CHICAGO (EGMN) – A phase I trial has demonstrated that the investigational oral agent crizotinib exquisitely targets a genetic abnormality in a subset of patients with advanced lung cancer.
The objective response rate was 57%, even among patients with a poor performance status of 2 or 3.
One would expect only about 10% of these patients to respond, given that 41% had received at least three prior treatments, according to a statement released by Pfizer Inc., which is developing the drug.
The disease control rate, including complete and partial responses and stable disease at 8 weeks, reached 87%, reported Dr. Yung-Jue Bang, a professor of internal medicine at the Seoul (South Korea) National University’s Cancer Research Institute. Responses were durable (range, 1-15 months). Almost all patients experienced tumor shrinkage.
The median progression-free survival has not been reached after a median follow-up of 6.4 months. The probability of being progression-free at 6 months was 72%, he said.
All patients had advanced non–small cell lung cancer (NSCLC) and alterations in the anaplastic lymphoma kinase (ALK) gene. A total of 96% had adenocarcinoma histology, and 76% were never-smokers.
“For patients with ALK-positive, non–small cell lung cancer, crizotinib may offer a potential new standard of care,” Dr. Bang said.
Crizotinib is the only ALK inhibitor in clinical trials and is not yet commercially available.
Alterations in the ALK gene are present in roughly 40,000 new NSCLC patients worldwide per year. There is no suggestion at this time that ALK alterations are more common in Asians, who made up 35% of the cohort, he said. The findings were presented at the annual meeting of the American Society of Clinical Oncology.
Invited discussant Dr. Martin J. Edelman said that there is no current approach for NSCLC patients who have failed three lines of chemotherapy, and he questioned whether a randomized trial is needed to confirm the “striking activity” and minimal toxicity observed with crizotinib, also known as PF-02341066.
“Although I suspect that a broader experience may temper these results, it is hard to imagine they will change significantly,” said Dr. Edelman, a professor of medicine with the University of Maryland Greenebaum Cancer Center in Baltimore. “While only representing 3%-5% of non–small cell cancer, these results represent an advance for the 6,000-10,000 patients [in the United States] and the tens of thousands worldwide with this disease. To place this in its proper context, the number of patients exceeds those with Hodgkin’s disease in this country.”
Only one patient discontinued treatment with crizotinib because of a drug-related adverse event, a grade 4 elevation in ALT. The most common adverse events were grade 1 nausea (52%), diarrhea (46%), and vomiting (43%). In addition, 42% of patients reported visual disturbances, particularly in the morning, Dr. Bang said. After a median treatment duration of 5.7 months, 77% of patients remain on crizotinib 250 mg twice daily.
Although the early-phase data were impressive enough to be featured during a plenary session and press briefing at the meeting, applicability remains a question. Most patients with advanced NSCLC are older than 70 years of age, whereas the mean age in the trial was 51 years.
Questions also exist over whether ALK screening should be offered only to never- or hardly-ever-smokers or to those with adenocarcinoma, and whether FISH (fluorescence in situ hybridization) testing is the best methodology for screening, said Dr. Edelman.
Because of the recent experience with the epidermal growth factor receptor (EGFR) mutation, the testing apparatus is in place nationally to identify ALK-positive patients via FISH testing, Dr. Mark G. Kris, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York, told reporters.
“What we had hoped following EGFR is that, as other driving mutations were discovered, they would be added to the portfolio, and that’s exactly what is going to happen here,” he said in an interview. “Once you have one test, it is very easy to do the other.”
The ALK protein was identified in the current cohort using FISH testing, and was verified in 85% of patients at a single laboratory at Massachusetts General Hospital, according to Dr. Jamey Skillings, senior director of oncology at Pfizer Global Research and Development.
“Clearly we are selecting the right patients, because they’re getting benefit,” she said in an interview.
Pfizer is working in collaboration with Abbott Molecular on a commercial standardized FISH test, with U.S. approval for crizotinib anticipated in mid-2011, Dr. Skillings said.
Dr. Bang said that the results support genetic profiling of patients with NSCLC and a personalized approach to NSCLC treatment.
