SABCS Wrap-up: A Chemotherapy-Free Future for HER2-Positive Patients?

Kathy D. Miller, MD; José Baselga, MD, PhD; George W. Sledge, Jr., MD


December 17, 2010

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Kathy D. Miller, MD: Hello. I'm Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine in Indianapolis. This is the Medscape Oncology Wrap-Up of the 2010 San Antonio Breast Cancer Symposium. It's my pleasure to welcome 2 truly notable colleagues. First, Dr. José Baselga, Associate Director of the Massachusetts General Hospital Cancer Center, Chief of Hematology and Oncology, and Professor of Medicine at the Harvard Medical School in Boston, and Dr. George Sledge, Professor of Medicine at the Indiana University Simon Cancer Center in Indianapolis and the current President of ASCO® [American Society of Clinical Oncology]. Welcome to both of you.

George W. Sledge, Jr., MD: Thank you.

Dr. Miller: As the 2010 San Antonio Breast Cancer Meeting winds down, I'd like to talk to both of you about what you consider to be the highlights of this year's meeting. José, when you think about this year, what stands out for you?

José Baselga, MD: Kathy, it was a very prolific meeting. We had a lot of new information. To me, perhaps, the most important data have been the demonstration in the neoadjuvant trials that dual blockade of HER2 is quite active. The studies combining pertuzumab and trastuzumab, the NEOSPHERE [Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation] and then the Neo-ALTTO [Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation combining lapatinib and trastuzumab] showing a doubling of pathologic complete response (CR) rates -- so that's something that is truly novel and that I thought was exciting.

Perhaps the other important news is some negative data that are going to help us better choose our therapies. We had the AZURE Does Adjuvant Zoledronic acid redUce REcurrence in patients with high-risk localised breast cancer?] trial[1] that showed the lack of benefit of bisphosphonates in early disease in terms of preventing recurrence, so I think that was also an important piece of information.

AZURE Trial: Negative Results

Dr. Miller: George, let's take the AZURE trial in a little bit more detail. There had been a lot of enthusiasm after the results of the ABCSG-12 [Austrian Breast and Colorectal Cancer Study Group 12] trial that found improvement with the addition of zoledronic acid. A pretty narrowly defined group of patients: premenopausal; ER-positive; by and large not treated with chemotherapy. We were reminded by Martine Piccart-Gebhart's ASCO presentation that we needed the results of other trials in a wider group, and we've all been waiting for the results of the AZURE trial.

Dr. Sledge: Waiting, and waiting, and waiting, and now it's here.

Dr. Miller: Could have been still waiting, I understand.

Dr. Sledge: Yes. In fact, there was a redo of the statistics to allow this to be presented. This was an exceptionally large trial -- and a well-conducted trial -- that looked at the broad population of breast cancer patients, rather than the much more narrow premenopausal ER-positive population that had been looked at in the ABCSG trial. Now this trial, in terms of its primary endpoint, was a negative trial. I've always believed that you should, in general, judge trials by their primary endpoint.

There was a subset analysis looking at postmenopausal women suggesting (in contrast, curiously enough, to the ABCSG trial) a benefit in the postmenopausal women. Now whether that's a statistical artifact is difficult to say. But this is certainly not something that would excite one overall about the use of bisphosphonate therapy as an adjuvant therapy in breast cancer, although it may suggest that, as with other therapy, we need to be thinking of bisphosphonate therapy perhaps as a more targeted therapy for particular subgroups.

Dr. Miller: The numbers got pretty small, right?

Dr. Sledge: In a hurry.

Dr. Miller: When they looked at the subgroup most comparable to the ABCSG population, premenopausal patients with ER-positive disease didn't look encouraging.

Dr. Sledge: It did not. When you roll the dice twice, sometimes you get different results, just through the play of chance, but this is certainly the largest trial that we have to date. I think, as the largest trial, it probably deserves the greatest amount of respect of all the trials that we've seen to date.

Dr. Miller: What does this mean for the folks at home who are treating patients?

Dr. Sledge: It certainly suggests that the use of adjuvant bisphosphonate therapy is not the standard of care at this point. I think many of us, when the ABCSG trial came out, wondered whether we should be treating more women with bisphosphonates in the adjuvant setting. After this meeting you'd certainly have to say that it's not the standard of care.

Of course, we still have one large adjuvant bisphosphonate trial -- that of the NSABP -- that hopefully will be coming out sometime in the next few years and will further inform us in terms of whether bisphosphonate therapy is a benefit.

