Introductions
Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2012 San Antonio Breast Cancer Symposium. Joining me today is Dr. Fabrice André, Associate Professor in the Department of Medical Oncology at the Institut Gustave-Roussy in Villejuif, France. Welcome.
Everolimus Extends PFS by 4 Months
At this meeting, you have given several updates on the clinical developments of the mammalian target of rapamycin (mTOR) inhibitors. We first heard about the BOLERO trial results almost a year ago. Remind us about the design of the BOLERO trial.
Fabrice André, MD, PhD: BOLERO 2 is a trial that evaluated the hypothesis that adding everolimus to endocrine therapy is going to improve outcomes in patients who are resistant to endocrine therapy. It's a phase 3 trial; the patients are selected to represent metastatic breast cancer in postmenopausal women who are resistant to nonsteroidal aromatase inhibitors. The standard arm is exemestane and the experimental arm is exemestane plus everolimus. The trial included 724 patients. The results showed that adding everolimus improved progression-free survival. In the standard group, the progression-free survival was 2.8 months, which increased to 6.9 months in the everolimus group, with a hazard ratio of 0.43. That is the starting point.
Dr. Miller: That's a big difference.
Dr. André: Yes, it's a big difference, and it was an unexpected difference because the magnitude of difference was 0.43. In other important trials in targeted therapy, it's in the same range as epithelial growth factor receptor (EGFR) inhibitors in EGFR-mutated lung cancer, so it's important. This drug is a first-in-class, the first drug to show important benefits. Now the question is, how do we move forward from this starting point?
Dr. Miller: Positive trials bring more questions than negative trials. First, we should go back to basics. What is mTOR and why did we think that inhibiting mTOR in this setting would be useful?
mTOR: The "Oil" of the Cancer Cell
Dr. André: mTOR is a kinase that mediates protein synthesis. It's very simple. If there is no mTOR, there is no protein synthesis, so the cancer cell cannot divide and cannot proliferate. I would call it the "oil of the cancer cell." The rationale for testing mTOR inhibitors with endocrine therapy is to find out whether mTOR induces phosphorylation of estrogen receptors and mediates resistance to endocrine therapy.
It is a very interesting situation, because we have 2 different perspectives on mTOR: The first is that mTOR is the mediator of protein synthesis, so it could be kind of a "universal mechanism" for cancer progression. If it is a universal mechanism of cancer progression, then everolimus would lead to improved outcomes in any cancer. The other perspective is that it is very subtle, and mTOR-induced phosphorylation of estrogen receptors is very specific to estrogen receptor-positive breast cancer. We have 2 different perspectives and we are going to see in the future which one is the most important.
Dr. Miller: I'm sure there are studies looking at adding everolimus to other standard therapies in other settings, because mTOR seems to play such a central role in cell growth and cellular processes. Where are those studies? Are the results coming out soon, or will we not be hearing about them for a while?
Dr. André: There are different sets of studies. The first set evaluates the hypothesis that everolimus reverses resistance to trastuzumab. These are BOLERO 1 and BOLERO 3, and we are expecting the results of BOLERO 3 in 2013.
Dr. Miller: So, relatively soon.
Adjuvant Everolimus: Now or Later
Dr. André: The second set of very important trials is trials in the adjuvant setting in ER-positive breast cancer. There are 2 different trials, one being conducted in the United States and the other in France. The 2 trials have a slightly different design, and the trial in the United States involves 1-year everolimus, in frontline, in patients selected to represent a high number of involved axillary nodes or a recurrence score of more than 25.
Dr. Miller: So, it's a group with higher risk, in whom endocrine therapy alone might not be enough.
Dr. André: Yes, but the higher risk is defined by the biology, and the everolimus is going to be given immediately after the chemotherapy.
The French study is totally different in design. The French trial will include patients who are free of relapse after 2-3 years of endocrine therapy. We are selecting patients on the basis of lymph node involvement, not on biology, but we are going to wait 2-3 years before adding everolimus. With the 2 different trials, it looks as though they test the same hypothesis, but actually it's 2 totally different hypotheses.
