Breast cancer highlights from ESMO 2019

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Published: 2 Oct 2019
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Dr Matteo Lambertini - San Martino Hospital, Genoa, Italy

Dr Mateo Lambertini speaks with ecancer at ESMO 2019 in Barcelona about the conference highlights in breast cancer research.

The studies he refers to are: 

TAILORx

MONARCH-2: Watch the press conference here, our interview with Prof George Sledge here and Prof Nadia Harbeck's comment here.

MONALEESA-3: Watch the press conference here, our interview with Prof Dennis Salmon here and Prof Nadia Harbeck's comment here.

KEYNOTE-522: Watch the press conference here, our interview with Prof Peter Schmid here and Prof Guiseppe Curigliano's comment here.

KEYNOTE-119

BROCADE-3: Watch our interview with Dr Véronique Diéras here.

KATHERINE: Watch our interview with Prof Michael Untch here

monarcHER 

KATE2

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

This ESMO 2019 has been a very exciting conference for the breast cancer field to improve the management of our patients. We had important news in all the three major subtypes of breast cancer – luminal, triple negative and HER2 positive disease. I will start with the luminal breast cancer, first with the early setting and then moving to the metastatic setting.

In the early setting the presentation I wanted to highlight is the TAILORx data in the 26-100 recurrent score population. The TAILORx is a well-known trial because we have had already three publications in The New England for patients with hormone receptor positive, HER2 negative, node negative breast cancer. Those with a low recurrence score received endocrine therapy alone, this was the first publication, very good outcomes without the need of chemotherapy. Then we had two publications in the intermediate risk score, so patients with a recurrent score between 11-25 in which chemotherapy is overall not needed with some patients, with premenopausal patients with a higher recurrence score that may benefit from the addition of chemotherapy. But we were still missing the high recurrence score, so patients with a recurrence score by Oncotype DX, the 21 gene expression profile, between 26 and 100. Today Dr Sparano presented the results for this cohort of patients. These patients received, almost all of them, chemotherapy followed by endocrine therapy. So this is a node negative population but a high risk biologically population because of their high recurrence score by the 21 gene assay. The results are quite important because Dr Sparano showed that the distant relapse free interval was more than 93% in the overall population, so despite having a biologically aggressive form of the disease the overall outcomes of these patients receiving standard chemo and endocrine therapy are quite good, so more than 93%, with an invasive disease free survival of around 87%.

Then the authors presented an exploratory analysis based on the type of chemotherapy that the patients received. Most of them received taxane-based chemotherapy with some patients that received also anthracyclines and a few patients that received non-anthracycline, non-taxane based chemotherapy. The message from the exploratory analysis is that taxane based chemotherapy is probably enough in this node negative but high recurrence score population, although of course this is an exploratory analysis within the main trial. So if we really need to add anthracycline chemotherapy to the taxane component in these patients remains a question mark but potentially we may avoid the use of anthracyclines for some selected patients in this setting.

In the advanced setting we had probably the most important results presented here at ESMO which are the overall survival data from two phase III randomised trials for patients with hormone receptor positive, HER2 negative advanced disease. These are the MONARCH-2 and the MONALEESA-3 trials results. MONARCH-2 was a phase III trial in patients with endocrine resistant disease that were randomised to receive fulvestrant alone with or without the CDK4/6 inhibitor abemaciclib. The MONALEESA-3 was, again, similar design – randomisation between fulvestrant alone and fulvestrant plus the other CDK4/6 inhibitor ribociclib with the main difference between the two trials that in the MONALEESA-3 there was both an endocrine resistant as well as endocrine sensitive population. The main message from these trials, both of them are positive in terms of overall survival so significantly better overall survival for patients receiving a CDK4/6 inhibitor in both the endocrine sensitive and endocrine resistant disease. In terms of absolute numbers in the MONARCH-2 trial 9 months improvement in overall survival which is a very exciting result. We still don’t know in terms of absolute numbers the benefit in the MONALEESA-3 trial which is also in first line setting in which the median survival for the experimental arm has not been reached yet. A hazard ratio of 0.75 and 0.72 in both trials so very, very important results. What we have to address in the coming future in this population is how to sequence the treatment we have and particularly how to decide which is the best endocrine therapy for these women to combine with CDK4/6 inhibitors. So should we start with fulvestrant, is it okay to start with AI plus CDK4/6 inhibitor? This is something that we need to digest more the data to understand how to best sequence this treatment.