Neo-ALTTO Trial

Dr. Miller: Let's turn back to some of those neoadjuvant studies that you mentioned, José. This, in my mind, goes down as the San Antonio of adjuvant and neoadjuvant therapy. That's really where the biggest news came from. The ALTTO [Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation] trial is still going on. It's a huge effort of over 8000 patients. The Neo-ALTTO trial, though, may give us some hints or predictions of the ALTTO results. Tell us about the design of the Neo-ALTTO trial and what differences you saw.

Trial description

Dr. Baselga: The Neo-ALTTO[2] is a neoadjuvant trial that had 3 arms. This was for patients who were HER2-positive, who had tumors that were 2 cm or larger in diameter, and inflammatory disease was ruled out. These patients (450) were randomly assigned to 3 arms. One of them had lapatinib. The second arm had trastuzumab. The third arm had a combination of both lapatinib and trastuzumab. Therapy with anti-HER2 therapy alone was given for 6 weeks, and then at week 6, paclitaxel was added on a weekly basis for 12 additional weeks. Then at week 18, patients underwent surgery. After surgery, patients received 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy times 3, and then they continued on the same anti-HER2 therapy that they were on before for up to a year.

Results: dual blockade effective

What we presented was the initial component until surgery. The study's primary endpoint was pathologic CR rate. What we observed is that the pathologic CR (PCR) rate with the combination of lapatinib and trastuzumab was much larger than with either lapatinib or trastuzumab alone. The numbers are quite remarkable. We are talking about a 51% PCR rate, as compared to 29% with trastuzumab. Clearly, it's an indication that with this combination there is something there.

Now are these data going to be confirmed in the ALTTO trial? We don't know. But to me, it's an indication that this concept of dual blockade is, perhaps, what we should be focusing on in the near future.

Dr. Miller: I was impressed with Eric Winer's discussion in which he reminded us of the sobering fact that while patients who achieve a PCR do very well -- and that has been a very consistent finding -- it has not been as consistent in the neoadjuvant trials that an improvement in PCR always translates to a difference in disease-free and overall survival.

Dr. Baselga: I agree with Eric that you have to be careful when you interpret the PCR, but we have to realize Eric was referring to the B27 study, which is a very good study, but B27 was not HER2-positive. In all the HER2-positive trials to date -- I think the newer study that was cochaired by Luca Gianni and myself that we published this year in The Lancet is a good example -- in HER2-positive disease, PCR has always correlated with improvement in disease-free survival.

Is this an indication that we should start doing this tomorrow? Absolutely not. What this is an indication of is to get the ALTTO study finished. We are 200 patients away. The ALTTO study, which is the large adjuvant study, has enrolled over 8200 patients. We are only 200 patients short of starting that. But for the question that you're asking, I think in HER2-positive disease, PCR does correlate very well with disease-free survival

Dr. Miller: In a way the adjuvant and neoadjuvant settings are very complementary.

Dr. Baselga: Yes.

Dr. Miller: You will have much greater assurance of those disease-free and overall survivals with the strength of the numbers of the large adjuvant trial. But the neoadjuvant setting is a biomarker goldmine because you can get that information on everyone. That had to be one of the goals of the Neo-ALTTO trials.

Dr. Baselga: Absolutely, and it was designed with that intention. The intention of Neo-ALTTO was to be the translational research companion, if you wish, of ALTTO. I think that's the way clinical trials should be done in the future. Neo-ALTTO had mandatory tumor biopsies, brief therapy on week 2, and then at the time of surgery. In addition, we had a cohort of patients who underwent PET/CT scan because functional imaging is going to be very important. We also had a subgroup of patients in whom we analyzed circulating tumor cells. Altogether, what we have in our tumor bank today for the Neo-ALTTO study is 11,000 biological samples. More than 90% of all the desired samples are already in our bank, so that will be a tremendous resource to study translational endpoints.

The hope and the idea is that Neo-ALTTO will be like the engine of hypothesis where we will check potential mechanisms of resistance or sensitivity, and whatever we find in Neo-ALTTO, we will be able to translate into ALTTO. We cannot underestimate the potential strength of this type of approach in which you have companion neoadjuvant and adjuvant studies.


Dr. Miller: George, another major neoadjuvant study in this population of HER2-positive patients is the NEOSPHERE trial.[3]

Trial description

Dr. Miller: NEOSPHERE is similar in that it looked at a combined blockade of the pathway, although this time with trastuzumab and the antibody pertuzumab, but somewhat uniquely including an arm that didn't receive any chemotherapy -- just the dual blockade.

Dr. Sledge: Yes. And while the results in that arm were not quite as good as the combination with chemotherapy, they certainly suggested that a significant percentage of the population probably -- if we believe the PCR rates -- could get by without chemotherapy.

