ORLANDO (EGMN) – At last, some favorable news regarding immunization against melanoma: The addition of a peptide vaccine to high-dose interleukin-2 therapy significantly improved clinical response for patients with metastatic disease in a randomized, prospective, phase III trial.
Investigators at the 21 centers reported a 14% complete response rate (the primary end point) in 86 patients who received the combined therapy vs. just 2% in 93 patients treated only with high-dose IL-2 (P = .003), Dr. Doug J. Schwartzentruber reported at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival, the secondary end point, also favored the vaccine plus IL-2 therapy. Immunized patients lived without a recurrence 2.9 months vs. 1.6 months with IL-2 alone after a median follow-up of almost 29 months, another significant difference (P = .01).
An equal proportion of each group (8%) had partial responses.
“If you add all responders – complete and partial – you get a 9.7% response vs. a 22.1% with the vaccine added,” said Dr. Schwartzentruber, a surgical oncologist and medical director of the Goshen (Indiana) Center for Cancer Care.
“There was more than a doubling of the [overall] response rate, with a highly significant P value of .022,” study discussant Dr. Antoni Ribas commented. “This is a clearly positive study any way we look at it, a rare event in this [ASCO melanoma] session.”
The positive study follows two failed high-profile melanoma vaccine trials. Last year at ASCO, European Organisation for Research and Treatment of Cancer (EORTC) investigators reported that a ganglioside vaccine was associated with worse survival for patients with stage II melanoma. In 2007, ASCO attendees heard that the international phase III trial of a combination of Calmette-Guérin bacillus and an allogeneic melanoma vaccine known as Canvaxin had been halted in the absence of any overall benefit to patients with stage III or IV disease.
Dr. Schwartzentruber and his associates randomized 185 patients with stage IV or stage III HLA-A2–positive metastatic melanoma to immunization with gp100:2009-217 (210M) peptide in Montanide ISA-51 followed by high-dose (720,000 IU/kg per dose) IL-2, or to high-dose IL-2 alone.
A central laboratory review of pathology and HLA genotyping confirmed the investigators’ findings. The lab reported an 18.6% overall response in the vaccine vs. 6.5% for high-dose IL-2 therapy alone. Although the numbers were smaller, the difference remained statistically significant (P = .013), Dr. Schwartzentruber said. Interestingly, overall response was primarily in M1b patients (those with lung metastases), he noted.
Overall survival was not a prespecified study end point, but there was a nonsignificant trend toward longer overall survival with combination treatment at 17.6 months vs. 12.8 months for IL-2 alone (P = .084).
“We don’t know the impact of response rate on overall survival with the IL-2 plus gp100 [treatment]. We need longer follow-up,” said Dr. Ribas, a member of the medicine and surgery faculties at University of California, Los Angeles.
Of the 91 patients randomized to the vaccine, 2 were ineligible and 3 withdrew from the study. Of the 94 patients randomized to the infusion of high-dose IL-2 alone every 3 weeks, none was ineligible and 1 withdrew. The six patients who received no treatment were excluded from the response and toxicity analyses but were included in survival calculations as randomized.
Two deaths were attributable to treatment in the vaccine group and one such death occurred in the control arm, Dr. Schwartzentruber said.
“Melanoma vaccines alone are not very active, with about a 3% response rate,” Dr. Schwartzentruber noted, reviewing relevant literature [Nat. Med. 2004;10:909-15]. One study revealed response rates in patients receiving the same combination therapy that ranged from 13% to 24%, depending on the dosing regimen (J. Clin. Oncol. 2008;26:2292-8). Another trial found a 25% response vs. 13% with high-dose IL-2 alone (Clin. Cancer Res. 2008;14:5610-8). “These retrospective, single-center findings ... look very similar to our multicenter results,” he said.
The current study raises several questions, Dr. Ribas said, including the following:
– How does high-dose IL-2 induce tumor regression? “With over 20 years of study, we still don’t have an answer.”
– How do gp100 peptides improve outcomes of high-dose IL-2?
Dr. Schwartzentruber proposed that the vaccine induces antitumor T-cell activity, and IL-2 causes proliferation of these T cells, “which we presume destroy tumors and in that manner mediate immune response.”
Both groups were well balanced in terms of anatomical site of disease, Dr. Schwartzentruber said. Men accounted for 63% of the vaccine arm and 67% of the control group; mean age was 50 years vs. 47 years; and both cohorts were predominantly white (97% vs. 99%).
All patients were enrolled between 2000 and 2007, and all had HLA-A0201 disease because the vaccine is specific to this HLA type. Dr. Ribas noted that this peptide specificity was responsible for the long enrollment period. ��It took 11 years from phase II to phase III testing, 7 years to accrue, and – despite meeting the primary outcome – it has an unclear impact on the standard of care,” he said.