Moving to the triple negative field, again very important data particularly in the early setting where we had the presentation of the phase III KEYNOTE-522 trial. In this trial patients received standard chemotherapy, paclitaxel carboplatin, followed by anthracycline cyclophosphamide based chemo. Patients were randomised to receive placebo or immune therapy with pembrolizumab given for the six months duration of neoadjuvant chemotherapy and then continued for six months in the adjuvant setting. The study met its primary endpoint showing a statistically significant improvement in the pathologic complete response in terms of absolute numbers from 51% up to almost 65%, so 14% absolute improvement in pCR. We know how important pCR is for triple negative patients. In terms of outcomes and in terms of event free survival the results are not mature yet because we had the presentation of the data up to 18 months. However, there is some signal not significant so far so we have to wait to really see a potential benefit in terms of survival is what we need to see and we want to see. But there is an interesting 6% absolute difference between the two treatment arms at 18 months so we need a longer follow-up in this setting.

In the metastatic setting we had the presentation of another phase III trial related to the field of immune therapy but unfortunately this study was overall a negative one. This was the KEYNOTE-119 trial, randomisation between single agent chemotherapy versus pembrolizumab alone as single agent. So the study was negative so no difference in survival outcomes between the two treatment arms with some signal of more activity for single agent immune therapy for the PD-L1 positive women but overall this was a negative study.

In the metastatic setting in the plenary session we had also a presentation of the study named the BROCADE-3 study. This was not only actually in triple negative because half of the population were hormone receptor positive but I believe that these results would apply mostly to the triple negative population. So this was a trial in the metastatic setting for patients with a germline BRCA mutation, again both ER positive or ER negative disease. The randomisation was between a chemotherapy combination of carboplatin and paclitaxel with or without the addition of veliparib, the PARP inhibitor veliparib. The study met its primary endpoint, so showed a significant improvement in progression free survival although in terms of absolute numbers this improvement was not that big in the sense that it was only two months improvement in progression free survival but the study met its primary endpoint from a statistical point of view with a hazard ratio of around 0.70. However, before probably moving this triple regimen to the clinical practice again we need to digest more the data and see also the final publication of this trial.

In the HER2 positive disease it’s probably where we have not really seen major news in the field or major positive news in the field. We had in the early setting the presentation of an exploratory analysis of the KATHERINE trial, so the trial that showed that TDM-1 in the post-neoadjuvant setting is better, is significantly better, as compared to trastuzumab alone. So this led to the approval of TDM-1 in the US for these patients, so patients with residual disease after neoadjuvant chemotherapy plus anti-HER2 therapy. Here at ESMO we had the presentation related mostly to the management of patients with CNS recurrence because in the original publication the authors observed that patients in the TDM-1 arm, even though overall the rate of distant recurrence was much lower as compared to the trastuzumab arm, more patients developed CNS recurrence as a first disease free survival event. So here at ESMO the authors showed that the time to development of CNS was longer in the TDM-1 as compared to the trastuzumab alone arm and, most importantly, that the overall survival of the patients that received TDM1 or trastuzumab was the same, meaning that the use of TDM-1 did not have any negative effect on the survival of patients that then developed brain metastases. The authors were speculating on the fact that the higher incidence of CNS events in this patient population may be related to a competing risk. So to the fact that these women have a longer time to develop a distant relapse and so this is why they are potentially at high risk of distant recurrence.

In the advanced setting we had probably the most interesting trial presented was the monarcHER trial in which patients with hormone receptor positive, HER2 positive advanced disease were randomised to receive standard treatment, chemotherapy plus trastuzumab, they were pre-treated patients with advanced HER2 positive disease. So standard treatment, chemotherapy plus trastuzumab, it’s a phase II trial, so they were randomised to this chemo plus trastuzumab standard arm or endocrine therapy – fulvestrant plus abemaciclib and trastuzumab and this was the main comparison. Then the third arm with the use of trastuzumab and abemaciclib without the use of endocrine therapy. The trial is only a phase II trial but the results are very interesting and promising in the sense that the use of this triple combination, endocrine therapy and two targeted agents, was significantly better in terms of progression free survival as compared to the standard treatment in this heavily pre-treated population which is chemotherapy plus trastuzumab. So very interesting results to potentially not only improve the outcomes of these patients with hormone receptor positive HER2 positive disease but also potentially postpone the use of chemotherapy in this later line of therapy.

Finally, we had also the presentation of another phase II randomised trial in which the authors randomised patients to receive TDM-1 alone or with the addition of atezolizumab, the PD-L1 inhibitor. This was overall a negative trial so no significant difference between the two treatment arms. We saw some signal of activity in the PD-L1 positive cohort.