Consistency of HER2+ Trial Results

I agree with my colleague that these 3 presentations were the height of this meeting. What impressed me about all of these, first, is the consistency of the results. Sometimes, when you see 3 different presentations, one will say one thing and one will say another thing. They all pointed us in the same direction: that combination anti-HER2 therapy is something that is going to increase the PCR rate, and certainly, as one pointed out, it suggests that we're likely to see that in the adjuvant setting. They appear to increase the PCR almost regardless of which HER2 drugs we combine -- which I also find quite fascinating -- and suggests that we're probably going to have multiple tools.

A question I wanted to ask: Do the results of the Neo-ALTTO trial suggest to us that single-agent lapatinib is not something that we should be using in this setting?

Dr. Baselga: No, I don't think so. The differences in our study -- the Neo-ALTTO -- between the lapatinib arm and the trastuzumab arm were not statistically significant. They were very similar. But I think the era of questioning whether lapatinib is better than trastuzumab is over.

Dr. Baselga: I saw the lapatinib arm as a control arm that was required just to make sure that we could interpret the data, because if we did not have that arm, the interpretation of the study would have been very difficult. But now that we have these data, we just have to move on.

Future Therapies With Less Toxicity

Dr. Miller: It also begs looking at triplets in a HER2-positive group, whether it's with trastuzumab, pertuzumab, and lapatinib, substituting -- perhaps some would say -- a better trastuzumab with TDM1 and using trastuzumab, both to target the receptor and to deliver chemotherapy. So there are a lot of places and directions that this could go, and I expect that we're going to see several studies in the future.

Dr. Baselga: Kathy, in this direction, I want to point you to a phase 1 study with TDM1 and pertuzumab that was reported. A phenomenal response rate, although you cannot overrate it -- I think that it's in support of your proposal that maybe triplets or maybe combinations with hormonal therapy would also be indicated. One question that occurred to me, looking at the NEOSPHERE data, is that in the arm that had no chemotherapy, there were a proportion of patients who were ER-positive. Had they added an antihormone at the same time, based on the models of Kent Osborne and Rachel Schiff?

Dr. Sledge: Indeed. Do we need chemotherapy for everyone who's HER2-positive?

Dr. Miller: In the NEOSPHERE trial, although in aggregate, the no-chemotherapy-just-dual-antibody approach was inferior. Despite that, I was struck by the fact that between 10% and 20% of patients achieved a PCR with no chemotherapy whatsoever. So even if most patients may still need some traditional cytotoxic chemotherapy, if we could identify the subset, that would be phenomenally important for them.

Dr. Sledge: A question that's raised by these data concerns the adjuvant setting. Let's say that the ALTTO trial shows results similar to Neo-ALTTO - I'm certainly encouraged that it will do so. Trastuzumab got us to somewhere in the 80%-90% long-term, disease-free survival range. If we see a similar reduction in ALTTO as we've seen in Neo-ALTTO, then probably somewhere north of 90% of patients will be long-term, disease-free survivors in the HER2-positive population in the adjuvant setting. Where do we go from here? Because we're now talking about much, much larger trials to get much smaller benefits.

Dr. Miller: There actually is a model for that, though. It almost becomes testes cancer.

Dr. Baselga: Indeed.

Dr. Miller: If you look at the history of testes cancer trials, the early studies were looking at moving the bar in efficacy. Once efficacy was north of 90%-95%, then the goal of the clinical trials became how do we preserve that efficacy while minimizing exposure to therapy and exposure to the toxicities? I think we are -- perhaps with the results of ALTTO, if Neo-ALTTO really does properly foreshadow them -- potentially in that range where that will become every bit as much our goal.

Dr. Baselga: Yes. An essential part of this is in the same session that Neo-ALTTO and NEOSPHERE was presented: a German study, GeparQuinto. They had very intensive chemotherapy, followed by docetaxel with trastuzumab. The PCR rate was 50%, so it was identical to the response rate with nontoxic therapy with a combination of lapatinib and trastuzumab. This is to your point.

The next direction will be to develop therapies that are less toxic. We could start in HER2-positive disease. The direction that we are taking with HER2-positive disease is one with less toxic chemotherapy. Actually, I just wrote an editorial for Journal of Clinical Oncology that will be coming out. The title of that editorial talking about neoadjuvant HER2 therapies is "The Road to Chemotherapy-Free Therapy in HER2-Positive Disease." That's very exciting. I think that if we wisely use TDM1, pertuzumab, lapatinib, and hormone therapy down the line, we may get by with a very limited amount of chemotherapy.

Closing Remarks

Dr. Miller: That's a wonderful, forward-thinking, and optimistic way for us to end. Thank you for joining us, José, and thank you, George. Thanks to our listening audience for joining us for this edition of Medscape Oncology Insights. This is Dr. Kathy Miller at the 2010 San Antonio Breast Cancer Symposium in San Antonio.


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