The ALK gene was originally discovered in anaplastic large-cell lymphomas in 2007, and has been subsequently identified as a driving factor in cancers such as NSCLC, neuroblastomas, and rare sarcomas. Alterations in the ALK gene lead to activation of the tumor-specific ALK protein, causing tumor growth.
Dr. Kris also remarked on the rapid clinical development of crizotinib and said it will offer patients an easier, less disruptive treatment option.
“In just 3 short years, we’ve gone from a description of an oncogene to a therapy, and I think that’s an amazing example of the power of how – once we understand a cancer cell – we can come up with a treatment very quickly,” Dr. Kris told reporters.
Enrollment is ongoing for two additional trials of crizotinib in adults with ALK-positive NSCLC. The randomized, phase III PROFILE 1007 trial will compare continuous crizotinib (250 mg twice daily) vs. pemetrexed (500 mg/m2) or docetaxel (75 mg/m2) in 318 patients who were treated with one prior platinum-based chemotherapy. The open-label, single-arm PROFILE 1005 trial will evaluate crizotinib at the same dose in 250 patients with progressive disease and one prior chemotherapy regimen.
A phase I/II trial is also being conducted in cooperation with the Children’s Oncology Group to identify the right pediatric dose and schedule in a variety of cancers, notably lymphoma, neuroblastoma, and other ALK-identified tumors that are fairly common in children, Dr. Skillings said.
The crizotinib trial reported at the American Society of Clinical Oncology meeting is supported by Pfizer Inc. Dr. Bang has served as a consultant or adviser for Pfizer, and along with several of his coauthors, has received research funding from Pfizer. Dr. Edelman has served as a consultant or advisor to Boehringer Ingelheim, Bristol-Myers Squibb Co., Endocyte Inc., Genentech Inc., Eli Lilly and Co., and OSI Pharmaceuticals Inc., and has received research funding from BMS, Cyclacel Pharmaceuticals Inc., Geron Corp., GlaxoSmithKline, Lilly, Pharmacyclics Inc., Schering-Plough Corp., and Tragara Pharmaceuticals Inc.
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芝加哥(EGMN)——一项I期试验显示，试验用口服药物克里唑蒂尼(crizotinib)可精确靶向于晚期肺癌亚组患者的异常基因。
即使在行为状态评分较差(2或3分)的患者中，客观有效率也能达到57%。
根据研发该药的辉瑞公司发布的一项声明，由于41%的患者此前曾接受至少3种治疗，因此原先预计的有效率仅为10%。