Participants were allowed to continue treatment if they responded. The combination group received 270 total cycles and the IL-2–only group completed 244 total cycles. “Keep this in mind as we look at toxicities,” Dr. Schwartzentruber advised.
Arrhythmias were the only significantly different toxicity, with 15 events in the vaccine group vs. 2 events in control group (P = 0.002) when adverse events were assessed after two cycles of treatment. “There were no grade 5 toxicities after two cycles; most were grade 3,” Dr. Schwartzentruber said.
When grade 3-5 toxicities for any cycle were evaluated, arrhythmias affected 19% of the vaccine group vs. 4% of controls (P = 0.002). Two other toxicities also were notably higher in the vaccine group: metabolic/laboratory abnormalities (48% vs. 21%; P = .002) and neurologic toxicity (26% vs. 12%; P = .018).
A meeting attendee asked whether immunization with gp100 peptide should be standard treatment. “There are a variety of possibilities,” Dr. Schwartzentruber responded. “We could potentially look at better adjuvants. We could look at other immune modulators. There are a variety of compounds that are exciting.”
“Can this combination be offered to patients in routine practice? That is limited by the availability of the peptides,” Dr. Ribas said, noting in response to an audience question that an Investigational New Drug application would need to be approved by the U.S. Food and Drug Administration.
Dr. Schwartzentruber said he has had conversations with the Cancer Therapy Evaluation Program (CTEP) at the U.S. National Cancer Institute. “Clearly, we need to do other studies. I’d like to be able to show a survival advantage in a larger trial,” he said.
The gp100 vaccine was provided by CTEP, holder of the Investigational New Drug application. The study was financially supported by the National Cancer Institute, Chiron/Novartis (which is developing the vaccine), Goshen Health System, Goshen Hospital and Healthcare Foundation Inc., and the Luke Brennan Research Fund. Each participating site received grant support from Chiron/Novartis. In addition, one coauthor had an additional disclosure: Dr. David Lawson is on the advisory council and speakers bureau for Chiron/Novartis.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
奥兰多(EGMN)——一些利用免疫法治疗黑色素瘤的好消息：根据一项前瞻性的随机对照三期临床试验结果，使用大剂量白介素(IL)-2和多肽疫苗联合治疗，能显著提高黑色素瘤转移患者的临床治疗效果。
Doug J. Schwartzentruber在美国临床肿瘤学会(ASCO)年会上报告了一项21家中心的联合研究结果。结果显示，86名接受联合治疗患者的完全缓解率(研究主要终点)为14%，与之相比，93名仅接受大剂量IL-2治疗的患者仅为2%(P 值为0.003)。
以无进展生存情况为研究次要终点，其结果同样显示应用疫苗和IL-2联合治疗更有效。经随访(中位随访期为29个月)，联合应用疫苗免疫患者无复发生存期为2.9个月，而仅应用IL-2治疗者则为1.6个月，二者差异显著(P 值为0.01)。
两组患者部分缓解率(8%)相同。