Dr. Miller: Why wait in the French trial?
Dr. André: Because we think that we could be wrong, that mTOR inhibitors are more effective when there is a secondary resistance to endocrine therapy. The French trial is testing the hypothesis that mTOR mediates secondary resistance to endocrine therapy.
Dr. Miller: So, the waiting is giving time for resistance to start to develop. That's not a comfortable thing to explain to patients.
Dr. André: It's not a comfortable thing, but we explain to patients that in ER-positive breast cancer, we will follow up with them because the risk for relapse can occur even after 5 years. The patients know that they have a large number of lymph nodes involved, and when they arrive after 2-3 years, they are happy to know that there is something new that can even reduce the risk for relapse, at least according to this hypothesis. The design was that of the Intergroup Exemestane Study, which tested an aromatase inhibitor sequentially after tamoxifen therapy. So, we don't think we will face big problems with recruitment. The other difference with the US trial is the length of everolimus treatment; it's going to be 2 years.
Then we have other clinical trials testing mTOR inhibitors. We have a very interesting trial in the United States at MD Anderson and Vanderbilt, testing the hypothesis that mTOR inhibitors reverse resistance to chemotherapy in triple-negative breast cancer. One trial was already reported, conducted at MD Anderson, where they showed in a phase 2 randomized trial that everolimus was associated with a slight increase in the clinical response, but no difference in pathologic complete response. That leads to the question of whether pathologic complete response is the right surrogate marker for this kind of therapy. Then there is the other perspective: How can we improve the research we already have with everolimus? Can we combine it with other targeted agents? Can we improve the bioactivity of the mTOR inhibitors?
Three Important Toxicities
Dr. Miller: I want to ask you a couple of other details about this because it's a fascinating field and a really major advance. We have to talk a little bit about the toxicities, because this drug does have some toxicities. What are the major toxicities that the patients experience?
Dr. André: I will focus on 3 toxicities. The first is stomatitis. Stomatitis is very frequent. The frequency of grade 3 stomatitis in BOLERO 2 was 8%. The second side effect is noninfectious pneumonitis, and the other side effect that is very important is hyperglycemia. There are some other side effects, but I don't think they will dramatically alter quality of life. The 3 adverse events that are on the table are these.
The question is, how do we manage them? At the beginning of the use of everolimus, it is recommended that patients who present with uncontrolled diabetes be excluded, and the oncologists might be very comfortable with that.
For noninfectious pneumonitis, we exclude patients who present with high-risk lung disease. It is very important to instruct the patient that if they have a cough or dyspnea, they need to see their oncologist. Then we come to the most important side effect, which is stomatitis. Once again, we educate the patient, provide careful follow-up, and if stomatitis occurs, stop the treatment and restart at a 5-mg dose. We don't yet know the mechanism of stomatitis; we don't know if it's a direct exposure of the drug or if it's mediated by the exposure in the blood. There have been several attempts to avoid these side effects, but until now they have not been effective. It must be emphasized that this drug is already being used in patients with kidney cancer and neuroendocrine tumors.
Dr. Miller: While it is new to those of us in the breast cancer field, oncologists in the community who treat a wide range of diseases are probably better at managing these side effects than I might be.
Dr. André: Exactly. This is probably something that is worth evaluating, whether general oncologists are more used to this kind of drug than breast oncologists. I would like to see whether the dose intensities are different according to these 2 different types of oncologists. In breast oncology practice, we are not used to targeted therapy, but our colleagues treating kidney cancer are using sunitinib, sorafenib, temsirolimus, and everolimus. They have plenty of drugs and they know better how to manage them. There are some side effects, but if the patients are well managed and well followed up, they are manageable overall. It's not like endocrine therapy, but it's still manageable.
A Trend to Overall Survival Benefit
Dr. Miller: I have 2 other important questions from BOLERO. We are all anxious to see the overall survival data, particularly with that unexpectedly big improvement in progression-free survival. Is there an overall survival difference? Are we still waiting for those data?
