/I3组所有23例患者均发生治疗相关不良事件。N3/I1组和N1/I3组的3级或4级不良事件发生率分别为23.8%（5例）和60.9%（14例）。未观察到与治疗相关的死亡。

3级或4级不良事件包括腹泻（N3/I1组1例，N1/I3组8例）、脂肪酶升高（N3/I1组3例，N1/I3组6例）和淀粉酶升高（N3/I1组1例，N1/I3组3例）。两组无其他3级或4级不良事件。此外，未观察到免疫治疗中常见的高级别肺部不良事件或肺炎病例。

N3/I1组和N1/I3组证实的客观缓解率（ORR）分别为43%（9例）和48%（11例）。随访40.1周时，N3/I1组患者的中位缓解持续时间为31.1周，N1/I3组患者未达到中位缓解持续时间。

在获得客观缓解的患者中，N3/I1组9例中7例和N1/I3组11例中9例患者的缓解在末次随访时仍持续存在。然而，仅N1/I3组1例患者获得完全缓解。N3/I1组和N1/I3组分别有9例和10例患者获得部分缓解。

N3/I1组和N1/I3组24周时的无进展生存率分别为65%和64%，高于既往在nivolumab单药治疗中观察到的结果。两组大部分患者的靶病变肿瘤负担均显著降低。

在获得持续缓解的患者中，N3/I1组9例中3例和N1/I3组11例中5例患者在因疾病进展之外的原因停止治疗后仍持续获得缓解。

研究者表示，这一结果促使他们计划开展III期研究，探讨这一联合治疗方案作为mRCC一线治疗的效果。

随刊述评

加州大学戴维斯分校的医学教授Primo Lara医生表示，鉴于既往研究发现nivolumab和易普利单抗单药治疗肾细胞癌的缓解率分别为20%~29%和13%，至少从目前来看，两者联用至少具有加性作用，并且疗效具有持久性。

然而，需重视两药联用产生的毒性（主要来自易普利单抗）。由于目前已开展的III期研究仅基于I期研究中21例亚组患者的研究结果，Lara医生认为这实在是勇敢之举，并提醒所有人，I期研究中观察到的毒性往往在样本量更大的III期研究中放大，因为参加研究的中心更多、入选标准不一并且实施这种带有毒性的联合治疗的医生可能经验不足。

该研究获百时美施贵宝（BMS）和小野制药公司资助。Hammers医生从BMS获得研究资金。Lara医生为多家药企（不包括BMS）担任顾问，并从这些公司获得酬金和研究资金。

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CHICAGO – A combination of two immune checkpoint inhibitors – ipilimumab and nivolumab – produced durable responses in patients with metastatic renal cell carcinoma in a phase I trial.

At 40.1 weeks of follow-up, the median duration of response for patients treated with nivolumab 3 mg/kg and ipilimumab (Yervoy) 1 mg/kg for four cycles followed by nivolumab maintenance was 31weeks, and for patients treated with nivolumab 1 mg/kg/ and ipilimumab 3 mg/kg the median duration of response had not been reached, reported Dr. Hans J. Hammers of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

"The objective response rate suggests greater activity than reported previously with nivolumab or ipilimumab monotherapy," Dr. Hammers said at the annual meeting of the American Society of Clinical Oncology.

"Responses appear durable even after discontinuation of study drug," he added.

Nonredundant checkpoints

Both drugs are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts as an early brake point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against cancer.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy against melanoma and other malignancies.

At ASCO 2014, investigators reported that the combinations resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma.

Dr. Hammers and his colleagues investigated the combination in a phase I trial comparing two different combinations of the checkpoint inhibitors.

Patients with untreated or previously treated metastatic renal cell carcinoma (mRCC) with clear-cell histology were randomly assigned to receive intravenous induction therapy every 3 weeks for four cycles with either nivolumab 3 mg/kg and ipilimumab 1 mg/kg (N3/I1) or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (N1/I3). Patients received two infusions during each induction, with nivolumab first, followed by ipilimumab started at least 30 minutes after completion of the nivolumab infusion.

Following induction, all patients went on to continuous nivolumab 3 mg/kg every 2 weeks until disease progression.

Adverse events

Treatment-related adverse events, the primary endpoint, occurred in 16 of the 21 patients (76.2%) assigned to N3/I1) and in all 23 patients assigned to N1/I3. Grade 3 or 4 adverse events occurred in 5 of 21 (23.8%) and 14 of 23 (60.9%), respectively. There were no treatment-related deaths.

The grade 3 or 4 adverse events included diarrhea in one patient in N3/I1 and eight patients in N1/I3, increased lipase in three and six patients, respectively, and increased amylase in one and three patients. There were no other grade 3 or 4 adverse events in either study arm. In addition, there were no high-grade pulmonary adverse events or cases of pneumonitis, which are often seen with immunotherapy, Dr. Hammers noted.

The confirmed objective response rate (ORR) was 43% (9 of 21) in N3/I1 and 48% (11 of 23) in N1/I3. As noted before, the median duration of response was 31.1 weeks in N3/I1 and not reached in N1/I3.

Of the patients who had objective response, the responses were ongoing at last follow-up in 7 of 9 on N3/I1 and 9 of 11 on N1/I3.

There was only one complete response, however, occurring in a patient who received N1/I3. Partial responses occurred in nine patients on N3/I1 and 10 in N1/I3.

The respective progression-free survival rates at 24 weeks were 65% and 64%, which "compares favorably with the nivolumab monotherapy experience," Dr. Hammers said.

The majority of patients in each study arm had significant reductions in tumor burden of the target lesions, he added.

Of the patients with ongoing responses, 3 of 9 in the N3/I1 arm and 5 of 11 in the N1/I3 arm continued to have responses after discontinuing therapy for reasons other than disease progression.

"This encouraging antitumor activity reported with this combination is the basis for a planned phase III combination trial in the first-line setting for the treatment of metastatic renal cell carcinoma patients," Dr. Hammers said.

‘Gutsy move’

Dr. Primo Lara, professor of medicine at the University of California, Davis, who was the invited discussant, commented that, "at least for now, I think we could say that combination checkpoint blockade in RCC is at least additive, recalling that the single-agent response rate in this disease for nivo[lumab] is about 20%-29%, and for ipi[limumab] is about 13%, and some of these responses are encouragingly durable."

He cautioned, however, that the toxicities with the combined drugs, primarily driven by ipilimumab, "are not inconsequential."

"We heard today that a phase III trial has been initiated, presumably with a lower-dose ipi[limumab] arm, but I think that’s really a gutsy move, considering that there were only 21 patients in that subset of patients that led to this phase III decision. Just a fair warning to everyone that toxicities observed in a phase I trial tend to magnify in a larger phase III when you have more centers, different eligibility criteria, and less experienced folks administering a pretty toxic combination," he said.

The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Hammers has received research funding from BMS. Dr. Lara disclosed serving as a consultant/advisor, and receiving honoraria and research funding from many companies, but not BMS.