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Publicaciones sobre Temas de Interés
CANCER DE MAMA/CONFERENCE REPORT
Breast Cancer at ASCO: Latest Trial Results and Emerging Therapies
By Kimberly Blackwell, MD
Professor of Medicine, Assistant Professor of Radiation Oncology, Duke Cancer Institute, Duke University, Durham, North Carolina
Interviewed by Anna Azvolinsky, PhD
21 de junio de 2012
Following the annual meeting of the American Society of Clinical Oncology (ASCO) CancerNetwork speaks with Dr. Kimberly Blackwell, professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University in Durham, North Carolina. Dr. Blackwell is involved in studying the angiogenesis process, and hormonal and neoadjuvant therapy for breast cancer, among other research topics, and is heavily involved in early- to late-stage clinical trials for breast cancer.
Kimberly Blackwell, MD1
CANCERNETWORK: A lot of the excitement at ASCO this year was due to the data you presented of the results of the EMILIA trial showing that the antibody-drug conjugate trastuzumab entansine (T-DM1) extended progression-free survival compared to standard of care in HER2-positive women previously treated for their metastatic breast cancer. Could you put these results in context for us? What does this mean for HER2-positive breast cancer patients?
DR. BLACKWELL: First of all, thanks for letting me join you to discuss the EMILIA study and some of the other interesting things that happened at ASCO this year. I was lucky enough to be able to present the EMILIA study, which was a study of over 980 patients—a prospective, registration-intense phase III study of T-DM1 vs standard lapatinib and capecitabine. These were patients that in the most practical terms were first-, second-, or third-line metastatic breast cancer patients, and all of the patients were required to have had a taxane as well as trastuzumab. A little over half the patients had seen over a year of trastuzumab, and the majority of the patients were receiving the treatment on study as a second- or third-line metastatic treatment. It was a global study with 213 centers, and between the two arms of the study the characteristics of both the patients and the disease were well matched. And as you alluded to, the primary endpoint of progression-free survival was met and the absolute improvement in median progression-free survival was about 3.2 months. Now that in itself is always very exciting. We also saw a not statistically significant improvement in overall survival. The hazard ratio was 0.62 with a P value of .0005. But because the survival analysis was an interim analysis, the P value had to be less than .0003 to reach statistical significance. And the absolute difference which was a planned analysis at 2 years was actually 18% absolute difference between those patients who received T-DM1, the new antibody-drug conjugate, vs the control arm, which was lapatinib and capecitabine.
So I think anytime we see a treatment option that improves outcome, people’s ears perk up and we all start thinking about when the drug becomes available, how we are going to use it. Probably the second most exciting finding in the EMILIA study was that the drug, which is a traditional cytotoxic known as DM1 and bound to trastuzumab, has very little toxicity associated with impact on quality of life and other measures such as grade 3 or greater adverse events. And this is a real proof-of-principle study in that it showed that if you can link a cytotoxin to an antibody and deliver it directly to the cancer cell, then the side effect profile will be quite favorable. We saw an 18% absolute difference in treatment discontinuation due to adverse events. It was higher in the control arm compared to the T-DM1 arm. If you look at the side effect profile of T-DM1, it is primarily lab-based abnormalities. We saw about 4% incidence of elevation in AST and ALT compared to 2% in the control arm and we saw about a 12% incidence of grade 3/4, thrombocytopenia. It is unclear what causes the thrombocytopenia, although a lot of people are looking at it. So in total we saw very mild liver toxicity, very mild thrombocytopenia. Compared to the known toxicities of lapatinib and capecitabine it was a very well-tolerated regimen. People are excited, even if they don’t take care of a lot of breast cancer patients, because of the proof of concept that maybe we could lessen the toxicity of chemotherapy by binding it to a tumor-directed antibody.
CANCERNETWORK: Sure, and as you said, both the safety and efficacy results of EMILIA were really exciting. When can we expect final overall survival data?
DR. BLACKWELL: So, that is subject to much discussion and as was highlighted to me multiple times during the national meeting, it really goes back to, How positive does a trial have to be in order to get a drug approved in the United States and throughout the world? The planned overall survival analysis is meant to occur when 500 deaths have occurred but the median overall survival for the T-DM1 arm has actually not been reached compared to 23.3 months for the control arm. So if the event rate continues to parallel where the survival curves have gone it would not be until early 2014, although I think many people are very anxious to have this drug available to their patients, and so I wouldn’t be surprised if there were a lot of discussion about having additional survival analysis, but that remains to be seen.