韩国首尔国立大学癌症研究所的内科学教授Yung-Jue Bang博士表示，8周时疾病控制率(包括完全缓解、部分缓解及疾病稳定)达87%。缓解时间较为持久(范围1~15个月)。几乎所有患者的肿瘤均出现缩小。
中位随访6.4个月后，在中位无进展生存期上未达到研究终点。他表示，6个月时无进展概率为72%。
所有患者均罹患晚期非小细胞肺癌(NSCLC)，并存在间变性淋巴瘤激酶(ALK)基因改变。共96%有腺癌病史，76%为非吸烟者。
Bang博士说：“对于ALK阳性非小细胞肺癌患者，克里唑蒂尼或许是潜在的新标准治疗。”
克里唑蒂尼是处于临床试验阶段的唯一ALK抑制剂，尚未上市。
全球每年新确诊的约40,000例NSCLC患者存在ALK基因改变。他表示，目前尚无证据表明，ALK基因改变更常见于亚洲患者(占该队列的35%)。该研究结果在美国临床肿瘤学会年会上进行了报告。
特邀评论员Martin J. Edelman博士表示，对于接受过3种化疗但仍治疗无效的NSCLC患者，目前尚无其他有效的方法。他质疑是否有必要通过随机试验对所观察到的克里唑蒂尼(亦称为PF-02341066)的“显著活性”和最小毒性加以证实。
巴尔的摩马里兰大学Greenebaum 癌症中心的医学教授Edelman博士说：“尽管我怀疑，更多的研究经验可能会在一定程度上改变这些结果，但很难想象会使它们发生显著改变。虽然这些结果仅代表3%~5%的非小细胞癌，但对于美国6,000~10,000例及全球数以万计的该病患者无疑是个福音。在美国，该病患者数量超过霍奇金病患者数量，这一比较应该更有助于我们认识该病的影响。
仅1例患者因药物相关不良事件(ALT水平4级升高)而停用克里唑蒂尼。最常见的不良事件为1级恶心(52%)、腹泻 (46%)和呕吐 (43%)。此外，Bang博士表示，42%的患者出现视力障碍，特别是在早上。中位疗程5.7个月后，仍有77%的患者留在研究中继续接受克里唑蒂尼250mg(2次/d)治疗。
尽管在全体大会及该大会新闻发布会上报告的这一早期研究结果份量十足，但其适用性仍然是个问题。大部分晚期NSCLC患者的年龄在70岁以上，而该试验中受试者的平均年龄仅为51岁。
Edelman博士表示，ALK筛查是否应仅面向从未或几乎从未吸烟者还是腺癌患者，并且荧光原位杂交(FISH)检测是否是最佳筛查方法，这些问题仍有待弄清楚。
纽约纪念斯隆-凯特林癌症中心胸部肿瘤科主任Mark G. Kris博士告诉记者说，得益于最近开展的表皮生长因子受体(EGFR)突变检测工作，全国各地所配备的检测设备均可通过FISH法对ALK阳性患者进行检测。
他在采访中说：“我们希望在EGFR之后，随着其他驱动突变被发现，整个基因图谱会更加完整，这正是眼下将要进行的。一旦掌握了一种检测方法，再用其去做其他检测就易如反掌。”
辉瑞全球研发部肿瘤学部的高级主管Jamey Skillings博士表示，通过FISH检测法在当前队列中检出了ALK蛋白，并且马萨诸塞州综合医院单个实验室在85%的患者中也证实了该ALK蛋白的存在。
她在接受采访时说：“显然，我们目前选择的是正确的患者，因为他们正在从中获益。”
目前，辉瑞正与雅培分子公司共同开发商业化标准FISH检测工具，并且预计2011年中期克里唑蒂尼将获得美国的批准。
Bang博士表示，这些结果支持绘制NSCLC患者的基因图谱，并制订个体化的NSCLC治疗方法。
2007年，研究者首次在间变性大细胞淋巴瘤患者中发现ALK基因，并随后发现其是NSCLC、成神经细胞瘤和罕见肉瘤等癌症的驱动因素。ALK基因改变可导致肿瘤特异性ALK蛋白活化及肿瘤生长。
Kris博士还对克里唑蒂尼的迅速临床发展进行了评论，称其是一种更简便、破坏性更少的治疗选择。
Kris博士告诉记者：“我们从发现及认识一种癌基因到开发出相应治疗仅花费了短短3年时间，我认为这有力地证明了，一旦我们认识某种癌细胞，我们就能在极短时间内开发出相应治疗。”
另外两项克里唑蒂尼试验目前正在招募ALK阳性NSCLC成人患者。随机III期PROFILE 1007试验将在318例此前曾接受过1种含铂类化疗的患者中对连续给予克里唑蒂尼(250 mg，2次/d)与培美曲塞(500 mg/m2)或多西紫杉醇 (75 mg/m2)进行比较。开放性单组PROFILE 1005试验将在250例此前接受过1种化疗的疾病进展患者中对相同剂量的克里唑蒂尼进行评价。
Skillings博士表示，目前也正在与儿童肿瘤协作组合作开展一项I/II期试验，目的是为了明确针对各种癌症(尤其是淋巴瘤、成神经细胞瘤和其他较常见于儿童的检出ALK的肿瘤)患儿的剂量和用药方案。
在美国临床肿瘤学会大会上报告的这项克里唑蒂尼试验获得辉瑞公司的支持。Bang博士及其几位同事是辉瑞公司的顾问，并从该公司获得研究资助。Edelman博士是勃林格殷格翰公司、百时美施贵宝公司、Endocyte公司、基因泰克公司、礼来公司和OSI Pharmaceuticals公司的顾问，并从百时美施贵宝公司、Cyclacel Pharmaceuticals公司、Geron公司、葛兰素史克公司、Pharmacyclics公司、先灵葆雅公司和Tragara Pharmaceuticals公司获得研究资助。
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