Dr Matteo Lambertini - San Martino Hospital, Genoa, Italy
The San Antonio Breast Cancer Symposium 2019 has been a very successful meeting. We had very important news, particularly in the field of HER2 positive breast cancer. So in the next few minutes I will do my highlights, mostly related to the HER2 positive field, in the advanced as well as the early setting, and then some quick information on the other two subtypes, triple negative and hormone receptor positive in which we also had some important news presented here in San Antonio.
For the HER2 positive disease I will start first with the advanced setting in which we had three important oral abstract presentations, two of them already published in The New England Journal of Medicine. So I will start, of course, from these two important presentation papers.
The first is the HER2CLIMB trial. This is a randomised trial in patients with HER2 positive advanced disease who receive at least trastuzumab, pertuzumab as well as T-DM1, so at least two prior lines of anti-HER2 targeted treatment for the advanced setting. The trial randomised 600 patients two to one to receive trastuzumab capecitabine plus tucatinib, a new TKI tyrosine kinase inhibitor anti-HER2, randomised to this treatment or to trastuzumab capecitabine plus placebo. The trial met its primary endpoint showing a statistically significant benefit for the addition of tucatinib on top of trastuzumab and capecitabine in terms of hazard ratio 0.54 which is a very good result. In terms of absolute numbers two months improvement in progression free survival, three times higher number of patients that are free from progression at one year following treatment start. But even more interesting are the results in terms of overall survival, again a statistically significant benefit, hazard ratio of 0.66, four months improvement in overall survival.
Probably on the top of these results, even more importantly, the trial included almost 50% of patients with brain metastases and this is one of the most important unmet needs in the breast cancer field, particularly important for HER2 positive patients that have a higher risk of brain metastases. So this is a trial that allowed the inclusion of these patients finally and, importantly, the addition of this drug to trastuzumab capecitabine showed to significantly prolong the outcomes of patients also with brain metastases. So these are very important results in the overall breast cancer population, HER2 positive advanced disease, but particularly for those with brain metastases.
This can be a potentially practice changing trial. As soon as we have this drug available it could be a potential third line treatment option for these women, these patients in general.
The second important trial published in The New England Journal of Medicine is the first phase II trial of a new kind of strong T-DM1. So it’s an antibody-drug conjugate with a more potent chemotherapy agent connected to trastuzumab. The name of this drug is DS-8201a or trastuzumab deruxtecan. This was a phase II trial in patients progressing on T-DM1 so 100% of patients already exposed to a trastuzumab based treatment and to T-DM1. The trial is called DESTINY-Breast01.
It’s a phase II trial in which all patients receive these drugs in the advanced setting. Importantly this was a very heavily pre-treated population, median number of lines of treatment received for advanced disease was six which is a heavily pre-treated population. But despite being a heavily pre-treated population very good results with this potent new agent with an objective response rate of more than 60% which is something that we have never seen in such a heavily pre-treated population. Very good also progression free survival results beyond 14 months. So very exciting results and we have already phase III trials ongoing with the use of this drug, at least two important trials in the HER2 positive field. In one of these trials the randomisation is between DS-8201, so this new agent, as compared to treatment of physician’s choice in patients heavily pre-treated progressing on T-DM1. But there is also already ongoing a phase III trial directly comparing T-DM1 with DS-8201, so potentially this drug could become our second line option very soon. So this is a very exciting agent and exciting results.
The third trial is actually an update of what we already knew from ASCO, it’s the update of the SOPHIA trial results. This was a study again in patients with advanced HER2 positive disease, heavily pre-treated, that were randomised to receive chemotherapy plus trastuzumab, which is the standard of care in this later line setting, or this new strong trastuzumab called margetuximab. It’s a kind of trastuzumab that has been engineered to enhance the potency of the drug in activating the so-called ADCC.
However, the trial met its primary endpoint, showing a statistically significant benefit in progression free survival, hazard ratio 0.76. However, in terms of absolute numbers the results are not probably that exciting with only one month improvement in progression free survival. Here we had also updated results at a longer follow-up that could not show any benefit in overall survival. So a small benefit in progression free survival, no benefit in overall survival. So we need more follow-up to potentially see a difference in efficacy between this drug and standard of care these days which is trastuzumab.
Interestingly, there are some data on the potential differences in treatment effect according to the genotype of the patient in the receptor called CD16. But again these are very interesting results but we need more research before moving this drug to the clinical setting.
This is for the advanced setting. For the early disease we had the presentation of two very important trials. One is the updated results of APHINITY and the other is the so-called ATEMPT trial.
The APHINITY we all know the first results published in The New England Journal of Medicine a couple of years ago. The trial included more than 4,000 patients with HER2 positive early breast cancer that received adjuvant chemotherapy with trastuzumab or with dual anti-HER2 blockade, trastuzumab plus pertuzumab. The trial met its primary endpoint, a significant improvement in disease free survival but the benefit was small and was mostly seen at the time of the first analysis in node positive and hormone receptor negative patients.
Here in San Antonio we have the updated overall survival and disease free survival data. The main message is that overall survival is not different between the two options, less than 1% difference in overall survival at six years between the two treatment arms and very good outcomes - more than 94% of patients alive at six years. In terms of subgroups of patients that may be the one potentially benefitting the most from this treatment, it’s again node positive patients. The benefit is becoming larger in this setting. Interestingly, while in the first analysis the benefit appeared to be only for hormone receptor negative patients, at longer follow-up the benefit was seen in terms of invasive disease free survival irrespective of hormone receptor status.