CANCERNETWORK: I see. We also saw the results of an interdisciplinary trial which showed that paclitaxel, in combination with bevacizumab was more efficacious and less toxic to either of the two newer chemotherapy agents when combined with bevacizumab. Paclitaxel is the current standard of care as first-line treatment for women with breast cancer. What is your interpretation of these results?
DR. BLACKWELL: The study that you are describing, the lead group presented very finely by Dr. Hope Rugo from UCSF. It is one of these, "Is the glass half full, or is it half empty?" I was excited to see that our old friend paclitaxel, which we have been using for the treatment of both metastatic and early-stage breast cancer, remains highly active in first-line metastatic breast cancer. In fact, the control arm of paclitaxel plus bevacizumab really mirrored that which was seen in ECOG2100 in terms of progression-free survival. I guess the glass is kind of half empty because we were all hoping that we had made improvements both in the use of traditional taxane therapy such as nanoparticle bound paclitaxel or ixabepilone, which is not a taxane but has a similar mechanism of a microtubule disruption but a different binding site. In fact, the two experimental arms when combined with bevacizumab really didn’t seem to make a significant improvements in outcomes for these patients with first-line metastatic breast cancer. There was some strong evidence that the dosing, the doses that were prescribed, at 150 mg/m2 3 weeks on, 1 week off for nab-paclitaxel, and ixabepilone at 16 mg/m2 3 weeks on, 1 week off, appear to not be very well tolerated and resulted in a fair amount of dose reductions and I think we will continue to hear some discussion about whether or not it was the dose reduction that impaired the ability to improve the outcomes in these patients. But at the end of the day, the toxicity really drove the inability to give the newer chemotherapy agents at the doses that were meant to be given in the context of this trial. So, it is good to know that paclitaxel continues to be a standard and effective option for the treatment of metastatic breast cancer. It is a little disappointing to know that we haven’t made improvements with some of the newer drugs that have become available.
CANCERNETWORK: So you mentioned the dosing that was used with these newer chemotherapies. Are the doses that were used in this trial, are those the doses that were approved?
DR. BLACKWELL: So none of the two taxanes and ixabepilone are approved in the dosings that were used in the context of Dr. Rugo’s study. We have known since Andy Seidman’s study, old-fashioned paclitaxel (cremophor-solubilized paclitaxel)—there is an improved outcome—when cremophor-solubilized paclitaxel is given weekly compared to every 3 weeks at a 175 mg/m2. We do not have an extensive database in terms of efficacy for either weekly ixabepilone or weekly nab-paclitaxel and again, that certainly could have affected the ability to see these drugs improving outcomes. They are both approved as monotherapies given every 3 weeks.
CANCERNETWORK: Are there any other ASCO result you would like to highlight?
DR. BLACKWELL: There was some interesting data in the neoadjuvant setting regarding Herceptin (trastuzumab) vs lapatinib vs the combination of the two. And although in general it looked as though lapatinib and Herceptin resulted in a slightly higher complete pathological response rate we didn’t really see the tremendous improvement in complete pathologic response that we saw with NeoALTTO in favor of the combination of lapatinib and Herceptin, so I think the NSABP neoadjuvant HER2 study kind of toned down, at least a little bit for me the enthusiasm I had about the combination of lapatinib and Herceptin in the neoadjuvant setting. I will continue to use it, especially for locally advanced breast cancer based on the NeoALTTO results.
I think Karen Gelmon’s study looking at first-line taxane, Herceptin vs taxane and lapatinib showing a survival detriment for the use of lapatinib in the first-line setting. This was a very late, late breaking abstract that certainly implies, at least in that setting when combined with a taxane, trastuzumab remains superior to lapatinib as a single agent in combination with a taxane.
