ESMO 2014-BREAST CANCER TRIALS

Gains in HER2-Negative Disease

Fabrice André, MD, PhD: I'm Dr Fabrice André, professor in the Department of Medical Oncology at Gustave Roussy in Villejuif, France. Welcome to this edition of Medscape Oncology Insights on breast cancer, coming to you from the 2014 Congress of the European Society for Medical Oncology (ESMO) in Madrid, Spain. Joining me today is Gunter von Minckwitz, managing director of the German Breast Group in Neu-Isenburg, Germany.

Today we are going to discuss several trials that have been presented during the ESMO conference. Let's start with those focusing on HER2-negative disease. Two different randomized trials were presented. What are your thoughts about the results of the IMELDA^[1] and TANIA^[2] trials?

Gunter von Minckwitz, MD, PhD: These trials addressed the question of what value bevacizumab might have in breast cancer. Over the past couple of years we have seen a series of negative results, especially in early breast cancer. Now two phase 3 studies are providing data in metastatic disease, with some quite interesting results.

In the IMELDA study^[1] patients started first-line treatment with docetaxel and bevacizumab. If they did not progress (we're talking about a type of maintenance therapy), they were randomly assigned to continue bevacizumab with or without capecitabine. In fact, the second-line chemotherapy was given before progression. Surprisingly, this concept was very effective. The progression-free survival (PFS) improved from 4.3 months in the bevacizumab alone arm to 11.9 months in the bevacizumab-capecitabine combination arm.

Dr André: Do you think it could change practice for patients with metastatic breast cancer? As far as I know, we don't have a report on the use of capecitabine in second-line treatment. What is your perspective on this concept of maintenance therapy plus bevacizumab in the field of breast cancer?

Dr von Minckwitz: Other studies have been conducted exploring maintenance treatment. The picture is a little bit heterogeneous, so there are trials that were negative, and another trial with gemcitabine and paclitaxel was positive.^[3] The hazard ratio in the IMELDA study was quite large [PFS (HR 0.38; P < .001; median 11.9 months bevacizumab-capecitabine vs 4.3 months bevacizumab); and overall survival, OS (HR 0.43; P < .001; median 39.0 months bevacizumab-capecitabine vs 23.7 months bevacizumab)].

It's either that the somewhat earlier use of capecitabine was of such importance (and I would question this) or it is this combination of the antibody with capecitabine. It was not only in the experimental arm that patients received capecitabine, but they received longer bevacizumab because they had such a good response to it. Therefore, the trial also compares somewhat longer use of bevacizumab vs stopping bevacizumab at a certain time.

Continued Bevacizumab May Extend PFS

Dr von Minckwitz: This nicely leads to the second study, TANIA,^[2] which was looking specifically for this concept of treatment through multiple lines. These were patients who received bevacizumab in first-line treatment and then progressed. They were randomly assigned to receive either two lines of monochemotherapy or two lines of monochemotherapy together with bevacizumab. We are reporting at this conference on the primary endpoint analysis on PFS, which showed that it was increased by 25% from 4 to 6 months when bevacizumab was given again. We still have to wait for the final outcome to understand what happens when bevacizumab is also given in third-line and what this means for OS.

Looking at the results of these trials, it appears that continued blocking of the vascular endothelial growth factor (VEGF) pathway might benefit the patient. That fits very well with results from preclinical models, as well as with results from colorectal cancer, for example.

Dr André: Until now, there was no strong evidence that bevacizumab improves OS. What you are suggesting in your analysis is that continuation of bevacizumab could improve PFS in metastatic breast cancer. Do you think there is room to perform a clinical trial testing bevacizumab during the whole evolution of disease compared with no bevacizumab, to show that this drug improves OS?

Dr von Minckwitz: When we designed the TANIA study, it wasn't considered ethical to prohibit patient crossover. We said that we have to define the second- and the third-line therapies. We considered that if postprogression survival is quite short (less than 1 year)—and probably this is the case for those patients entering fourth-line treatment—survivors can be better influenced by the pretreatment. That was probably a compromise, but the largest compromise of the TANIA study is that we did not use OS, but rather second-line progression, as the primary endpoint. The trial might not be powered enough to show what we would like to see.

Dr André: What is your perspective in this field of results, in terms of new combinations or new trial design?

Dr von Minckwitz: Taken together with our GBG26 study^[4] (treatment beyond progression with trastuzumab), where this antibody-derived cellular cytotoxicity (ADCC) concept was considered as a specific mode of action from an antibody, we might have to explore further how far this concept works—not only in trastuzumab, but also with other antibodies [including bevacizumab], and then use this as something to build on in further clinical research.

Extending the Cure Rate for HER2-Positive Disease

Dr André: We are going to move to the second part of this discussion that relates to HER2-positive breast cancer. We want to discuss two trials, CLEOPATRA^[5] and the ALTTO trial.^[6]

Dr von Minckwitz: The CLEOPATRA study^[5] was presented here with longer observation. These results finally led to the registration of pertuzumab in first-line treatment. The message to our patients is that there is a combination of docetaxel/trastuzumab/pertuzumab. The median OS has been 56.5 months, or almost 5 years, which is an incredible result. That shows that HER2-positive disease is much more favorable compared with other non-HER2-expressing subtypes. The study supports the development of this compound and leads to the ongoing adjuvant APHINITY study.^[7] We will see how far we can improve the cure rate in these patients.

The other study that was presented is an additional analysis of the ALTTO study. The ALTTO study was presented at ASCO^[8] and did not show significant results from the addition of lapatinib to trastuzumab. At this conference the results from lapatinib alone arm were presented. This was the arm that was stopped by the independent data monitoring committee very early, which was appropriate because the hazard ratio of this arm compared with the trastuzumab arm was 1.34. That means that these patients had a 34% higher risk for relapse and also for dying. This was found despite the fact that some of the patients were invited to receive trastuzumab later. The initial delay in receiving the more active compound could not be made up at the end. I'm quite happy, because I am a supporter of the neoadjuvant approach, that these results were very nicely predicted by the GeparQuinto study^[9] in which the lapatinib neoadjuvant arm was significantly worse than the trastuzumab-chemotherapy combination. We have quite a nice surrogacy here.

When we look at the whole set of trials that studied the trastuzumab-lapatinib combinations, there were positive trials, such as the neoALTTO,^[10-12] but there also were two or three negative trials. The trend that was observed in ALTTO, but could not be confirmed because of early analysis and other reasons, may have been very nicely predicted by the neoadjuvant studies. That is good news for the German breast groups because we are relying on this surrogacy.

Dr André: Do you have any other comment about this ESMO conference in breast cancer?

Dr von Minckwitz: It was a very nice conference with a good selection of oral presentations. We picked the four most important results, in my opinion.

Dr André: Thank you, Gunter. Thank you for joining us for Medscape Oncology Insights in breast cancer. This is Fabrice André, reporting from ESMO 2014 in Madrid.