Can HER2-Positive Patients Go Chemotherapy Free?

Introduction

Kathy D. Miller, MD: Hello. I'm Dr. Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine in Indianapolis. This is Medscape Oncology Insights in Breast Cancer coming to you from the 2010 San Antonio Breast Cancer Symposium. Joining me today is Dr. Luca Gianni, Medical Director at the Istituto Tumori Milano in Milan, Italy. Welcome, Luca.

Luca Gianni, MD: Welcome.

The NeoSphere Trial

Dr. Miller: Today I'd like to talk to you about chemotherapy in the neoadjuvant setting, which was a really important topic at this year's meeting, and specifically the NeoSphere [Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation] study^[1]that you presented in San Antonio. First, can you remind our audience about the design of the NeoSphere study?

Trial description

Dr. Gianni: The NeoSphere study had a very simple goal. We aimed to rank different regimens that contained HER- directed therapies with or without chemotherapy in women with HER2-positive breast cancer. The goal was simply to provide insight as to whether there would be a winner among 4 different regimens consisting of the classical docetaxel and trastuzumab or docetaxel and trastuzumab with the addition of pertuzumab (another HER2-directed monoclonal antibody) and finally 2 monoclonal antibody and either trastuzumab or pertuzumab with docetaxel.

Dr. Miller: So you have the same chemotherapy in 3 of the arms, either trastuzumab, pertuzumab, or the combination.

Dr. Gianni: Yes.

Dr. Miller: And then an arm that I think some might have thought was a bit risky in the neoadjuvant setting, one that uses just the 2 monoclonal antibodies with no chemotherapy at all. What was the impetus for looking at that combination?

Dr. Gianni: The reason for looking at that combination came from evidence in laboratory and animal models suggesting that the combination of the 2 monoclonal antibodies could overcome the problem of resistance to each individual monoclonal antibody, as well as to provide evidence for synergistic activity. On that basis, plus evidence coming from the study of women with metastatic breast cancer and HER2-positive disease who had already received trastuzumab as last therapy without success who had indeed benefited from the addition of pertuzumab to trastuzumab without any chemotherapy. These 2 elements provided us with the insight that 2 antibodies could work very well, also at an earlier stage of the disease.

If I could comment on the risk associated with this, it's relative, because the trial design stopped at time of surgery, after 4 cycles but after surgery all patients went on with a combination of treatment that provided the best possible therapy to all of them so that if something was less than optimal in the neoadjuvant setting, they didn't miss the opportunity of receiving the best treatment.

Results

Dr. Miller: So you had pathologic complete response as the primary endpoint to evaluate these 4 different options. What did you see? Were there differences?

Dr. Gianni: They were very interesting differences. For instance, the combination of trastuzumab and percizumab with docetaxel afforded a great pathologic compete response of 46% to 47%, which is very encouraging for 2 reasons. The first is that it is one of the highest that has been reported so far including the field of HER2-positive breast cancer, and the second is that it was obtained in spite of a relatively short duration of exposure to HER2-directed therapies. The other important aspect is that this was statistically significantly superior to the activity of the conventional docetaxel and trastuzumab. Pertuzumab when combined with docetaxel was still good providing a 24% pathological complete response rate and the combination of the 2 monoclonal antibodies alone without the addition of any chemotherapy still afforded a 17% pathologic complete response [pCR] rate.

pCR achieved without chemotherapy

Dr. Miller: In hearing people discussing the results after your presentation I was fascinated that there were some folks who found the dual antibody combination to be a bit disappointing and suggested that most patients probably still need some cytotoxic chemotherapy. I looked at it differently, though, that although most do, you identified a subset of patients who achieve a pCR without chemotherapy. If we could identify who those women are before giving them all chemotherapy, that could be a big advance for them.

Dr. Gianni: Thank you for pointing this out, and if I can elaborate further I'm not only agreeing with your view but I would also like to stress one aspect of the trial. The trial was aiming at just ranking the regimens; we were not trying to exploit each individual regimen to its best and optimal result. When we consider neoadjuvant therapy we are linked to the concept that we want rapid shrinkage similar to what we expect from chemotherapy. My perception is that when you use 2 monoclonal antibodies to modulate and target a receptor, you will have a different timeframe in front of you, and indeed, this is what appears to be the case with pertuzumab and traztuzimab in women with metastatic breast cancer. There were a few patients who achieved an almost immediate shrinkage of the tumor but there were several if not the majority of patients whose tumors didn't start to shrink until 4 or 5 or 6 months. We should design a trial in a different way to address the question of the full potential value of combining monoclonal antibodies without chemotherapy.

Dr. Miller: This sounds a bit analogous to neoadjuvant hormone therapy in those patients with hormone-sensitive tumors where getting the maximum response frequently takes longer than 3 or 4 months and you may not achieve that maximum response for 6 or 9 months because the tumors continue to slowly shrink.

Dr. Gianni: That is exactly the right parallel with 1 additional point, that in the case of hormonal neoadjuvant therapy usually you don't observe pCR, whereas we observed 17% pCR with the 2 monoclonal antibodies after just the 4 cycles.

Dr. Miller: That was actually one of the questions you were asked after your presentation which is, a real proportion of your patients were also hormonal receptor positive and perhaps the results could have looked even better particularly in the group that didn't get chemotherapy if you had also concurrently inhibited the estrogen receptor.

Dr. Gianni: This is I think a very important line of clinical research for the future. What is emerging clearly is a scenario whereby in the subgroup of women with HER2-positive breast cancer, the estrogen and progesterone receptor does matter, and we should start to look at the 2 subsets of hormone-receptor positive and hormone-receptor negative patients separately in the HER2-positive subset.

Dr. Miller: So the NeoSphere [study] was really a tour de force and will continue to yield results from all over the correlative samples.

Future Areas of Study

Dr. Miller: I'm wondering where you're headed next in this population.

Dr. Gianni: I think that there are 2 main problems. One is to consider whether the 2 monoclonal antibodies could be combined with a tyrosine kinase inhibitor (TKI) to see whether dual inhibition by tumor monoclonals and TKI can afford an even better control of the disease. The other problem is to expand on the topic that I just mentioned and focus on the expected differences between hormone- receptor positive and hormone-receptor negative patients, which can provide better insight into the possibility of modulating the tumor growth. Finally, which is to me the most important aspect, is whether the results in the new adjuvant setting translate to similar results in the adjuvant setting and so that we do not any longer need to conduct thousands of patient trials in the future but we can derive adequate information. To do that we could explore the tumor bank and the biobank that we have collected but we could also explore what the different design is in the future.

Closing Remarks

Dr. Miller: Thank you, Luca, for coming in today, and thanks to our audience for joining us for this edition of Medscape Oncology Insights. This is Dr. Kathy Miler at the 2010 San Antonio Breast Cancer Meeting in San Antonio.

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