MILAN (EGMN) – One-fourth of women with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma cancer obtained clinical benefit from treatment with an experimental, targeted agent used as monotherapy in a small phase II study.
The early trial results show that the Aurora A kinase inhibitor MLN8237 was associated with an objective response rate of 10% in the 31-patient study. Among three patients who responded by CA 125 criteria was one woman who also had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors).
Another five women had prolonged stable disease, bringing the clinical benefit rate to 26%. The investigators defined clinical benefit as the achievement of a complete, partial, or CA 125 response or stable disease with no progression for at least four treatment cycles.
Dr. Ursula A. Matulonis, medical director of gynecologic oncology at the Dana-Farber Cancer Institute in Boston, and coauthors reported the results in a poster at the annual meeting of the European Society of Medical Oncology.
“In patients who have platinum-resistant ovarian cancer, there are very few options available. ... The duration of chemotherapy is at most 3 or 4 months before they start to show progression,” Dr. Matulonis said in an interview.
“The fact that four patients were able to stay on treatment for 12 months or longer I think is significant, and I think the significance is going to become more important as we try to pick which patients are going to be able to respond to the drug,” she added.
Most patients (25) in the trial had ovarian cancer. Median progression-free survival was 36.5 days in patients with platinum-refractory disease and 77 days in patients with platinum-resistant disease.
Serious adverse events occurred in 11 patients (35%) during the first one or two cycles of treatment, and included myelosuppression (neutropenia, anemia, leukopenia), pyrexia, abdominal pain, small intestinal obstruction, and stomatitis. Dose reduction, withdrawal, or administration of appropriate concomitant medication generally reversed these effects, and no on-treatment deaths were reported.
“This is a very interesting study,” said James Brenton, Ph.D., an honorary consultant in medical oncology for Cancer Research UK at the University of Cambridge (England), who was invited to discuss the trial. “What is striking is that, in what is of course a fairly heavily pretreated population of patients, the number of doses of MLN8237 given on a 3-weekly cycle was rather limited,” he said.
Platinum-resistant patients received a median of one and a half treatment cycles, whereas platinum-refractory patients received a median of three cycles, but Dr. Brenton pointed out that there were six patients who only received one cycle of the drug, whereas there were four patients in whom treatment was ongoing and they had received 12 cycles or more.
“The response rates in platinum-refractory patients are not surprisingly low,” Dr. Brenton said, noting that they were a little higher in patients with platinum-resistant disease, although the 77-day progression-free survival achieved was “pretty similar to historical controls.”
To be “very charitable about the study,” three (10%) patients showed some evidence of achieving a partial response, Dr. Brenton observed, “but the key question is, what is the genotype/response relationship? We’ve got a molecular target; what are the [bio]markers?”
In an interview, he added that although the effects of MLN8237 were not particularly dramatic, there were “some very interesting outliers.” For instance, “one patient who had stable disease after treatment, at the end of the year of treatment has had significant disease reduction,” he said.
“Aurora A kinase is a great theoretical target,” Dr. Brenton noted, adding that “while we haven’t seen overwhelming efficacy with this agent,” it is perhaps not surprising given the multiple functions that Aurora A kinase performs.
MLN8237 is being tested in combination with paclitaxel in the same patient population in a phase I/II study to see whether it can improve response to taxane therapy.
Millennium Pharmaceuticals Inc. funded the research. Dr. Matulonis and some coauthors had received research funding from or were employed by the company. Dr. Brenton had no conflict of interest.
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米兰(EGMN)——美国波士顿 Dana-Farber癌症研究所妇科肿瘤科主任 Ursula A. Matulonis博士及同事在欧洲医学肿瘤学会年会上的壁报交流中报告，他们开展的一项小规模Ⅱ期临床研究发现，四分之一的铂类药物治疗无效或治疗效果不佳的卵巢上皮癌、输卵管癌或原发性腹膜癌女性患者可从实验性靶向治疗药Aurora A激酶抑制剂MLN8237单药治疗中获益。
该研究入组患者31例，多数(25例)为卵巢癌患者。铂类药物治疗无效患者接受治疗的中位疗程数为1.5个，而铂类药物治疗效果不佳患者的中位疗程数为3个，其中6例患者仅接受1个疗程的治疗，而另有4例患者已经接受了12个或更多疗程的治疗。早期研究发现，Aurora A激酶抑制剂MLN8237的客观反应率为10%。CA125标准下有反应的3例患者中，有1例在实体瘤疗效评价标准(RECIST)下也获得部分反应。另外5例患者病情长期稳定，使得临床获益率达到26%。铂类药物治疗效果不佳患者的中位疾病无进展生存期为36.5天，而铂类药物治疗无效的患者为77天。
在前1或2周期疗程中，11例(35%)发生严重不良反应事件，其中包括骨髓抑制(中性粒细胞减少症、贫血、白细胞减少症)、发热、腹痛、小肠梗阻和口炎；大多经药物减量、撤药或对症治疗后得到缓解，无一例治疗死亡。
研究者表示，铂类药物治疗效果不佳者的反应率并非低的惊人，铂类药物治疗无效者的反应率稍高，而获得的77天疾病无进展生存期“与历史对照不相上下”。
本研究由千年制药公司资助。研究者声明接受过该公司的经济资助。
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