And then I think in a very practical, but less exciting way, the results presented by Dr. Swain of NSABP38 (National Surgical Adjuvant Breast and Bowel Project) which was a much-awaited study looking at six cycles of docetaxel/doxorubicin/cyclophosphamide (TAC) vs dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel or a third arm which was dose-dense AC followed by gemcitabine-paclitaxel. This study showed basically no difference between the three arms of the study. And so I think for those of us who used to sit around in the old days and debate dose-dense vs TAC it provided very strong rationale both in terms of disease-free survival and overall survival that there really is no difference between the three arms in the adjuvant breast cancer setting. I think most of us would have predicted a higher hematologic and probably all-grade toxicity for the TAC arm—what was surprising in the study was there was actually a higher cumulative incidence of significant adverse events in the dose-dense arm compared to the TAC arm and that is not something probably most of us would have predicted. So at the end of the day, it looks like three arms were about equivalent in a pair-wise comparison model, and the adverse events were pretty similar with not one arm looking a lot worse or a lot better in terms of toxicity. So those are the three studies, besides EMILIA that I will take home with me, and although they are not exciting they are very important studies that really define our continued use of chemotherapy and first-line Herceptin and taxane-based therapy.
CANCERNETWORK: And just as a last question, briefly, what do you see as among the biggest unmet needs in the treatment of breast cancer patients in general?
DR. BLACKWELL: Well, I can tell you it's triple-negative breast cancer. I think chemotherapy works in triple-negative breast cancer in preventing it from coming back and also in treating the disease, but it appears as though in both the metastatic setting where resistance is common and in an adjuvant setting, where unfortunately a high percentage of triple-negative breast cancers come back, I think we need to the HER2 domain and say, "Why don’t we have drugs like this for triple-negative breast cancer?" and really work with our pharma colleagues and basic science colleagues and say we need to do better in the treatment of triple-negative breast cancer
CANCERNETWORK: Thank you so much for joining us Dr. Blackwell!
DR. BLACKWELL: Thanks for having me!
CANCER DE PULMON/CONFERENCE REPORT
Lung Cancer at ASCO: Latest Trial Results and Emerging Therapies
By Rachel Warren
Editorial Director, Oncology
15 de junio de 2012
CancerNetwork speaks with Joel Neal, MD, PhD, assistant professor in the department of medicine at Stanford University. Dr. Neal was a discussant in the non–small-cell lung cancer session at this year's annual meeting of the American Society of Clinical Oncology (ASCO) and is an expert on non–small-cell lung cancer.
Joel W. Neal, MD, PhD
CANCERNETWORK: I know there was a lot of news about non–small-cell lung cancer at ASCO this year, and that this is your area of research—can you give me a wrap-up of what you think the most important findings were?
DR. NEAL: Well, I think what was most important depends on who is listening. For the community oncologists, the biggest finding is probably the overall survival analysis of the PARAMOUNT trial. This trial, presented by Dr. Paz-Ares, showed that maintenance pemetrexed, after induction cisplatin/pemetrexed had an overall survival benefit, in addition to the progression-free survival response that we saw earlier. The overall survival showed that patients who got maintenance pemetrexed following four cycles of cisplatin/pemetrexed had an overall survival of 13.9 months. If you count from the time of induction it was actually 16.9 months. The placebo group was 11 months, or 14 months from the time of induction. This was a significant result with a hazard ratio of 0.7, so there is some evidence to say that continuation maintenance of pemetrexed, in addition to switch maintenance pemetrexed, which is already FDA-approved, may be useful.
Some of the other data that we saw was from Dr. Lilenbaum, showing us phase III data with a couple of hundred patients showing that carboplatin and pemetrexed in performance status 2 patients vs pemetrexed alone was superior in terms of progression-free and overall survival. This tells us that patients—even with decreased performance status—should get carboplatin if they can tolerate it, and we’d seen similar data 2 years ago from the French group.
Some of other results were toward specific molecular subtypes of lung cancer. We saw some data in RET, we saw some data in ALK-resistant, we saw some promising data in KRAS mutants in non–small-cell lung cancer with a drug called selumetinib, which is a MEK inhibitor, and some data that showed that erlotinib doesn’t look as good as docetaxel in the TAILOR trial in EGFR wild-type patients.
We also saw that, in EGFR mutants (in the LUX Lung-3 trial) afatinib, which is a next-generation EGFR inhibitor which is irreversible and may have some activity against T790M, was superior frontline to cisplatinum/pemetrexed, with a progression-free survival of 11 months vs 7 months, but we haven’t seen the overall survival results so that goes along with previous trials that have told us that for EGFR mutants, first-line tyrosine kinase inhibitor therapy is important.
One of the most exciting results I think we saw was from Julie Brahmer, about the programmed death 1 (PD-1) drug. PD-1 is an inhibitory receptor expressed on T cells and a lot of tumors produce something called PD-1 ligand; it’s expressed on many solid tumors. In a phase I trial including about 100 non–small-cell lung cancer, they saw a response rate of about 18% in heavily pretreated patients, and some of those responses lasted for more than 24 weeks. The drug had fairly low side effects, just a little rash, diarrhea, fatigue, and itching because it’s an immunotherapy, so really this shows us that moderating the immune system may be a potential target in non–small-cell lung cancer.
