Everolimus for postmenopausal women with advanced breast cancer

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Published: 16 Dec 2011
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Dr Gabriel Hortobagyi - MD Anderson Cancer Center, Houston, Texas, USA

At a press conference during the ASH 2011 Annual Meeting, Dr Hortobagyi give an update on the BOLERO02 phase III trial.

 Dr Hortobagyi explains that the mTOR pathway is constitutively activated in hormone-resistant advanced breast cancer. In phase II trials, everolimus showed promising efficacy both as monotherapy and in combination with endocrine therapy in patients with estrogen receptor–positive advanced breast cancer. This double-blind, placebo-controlled, phase III study evaluated EVE plus exemestanein patients with ER+ advanced breast cancer refractory to letrozole or anastrozole.

2011 SABCS, San Antonio Breast Cancer Symposium, 6-10 December, San Antonio, USA


Everolimus for postmenopausal women with advanced breast cancer


Dr Gabriel Hortobagyi – MD Anderson Cancer Center, Houston, Texas, USA


Good morning ladies and gentlemen, it’s a pleasure to share this early morning with you and present the results on behalf of my co-investigators and the several hundred patients who participated in this. My disclosure is on this slide.


So endocrine therapy, or hormonal therapy, is the treatment of choice for the majority of patients with metastatic breast cancer whose tumours express the oestrogen receptor. This represents about three-quarters of postmenopausal women or women over the age of fifty and our standard practice is to use the multiple endocrine regimens in sequence in order to get the maximum mileage out of all of our endocrine treatments. On this cartoon I show you what has been proposed as one of several mechanisms of resistance to endocrine therapy because in the metastatic setting the sad truth is that after a number of months of successful control of tumour growth with one endocrine agent, tumour cells become smarter, they develop resistance to that agent and then we need to change to something else. Now this shows a cross-section of a cancer cell and what you see on the outside of the membrane is a number of growth factors, the EGFR, HER2, as you heard from my colleague earlier, VEGFR, the insulin-like growth factor receptor etc. And while the oestrogen receptor binds oestrogen and activates a number of cellular activities in the nucleus, these growth factors can activate the oestrogen receptor in the absence of the natural ligand, which is oestrogen, by activating some of these intermediate nodules, the PI3 kinase, AKT, mTOR pathway. This pathway seems to be central to a number of functions of the cell and can be activated through multiple sources so the hypothesis arose, upon learning this, that inhibiting either PI3 kinase or mTOR might be a good strategy for overcoming resistance to endocrine therapy and, in fact, there is a lot of preclinical data to suggest that mTOR activation is a common mechanism of hormonal resistance.


My co-investigator, Dr Baselga, generated some earlier data in a smaller phase II neoadjuvant trial in which postmenopausal women with hormone receptor positive early breast cancer were randomly assigned to treatment with neoadjuvant letrozole and placebo or letrozole plus everolimus and then, at the time of surgery, the response to these interventions was assessed. And, as shown at the bottom of this slide, the combination showed an increased response rate which was an important trend and a significant anti-proliferative response as determined by a diminution or a reduction in key 67, which is a marker of proliferation in breast cancer and other cancers.


A second earlier trial was a randomised phase II in which tamoxifen was the endocrine therapy, this was in postmenopausal women with hormone receptor positive advanced breast cancer. And as these curves show, while it was a small phase II study with about a hundred patients, this also showed a significant prolongation of time to progression and overall survival.


So based on a solid scientific hypothesis and some preliminary preclinical and clinical data, we then developed the BOLERO-2 strategy. This protocol was intended to be a phase III randomised trial to assess the contribution of everolimus to endocrine therapy in patients who were postmenopausal, had ER positive disease and had progressed on a prior aromatase inhibitor. So this was a 2-2-1 randomisation, we see the doses of both everolimus and exemestane on the respective boxes; the primary endpoint of the study was progression free survival as determined by the local treating investigator although we also had an independent radiology review performed centrally. Secondarily we looked at overall survival, response rate, quality of life and, of course, safety and a variety of correlative markers.


The protocol was designed to detect statistically a hazard ration of 0.74, that is to say a 26% reduction in progression events with 90% power. For that it required initially 528 progression events with interim analysis after the first 359. At that interim analysis the progression free survival actually crossed the boundaries that were mentioned by Dr Baselga earlier for the CLEOPATRA study so that means that the differences were greater than we initially projected and the study became a positive study earlier than projected.


