Refining Advanced Breast Cancer Management: Developing Treatment Strategies to Improve Outcomes 专家讲座视频 http://www.peervoice.com/refining-advanced-breast-cancer-management-developing-treatment-strategies-improve-outcomes?person_id=5075234specialty=Oncology#featured-presentations Now Playing Presentation 1 HR‐Positive/HER2‐Negative Advanced Breast Cancer: Optimising Treatment and Managing Adverse Events With Targeted Therapies Hope S. Rugo, MD University of California, San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco, California, USA Now Playing Presentation 2 HER2-Positive Advanced Breast Cancer: Targeted Options Beyond Trastuzumab Therapy Sara Hurvitz, MD, FACP UCLA Jonsson Comprehensive Cancer Center Los Angeles, California, USA 【原来，今天是无胸罩日】7月9日，无胸罩日（No-bra Day），是为预防妇女乳房疾病高发，倡导所有的女性这天不戴胸罩，目的是号召女性朋友在这天让乳房自由放松，远离疾病。研究指出，每天戴胸罩超过十二小时者比短时间或不穿内衣者，患乳腺癌的几率高出20倍以上。 Emerging Treatment Options for Crizotinib-Resistant ALK -Positive NSCLC Alice Shaw, MD, PhD Massachusetts General Hospital Cancer Center Boston, Massachusetts, USA Go Online Now Online Extras Podcast MP3 Printable Transcript Slides Dr. Shaw: My name is Alice Shaw; I’m one of the thoracic oncologists at Massachusetts General Hospital in Boston. While crizotinib is very effective for patients with advanced ALK -positive lung cancer, unfortunately, by about a year, many patients will have signs of developing resistance. This is a huge barrier in terms of the benefit of crizotinib. Today I’ll be talking about resistance to the ALK inhibitor crizotinib and some of the exciting new developments in overcoming crizotinib resistance; this focuses primarily on a whole class of new drugs that are called next-generation ALK TKIs . back to top Dr. Shaw: There’s been a lot of research into this question of crizotinib resistance how it develops in patients. One of the well-established mechanisms of crizotinib resistance involves alterations in the ALK gene. And that can either be in the form of a new resistance mutation that occurs within the ALK tyrosine kinase domain, or it can be amplification of the ALK fusion gene—and because of either a mutation or amplification of the target gene, that confers resistance to crizotinib. This particular category of crizotinib resistance mechanisms has been very well worked out, and we see resistance mutations or ALK fusion gene amplification in about one-third of our patients who have become resistant to crizotinib. In the remaining two-thirds of patients, a subset of them have evidence of activation of alternative signalling pathways—we often call these bypass tracks because they allow the tumour cells to bypass inhibition of ALK and now to use other signalling pathways, for example, EGFR signalling or KIT signalling. And this is just beginning to be validated in patient samples. back to top Go online to view the complete activity Dr. Shaw: The first report of a patient with crizotinib resistance was a younger patient who was ALK -positive and had been on crizotinib and responded, but unfortunately relapsed after just only about five months. And at the time of relapse, they re-biopsied his resistant tumour, and they identified two resistance mutations. The one that was most notable was the gatekeeper mutation in ALK , which is called L1196M , because it’s analogous to the T790M mutation in EGFR . The gatekeeper mutation is believed to confer resistance through steric interference of crizotinib binding to ALK . These authors also found a second independent resistance mutation, C1156Y . Since then, there have been a number of crizotinib-resistant patients identified that tell us that there are actually quite a few different resistance mutations beyond the gatekeeper L1196M . This is really in contrast to what we see with EGFR -mutant lung cancer, where T790M is really the only resistance mutation that we identify in EGFR -resistant patients. back to top Dr. Shaw: So with that background, we’ll move onto these new ALK inhibitors. This slide shows three ALK inhibitors that are the most advanced in clinical trials. This includes LDK378, which just opened phase 2 trials globally. The phase 1 trial of LDK378 has enrolled over 200 patients to date, so by far we have the most data on LDK378 compared to any of the other ALK inhibitors in development. That one is the one to keep an eye on, particularly in terms of registration trials, as well as potentially accelerated approval because the activity looks so promising in the crizotinib-refractory population. There’s also a compound called CH542802 (we often just call it AF802) that’s currently in a phase 1/2 study, and then, there’s a compound, AP26113, that’s currently in a phase 1 study in the US. What’s notable about all three of these compounds is that they are very selective for ALK, and they’re more potent against ALK than crizotinib. The other notable thing is that they inhibit ALK just like crizotinib, but they don’t inhibit MET. Crizotinib actually was first developed as an anti-MET drug, and it was only subsequently then developed to target ALK. None of these three drugs has any significant activity against MET, but they do have activity against other kinase targets. back to top Narrator: These potent ALK inhibitors have demonstrated preclinical activity that formed the rationale for recent and ongoing clinical trials, with LDK378 being furthest along in development. As of March 2013, the US FDA has granted LDK378 breakthrough drug status. Dr. Shaw: What’s notable immediately is that the response rate to LDK is remarkably high in these patients—80% at doses of 400 mg or higher—the majority of