So the main message from this trial is that in the overall HER2 positive population we do not need probably the dual anti-HER2 blockade. But for patients at high risk of disease recurrence, mostly node positive patients, irrespective of hormone receptor status, the addition of pertuzumab to trastuzumab can be beneficial and can be considered if available.
The other important trial, we were really waiting for this study called ATEMPT. This was a randomised study for patients with stage 1 HER2 positive disease, so node negative, less than 2cm, tumour smaller than 2cm, so a low risk population which is the population of patients that we currently treat with weekly paclitaxel and trastuzumab for a year. This is the standard of care in this setting.
This trial randomised patients three to one, these patients three to one, to T-DM1 for a year as compared to weekly paclitaxel plus trastuzumab. The trial was not designed for a comparison between the two treatment arms but we wanted to mostly show the outcomes of patients that received T-DM1. So a chemo-free regimen in the adjuvant setting.
The results are very interesting. 97% disease free survival at three years with only two distant relapses described with the use of T-DM1 which are exciting results. But on the negative side of this trial, this was commented a bit negative by the discussant here in San Antonio, we have to consider that more than 20% of patients discontinued the treatment due to toxicity, most of them, but also other reasons. Then, of course, there is the financial toxicity because T-DM1 given for a year to all women with this type of disease is much more costly than giving weekly paclitaxel plus trastuzumab.
So taking these two trials into the current available data in this setting we can say that so far in patients with tumours larger than 2cm or node positive disease standard treatment is a neoadjuvant approach with a taxane based chemotherapy and possibly dual anti-HER2 blockade, trastuzumab pertuzumab if available. Then in patients with pCR, pathologic complete response, at the time of surgery we continue the anti-HER2 treatment for a year with trastuzumab and maybe in high risk patients or patients at the time of diagnosis at high nodal burden and maybe the addition of pertuzumab could be helpful there. In patients not achieving pCR the standard treatment these days is T-DM1 given for a year.
In patients with stage 1 disease first surgery and then adjuvant treatment with weekly paclitaxel trastuzumab that remains the current standard of care. But these results for the T-DM1, these efforts in de-escalating, further de-escalating, the treatment in this setting are very interesting and maybe we have to wait for a longer follow-up to really consider this treatment as a potential option in this setting.
Updates in triple negative breast cancer
Moving to other types of diseases, more briefly on the triple negative as well as the hormone receptor positive. For triple negative disease I wanted to give two main information, the first is on the role of capecitabine. We had a big individual patient data meta-analysis presented to investigate the additional benefit of capecitabine on top of standard chemotherapy. The main message is that capecitabine may be of benefit for triple negative breast cancer patients.
Then there was a Chinese trial, a randomised trial, in the adjuvant setting with anthracycline taxane based chemo with or without capecitabine again showing a potential effect of this drug. So the results presented here at San Antonio further reinforced the potential need to use capecitabine in patients that do not achieve a pCR, triple negative breast cancer patients that do not achieve a pCR, at the time of surgery.
The second main topic discussed here in San Antonio is the role of immune therapy in triple negative disease. We had one trial in the advanced setting, two trials in the neoadjuvant setting. In the metastatic setting the message is that durvalumab as compared to standard chemotherapy as maintenance treatment in the overall breast cancer population appears not to be beneficial. However, if we look at the triple negative and the PD-L1 positive population we see some signals there but we need more data to consider this option as a potential standard one.
In the neoadjuvant setting we had two trials presented, the KEYNOTE-522, already presented at ESMO and updated here in San Antonio, that confirmed the benefit of adding pembrolizumab on the top of anthracycline taxane and carboplatin based chemotherapy. Then we had an Italian trial, the NeoTRIP study in which they investigated atezolizumab on top of taxane based chemotherapy and did not show any difference in pathologic complete response.
There was a very nice discussion of these two trials, how to explain the different results. One of the possible explanations is the fact that all the chemotherapy, so taxane, carboplatin and anthracycline was given neoadjuvantly with pembrolizumab in the KEYNOTE trial, while in the other trial the anthracycline part of the chemo was given after surgery. So the neoadjuvant treatment with taxane based and carboplatin chemotherapy plus immune therapy was shorter for the NeoTRIP trial.
Updates in hormone receptor positive breast cancer
A few more messages on the hormone receptor positive disease. For this disease we had first some important data from the Early Breast Cancer Trialists Cooperative Group – a large meta-analysis that tried to investigate if there has been any survival gain over the last few years for women with ER positive disease that receive five years of endocrine therapy. Indeed, the study showed that the prognosis of these women is improving with the treatment we are giving in the last two decades.
Then there were two important trials trying to compare chemotherapy to endocrine therapy plus CDK4/6 inhibition; one of these trials from the group of Aleix Prat in Barcelona, the CORALEEN trial in the neoadjuvant setting, letrozole plus ribociclib, and the other trial in the metastatic setting with exemestane plus palbociclib. The main message is that we cannot really say that this combination is superior to chemotherapy but there are interesting findings in both studies suggesting the efficacy of this combination that could be potentially compared to the efficacy of chemotherapy.
So overall this has been a really exciting San Antonio Breast Cancer Conference with many important data, particularly in the HER2 positive setting.