Now the cut-off date for the update I’m going to present to you was July 8th and at that time the median follow-up was 12.5 months and we had reached 457 PFS events. These are the basic characteristics: since the eligibility required patients to be postmenopausal the median age is about ten years older than those patients in Dr Baselga’s earlier study. The majority were Caucasian, about 60% had excellent performance status and about a third each had liver and/or lung involvement. About 70% had measurable disease, the rest being patients with predominantly bone metastases which are not considered strictly measurable. The study was performed internationally in 34 countries over five continents so it actually reflects a variety of ethnic groups in addition to what you see in North America and Western Europe.  About 80% of patients had demonstrated sensitivity to previous hormonal therapy, I remind you again that all of them had received and had progressed on an aromatase inhibitor, namely letrozole or anastrozole. I also call your attention that, in addition to that, 50% had received prior tamoxifen, about 15% had received prior fulvestrant, 25% had received prior chemotherapy for metastatic breast cancer in addition to what they may have received in the adjuvant setting and more than half had received more than three prior therapies in the metastatic setting. So this is a more heavily pre-treated population than what you saw in the previous study. Perhaps that was an excellent choice because, since we are pursuing a mechanism of resistance, this is clearly a population where resistance has set in.


Again this is a 2-2-1 randomisation, discontinuations occurred with greater frequency in the exemestane alone arm or the placebo arm and most of the discontinuations in both arms occurred because of disease progression, very few patients discontinued due to adverse events. This is a primary efficacy variable and it demonstrates not the projected 26% reduction in events but a 56% reduction in events, a hazard ratio of 0.44 and a p-value for which I don’t have enough fingers to count. The median progression free survival went from 3.2 months to 7.4 months in the local investigators assessment and, as you can tell, these curves continue to diverge with time.


Again we are at an early stage with a median follow-up of 12.5 months so, as we approach maturity, we will be more certain of these results. This is the central imaging review, this was equally positive with a hazard ratio of 0.36 and again a highly significant p-value, minor differences in the median progression free survival results. So you have to realise that the local investigator has more information at his sense because he is seeing the patient, the central reviewers have a set of X-rays and they have to judge on that basis. So it is not infrequent to have these minor variations between the local and the central review. The forest plot here shows the internal consistency of these results with benefit shown on all subsets of patients we analysed so this is clearly an effective intervention in this group of postmenopausal hormone resistant patients. The response rates and clinical benefit rates also favoured significantly the combination arm with about 50% of patients who had received prior endocrine therapy benefitting from this combination. The overall survival results are early, remember that the median survival of postmenopausal patients with hormone receptor positive breast cancer ranged somewhere between 2.5 and 4 years and we are at a 12.5 month follow-up, so it will take us probably another year, year and a half, of follow-up until the survival figures mature. I can tell you that at the interim analysis there were more deaths in the placebo arm than in the everolimus arm but those differences are not significant for the same reasons as Dr Baselga mentioned in the previous study. The final analysis will occur after 392 deaths will have occurred.


Common side effects, and I’d like you to concentrate on the grade 3 and grade 4, the commonest one was stomatitis or oral mucositis, which was seen with greater frequency in the combination arm than in the single agent arm, and ration fatigue which are commonly seen and known to occur with this agent, and diarrhoea. Others that are not listed here because they occur with less than 20% frequency included non-infectious pneumonitis, hyperglycaemia, which is an effect of inhibiting mTOR in general and anaemia and those were some of the common and expected toxicities.


We looked at quality of life and the yellow line corresponds to the combination so, despite the list of side effects you saw in the previous slide, the quality of life of these patients was not affected any more than what exemestane alone would cause. The p-value is 0.03 but we consider these curves to be superimposable. Interesting observations - as you know, aromatase inhibitors result in a marked reduction in oestrogens and oestrogen deprivation leads to loss in bone density and in its most extreme form that leads to pathological fractures, osteoporosis etc. In the blue lines and the blue bars on this slide you see an increase in bone resorption markers in the group of patients treated with exemestane alone, that is a known and expected effect of all aromatase inhibitors. In the yellow bars it is the combination, so actually the combination not only does not make bone resorption worse but it decreases bone resorption and bone formation markers. So this might be actually a positive one, I don’t know that we will want this as treatment for osteoporosis but certainly it is reassuring that it does not aggravate that problem. Clinical pharmacology was reassuring, the only change we saw was that everolimus increased the serum concentrations of exemestane but this increase does not result in any significant side effects or changes in oestrogen levels.


So, in summary, the addition of everolimus to exemestane clearly and significantly prolonged the progression free survival in this group of patients with ER positive HER2 negative breast cancer that were refractory to previous non-steroidal aromatase inhibitors and other endocrine interventions with about a four month prolongation of PFS and a 56% reduction in progression events. The benefit was observed in all subgroups. The time to deterioration of quality of life was similar in the two arms; bone resorption and formation markers increased in the exemestane arm but decreased in the combination arm and adverse events were consistent with previously described adverse events with everolimus.


So we believe that these results underline the fact that everolimus is the first agent to significantly enhance the efficacy of a hormonal therapy in patients with ER positive HER2 negative breast cancer and that this combination in advanced breast cancer might represent a change in practice or paradigm shift in the management of this population.


These are the countries that contributed to this study, mostly Europe and North America but other countries too, and of course my thanks to all participants in this trial. Thank you very much.