who had become resistant to crizotinib, although we also do have some patients who are crizotinib-nave. I should note that the phase 1 study of LDK378 has already established the maximum tolerated dose to be 750 mg. And this is the dose that has gone forward into the expansion phase of the phase 1 study, as well as the current phase 2 studies. back to top Dr. Shaw: This slide shows a patient who had crizotinib-resistant ALK -positive lung cancer and started on LDK378 at 400 mg a day. He was relapsing on crizotinib and very, very symptomatic—to the point where he had to be hospitalised. His CT scan shows significant lung disease bilaterally. This patient started on LDK378 and within a few days had a really remarkable clinical improvement; he was discharged from the hospital. By six weeks, you can see significant improvement in the disease in his lungs. And this patient was confirmed partial response. back to top Dr. Shaw: This has held up in most of the patients who have enrolled on the LDK378 study. This is a waterfall plot summarising the best response of patients who were treated with LDK378 at doses of 400 mg and higher—the response rate is close to the 80% mark. So very remarkable efficacy of this drug, particularly in a TKI-resistant population. back to top Dr. Shaw: Also, LDK378 does appear to have fairly good activity in the CNS. This clinical protocol allowed us to enrol patients with untreated, asymptomatic brain metastases. And in almost all of the patients we have observed a radiologic response. So this suggests that LDK378, because it is such a potent ALK inhibitor, does have the ability to penetrate the CNS, although we don’t know to what extent. back to top Dr. Shaw: AF802 is another highly potent selective ALK inhibitor. It has very potent activity against ALK and some of the resistance mutations that occur with an ALK it really has very little activity against any other kinases, and this includes METs and ROS. They established the treating dose to be 300 mg twice a day, and what they found is that the objective response rate in this crizotinib-nave population was very high at 85%. back to top Dr. Shaw: Here’s the waterfall plot showing you all the different responses of the crizotinib-nave population. Almost every single patient did respond to the AF802 compound. back to top Dr. Shaw: Finally, we’ll touch on the third ALK inhibitor, AP26113. This compound is interesting because it seems to inhibit quite a few other kinases, one of which is EGFR with an activating mutation together with the resistance mutation, T790M. And so there has been a lot of interest in trying to develop this compound for patients with EGFR-mutant lung cancer who have become resistant to EGFR inhibitors like gefitinib. So the preliminary results were presented, and I think the data was remarkable for the high response rate that has been seen in crizotinib-resistant patients—similar to what’s been reported for LDK378. So far these responses appear to be quite durable, but this study is still ongoing. back to top Dr. Shaw: Shown here is an example of a crizotinib-resistant patient who responded to AP26113 at the 180-mg dose after just four weeks. back to top Dr. Shaw: Like LDK378, AP26113 appears to have activity in the CNS. After just eight weeks of AP26113, you can see that there was near-complete resolution of this brain metastasis, suggesting that AP26113 does penetrate into the brain at least to levels high enough to inhibit ALK. back to top Narrator: Preliminary safety data suggest that these next-generation ALK inhibitors are generally well tolerated. Dr. Shaw: The most common side effects of LDK378 are gastrointestinal—so nausea, vomiting, and diarrhoea, seen in over 50% of patients. So these should be managed with antinausea medicines, oftentimes prophylactically, and also with antidiarrhoeal medicines. Other important adverse events to note include fatigue and asthenia, and transaminase elevation was also reported in a significant fraction of patients. Also, the AP26113 compound appeared to be very well tolerated, with some expected side effects from an oral TKI, like nausea, vomiting, diarrhoea, and some transaminase elevation. But the numbers of patients who have enrolled are still on the low side, so we probably don’t have a full profile yet, in terms of adverse events. back to top Dr. Shaw: So in conclusion, crizotinib is now a globally approved drug for patients with advanced ALK -positive lung cancer. Unfortunately, even though crizotinib is highly active, most patients will relapse, and so the new paradigm that has emerged in this field is that next-generation (or more potent) ALK inhibitors can salvage almost all patients who have relapsed on crizotinib. So I think going forward what we’re going to see is that the treatment paradigm for ALK -positive lung cancer will be to start with crizotinib and then at the time of relapse, to move to a more potent ALK inhibitor like LDK378. It’s very possible that these more potent ALK inhibitors will be able to get approval for the crizotinib-refractory population, and we’ll see whether or not those compounds will move even earlier to the crizotinib-nave population. And so larger phase 2 trials, and also even phase 3 trials, will be opening, looking at whether or not these more potent ALK inhibitors should be used first instead of crizotinib. back to top Go online to view this audiovisual presentation References and abbreviations available online. Expert perspectives • Concise 7-9 minute interviews • Interactive scientific discourse
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