And finally, another molecular target was ROS1. ROS1 is very much like ALK, which is treatable with crizotinib, and we saw from Dr. Shaw at Mass General that ROS1 patients, similarly to ALK patients, had a 57% response rate on crizotinib, which is FDA approved for ALK.
So that’s a wrap-up of the big things in the oral sessions for non–small-cell lung cancer, at least in the metastatic session.
CANCERNETWORK: Give us your thoughts on the study that showed FDG-PET scanning has substantially lower sensitivity and specificity than was previously thought?
DR. NEAL: This data was from Dr. Grogan and this was an early-stage clinical trial; it was clinical stage I non–small-cell lung cancer and it enrolled almost 1,000 patients. The trial was trying to do serum proteomic analysis of resected non–small-cell lung cancer to demonstrate whether or not you could use proteomics to diagnose non–small-cell lung cancer. For a secondary analysis they used FDG-PET scans and compared whether or not the PET scans plus the CTs were reliable for predicting whether someone had non–small-cell lung cancer. The question at its essence was, "If someone has a small lung nodule and that was diagnosed by CT only, can you use a PET to tell whether or not it might be cancer and therefore whether or not it might need to be resected?" What they found was that PETs were 82% sensitive, which is not terrible, but they were very nonspecific—with only a 31% specificity. There were a lot of false positives—a lot of these false positives were granulomas, suggesting prior or current fungal infection. The accuracy of FDG-PET improved with the size of the lesion, presumably because granulomas would generally be small.
This doesn’t mean that for stage IV, metastatic non–small-cell lung cancer, PETs are insensitive at all, they’re a very valuable tool for staging patients and they can show distant metastatic disease, but what it means is that for the majority of lesions that are PET avid, if you do a PET scan on people as a screening tool, it will not be a great discriminator of whether something is lung cancer or not so they probably have to be paired with another test.
CANCERNETWORK: Finally, can you talk a little about where we are as far as biomarkers for lung cancers—both subtypes and targets?
DR. NEAL: For non–small-cell lung cancer, we saw a lot of evidence at the meeting for exciting new targets, as well as more data about the targets we already knew. Within adenocarcinoma, which is the one that’s best molecularly characterized, the most common are KRAS mutations, which are somewhere between 20% and 30% in frequency. We saw that selumetinib plus docetaxel is a potentially effective therapy for that group, although that’s still in clinical trials and has yet to be validated. EGFR-mutant non–small-cell lung cancer is the next biggest share, and for this group we saw that in the LUX Lung-3 trial, afatinib vs cisplatinum/ pemetrexed, that afatinib looks like a great drug in first-line treatment of EGFR-mutant lung cancer.
We also saw that ALK mutants, which are around 5% of patients, fall into a few subcategories, in a series of patients from the University of Colorado. In some of those mechanisms, resistance may be overcome. And finally in ROS1, which is about 1% frequency, and RET translocations, which are about 1% frequency, these may each be targetable with drugs that are already available. So even though they’re very low frequency, we might be able to find effective therapies. We have yet to see those effective therapies work, but with a response rate of 57% in ROS1 to crizotinib, and with crizotinib already FDA-approved, and with the identification of RET translocations, which are a different subgroup, that may respond to sorafenib or sunitinib, I think we have hope that we may not have to start reinventing drugs and starting from ground zero, and that we might be able to use already approved things.
We also saw in squamous non–small-cell lung cancer, which up until a couple of years ago had no identified driver alterations, some data from Paul Paik at Memorial Sloan-Kettering. They’ve used some squamous multiplex testing and have identified FGFR1 amplification, by FISH analysis, as a recurrent alteration in about 25% of squamous-cell carcinomas, and this could be targeted potentially by FGFR inhibitors that are starting to enter clinical trials. They also reported that PI3 kinase alterations and P10 alterations are recurrent and common. Dr. Govindan from Washington University presented a larger series in the earlier oral session of 180 patients, and also identified FGFR1 and the P10 and PI3 kinase alterations as being recurrent and common in squamous non–small-cell lung cancers. So it looks like squamous might have some targetable alterations as well—which is something relatively new since the last ASCO.
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