外科肿瘤学家、Goshen肿瘤治疗中心医学主任Schwartzentruber医生指出：“如以总缓解率，即完全和部分缓解率之和，为研究终点，结果显示增加疫苗治疗与未加相比，相应的总缓解率分别为22.1%和9.7%。”
与会的Antoni Ribas医生评论说：“两组间总缓解率相差一倍以上，统计学上有极显著意义，P值达0.022。这显然是一项我们期待的阳性试验，在本次ASCO年会黑色素瘤专题中尚属少见。”
该阳性研究成果是在两项备受瞩目的黑色素瘤疫苗研究失败后取得的。去年，ASCO以及欧洲肿瘤研究和治疗组织(EORTC)研究者指出，接受神经节苷脂疫苗治疗的II期黑色素瘤患者的生存期会减少。2007年，ASCO人员获知一项联合应用卡介苗和异基因黑色素瘤疫苗(Canvaxin)的国际性临床三期试验因该治疗未能有效提高III期或IV期黑色素瘤患者总缓解率而停止。
Schwartzentruber医生及其合作者选择185名人类白细胞抗原(HLA)-A2基因阳性的IV或 III期转移性黑色素瘤患者，并随机分为两组。他们将疫苗gp100:2009-217 (210M)多肽置于免疫佐剂中，用以免疫其中一组患者，同时联合应用大剂量IL-2(每人剂量为720,000 IU/kg)。而另一组仅应用大剂量IL-2进行治疗。
一个中心实验室通过回顾患者病理和HLA基因分型确认了研究者的发现。Schwartzentruber提出，根据该实验室的报告，加入疫苗治疗，患者总缓解率为18.6%，而仅使用大剂量IL-2治疗则为6.5%。该研究虽然病例数较少，但两组差异仍具有统计学意义(P值为0.013)。他还强调，出现缓解的病例主要为M1b期患者(具有肺转移)。
联合治疗组患者总生存期为17.6个月，单独使用IL-2组为12.8个月。总生存期并非此项前瞻性研究的研究终点，联合治疗也未显示出增加生存期的显著趋势(P值为0.084)。
加州大学洛杉矶分校内科和外科学院的Ribas医生指出：“联合应用IL-2和疫苗gp100治疗后，我们尚不清楚缓解率对总生存期的影响。我们需要更长时间的随访。”
91例随机分至联合疫苗治疗组的患者中，2例不符合纳入条件，3例退出研究。94例随机分至每3周输入大剂量IL-2治疗组的患者，无不符合条件者，1例退出。这6例未接受治疗的患者未纳入至缓解情况和毒性反应分析中，但被随机纳入至生存情况的计算中。
Schwartzentruber医生同时说明，联合疫苗治疗组有2例患者死亡，而对照组有1例死亡。
Schwartzentruber医生回顾过相关文献(Nat. Med. 2004;10:909-15)后认为：“单独使用疫苗治疗黑色素瘤效果有限，缓解率仅为3%。”一项研究发现，使用同种联合治疗的患者，缓解率可从13%到24%不等，治疗效果取决于用药具体剂量(J. Clin. Oncol. 2008;26:2292-8)。另一项研究则发现联合治疗组患者缓解率为25%，而单独使用IL-2治疗组为13%( Clin. Cancer Res. 2008;14:5610-8)。他指出：“这些回顾性、单中心研究结果与我们此项多中心研究的结果非常相似。”
Ribas医生提出，现有研究有几个问题，包括以下几点：
– 大剂量IL-2是如何诱导肿瘤消退的？“虽然经过20多年的研究，我们依然不知道答案。”
– gp100多肽是如何增进大剂量IL-2治疗效能的？
就上述问题，Schwartzentruber医生认为，疫苗可能通过提高抗肿瘤T细胞的活性发生作用，而IL-2能促进此类T细胞增殖。“这就是我们针对消灭肿瘤的原理以及介导免疫反应的方式提出的假设。”
就病例分组问题，Schwartzentruber医生做出了说明。两组病例从病变的解剖部位来看，比较平衡。联合疫苗治疗组男性患者占63%，而对照组为67%；中位年龄分别为50岁和47岁；两组患者均为白种人占优，分别为97%和99%。
所有患者都在2000年至2007年进行的癌症登记。因所用疫苗对HLA-A0201基因型特异，故所选病例均为此基因型阳性。Ribas医生指出，此种多肽疫苗的特点起效时间长。“从二期试验到三期试验经历了11年，增加了7年时间。尽管取得了初步成果，但其对于标准治疗方案的影响仍不清楚。”
如果受试者病情得到缓解，可继续进行治疗。联合治疗组接受了总计270期治疗，而单独IL-2治疗组进行了244期治疗。Schwartzentruber医生建议：“当我们讨论药物毒性问题时，要考虑到上述数据。”
经2期治疗，在评估不良反应时发现，心律失常是两组间惟一显著的药物毒性差异，在联合疫苗治疗组和对照组中分别出现了15例和2例(P值为0.002)。Schwartzentruber指出：“经2期治疗后，患者均未出现5级毒性反应，多为3级反应。”
对任意治疗期的3~5级毒性进行评估发现，心律失常在联合疫苗治疗组发生率为19%，而对照组则为4%(P值为0.002)。其他两种毒性反应在联合疫苗治疗组也较为突出：代谢性/检验值异常(发生率分别为48%和21%; P 值为0.002)和神经毒性(发生率分别为26% 和12%; P值为0.018)。
一位与会者提出是否可将gp100多肽免疫作为常规治疗手段。Schwartzentruber医生回答道：“有各种可能性。我们可以寻求更好的辅助剂，寻求其他的免疫方式。还有多种化合物值得期待。”
有听众提出，一项研究用新药应用项目需得到FDA的认证，Ribas医生未对此进行回应，只是称：“能否将此种联合治疗应用到日常工作中，取决于是否能获得合适的多肽疫苗。”
Schwartzentruber医生称他已与美国国家癌症研究所(NCI)的肿瘤治疗评估项目(CTEP)联系过。他说：“显然，我们需要做其他研究。我希望能在大宗病例研究中同样展现此项治疗对提高患者生存期的作用。”
CTEP为研究用新药应用项目的持有者，研究用gp100疫苗由CTEP提供。本研究所需资金由美国国家癌症研究所、诺华 Chiron公司(该公司正在开发此疫苗)、Goshen健康系统、Goshen医院和健康基金公司以及Luke Brennan研究基金提供支持。每个参试单位都获得了诺华Chiron公司的拨款支持。此外，本研究的共同作者David Lawson医生作为诺华Chiron公司顾问团及讲师团成员，与该公司关系密切。