Dr. André: It was reported at the American Society of Clinical Oncology that there was a trend toward a difference in overall survival that did not reach the prespecified P value, but it was a very strong trend. This question is actually a global question about what we can expect in terms of overall survival, in a study that included what I would call "endocrine-sensitive" patients.
Dr. Miller: These are patients who tend to live with their disease for quite a long time, so we may be waiting quite a while for those final survival data.
Dr. André: Yes, and we might have to wait for a long time. If you improve progression-free survival by 4-6 months, and the post-progression-free survival duration is 3-4 years, at the end, if you increase overall survival by 3-4 months, it won't reach significance. So, I do not expect a major difference in overall survival. We have a difference in progression-free survival that is of high magnitude, so I will not wait for that. We expect to have the results, we expect the survival trend, but I don't think that a 4-month improvement in progression-free survival will translate into a 6-month or 1-year improvement in overall survival.
Dr. Miller: It's frustrating, but I think you are right. That is a big hurdle for what we have seen.
Dr. André: But now we know that targeting mTOR is improving outcomes in ER-positive breast cancer. The problem is that some of the patients who were included in BOLERO 2 had adjunct therapies, such as P13 kinase inhibitors, in the context of phase 1 or phase 2 trials. That is going to dilute even further the impact on overall survival.
Targeting a Process Rather Than a Mutation
Dr. Miller: The other way to make this therapy more effective is to figure out who is most likely to benefit and who might not benefit. While this was a major advance, it certainly didn't benefit everyone who was treated with this agent. Do we have any hints from the biomarker studies embedded in BOLERO 2 that might allow us to use this agent in a targeted way?
Dr. André: I have 3 answers. First, you call it a targeted agent, but everolimus is not the same kind of targeted agent as an EGFR inhibitor in EGFR-mutated lung cancer. This mTOR inhibitor is more like a small molecule that will inhibit a universal mechanism of cancer progression. It's not a targeted therapy in the way that it targets oncogenic events; it's targeting a process that leads to cancer cell proliferation. So, we can create targeted therapy because it's targeted against mTOR, but the concept is a little bit different from crizotinib or an EGFR inhibitor.
Dr. Miller: Okay, so I won't look for a single factor. I still want something.
Dr. André: I do not expect one single mutation to be driving the high efficacy of the mTOR inhibitor. I think we are going to find that some mutations will be associated with resistance and some mutations will be associated with sensitivity, but the most important thing will be whether we can quantify mTOR activation, because in the end what is important is whether the patient has an mTOR activation or not. There are some efforts to develop some new tests to quantify the phosphoprotein. If we can quantify the phospho-4BP1 -- the downstream protein -- we will certainly have a better idea about which patient has an activation of mTOR and which patient does not have activation of mTOR. This is probably really important.
In terms of genetic biomarkers, there is a strong effort by BOLERO investigators to sequence the primary tumor samples from the BOLERO trial. They are doing next-generation sequencing on 400 samples from the BOLERO 2 trial and we will see what they find. I expect that they will find that the oncogenic mutations, although not located on the mTOR pathway, will be associated with resistance. For example, if a patient has EGFR amplification, it might be associated with resistance to mTOR inhibitors. Still, to identify the sensitive patient, we will need some other kind of technology. The phosphoprotein evaluation is going to be interesting, and there are already some preliminary data from the TAMRAD trial, which is a small phase 2 randomized trial in France. We have done some biomarker analysis, and phospho-4BP1 is associated with sensitivity to everolimus. So, the good thing about this drug is that it is opening new fields, not only in the outcomes, but also in the research and biotechnology field, because now people are trying to develop some technologies to quantify the phosphoproteins. The drug is going to have an effect on basic science and biotechnology research. It's interesting.
Dr. Miller: It is a fascinating field and one that really has advances for our patients. Thank you for coming in today, Fabrice.
Dr. André: Thank you.
Dr. Miller: Thank you for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller at the 2012 San Antonio Breast Cancer Symposium.