Which Chemotherapy With Adjuvant Trastuzumab and Pertuzumab?
Insights From: Debu Tripathy, MD, University of Texas MD Anderson Cancer Center; Ruta D. Rao, MD, Rush University Medical Center
Debu Tripathy, MD: I typically treat patients with HER2-positive breast cancers in the neoadjuvant setting because I get that additional benefit of knowing whether the patient has had a pathologic response or not, which could influence therapy. We’re not quite at the point where we would routinely use it, but it does give us more information. Now, there is an important exception to that. For patients who have a low-stage disease like stage I, we still have an excellent outcome from a less intense therapy, which is weekly paclitaxel post trastuzumab [Herceptin] given with paclitaxel, completed for a full year of adjuvant therapy. We have data from an uncontrolled study that the recurrence rate is very low. It’s in the 1% to 2% range or even lower for lower-stage disease, for stage I disease even up to 3 cm with negative nodes. So if you have someone who is clinically stage I, it’s probably better to proceed with surgery first. Remember, some patients may get upstaged—they may have positive nodes that weren’t expected—but if they end up still being stage I, then they may be a candidate for less intensive therapy.
This gets to the second question: What are the additional toxicities of more intensive therapy? If you just get weekly paclitaxel and trastuzumab, you avoid some of the toxicities associated with docetaxel and with platinum agents such as the docetaxel/carboplatin regimen, or, if you were initially going to use an anthracycline, you avoid the toxicities of an anthracycline, the additional risk of cardiotoxicity, and even a small risk of leukemia. I am typically using non-anthracycline therapy for my patients. If they’re going to get pertuzumab, the factors I consider there in terms of the toxicities that are asked about would include things like diarrhea. I think that’s the most important toxicity that people get. As I mentioned, there may be a slightly higher risk of infection and fatigue, so I balance that against the benefits that patients might see.
How long do you use pertuzumab is a very interesting question because when pertuzumab received conditional approval on the basis of neoadjuvant data that it improved the complete pathologic response rate, it was approved only in combination with chemotherapy. That’s how we mostly use that drug, based on the FDA approval. When it recently received an indication for full maintenance therapy, we switched to that because that is now the FDA-approved method. Now, we don’t have a formal comparison about using pertuzumab only with a chemotherapy versus the full maintenance. The APHINITY study was all or nothing. You either got trastuzumab during both the chemotherapy and maintenance settings or you got pertuzumab for both. We don’t really have a way to answer that question. I feel that if you’re using pertuzumab, you probably should just use it the whole time unless you’re having extraordinary toxicities or notable toxicities. For some people, most of the diarrhea that they get with the regimen is during the time of chemotherapy. But there are some patients, maybe 5% to 10% of patients, who will have significant diarrhea just with the antibody alone. At that point, you could decide to stop early.
But the cost issues are something important too. It’s hard for us as physicians to factor cost in because many of our patients have coverage. They have variable degrees of coverage. Sometimes it’s very hard for us to know how we’re impacting the patient, and the patient actually wants to get the best therapy there is. Even though I think we all have to be conscious of the cost issue, it’s difficult to apply in individual patient care. But I think this is more of a societal question that we all have to ask when we’re looking at benefits compared with cost. This comes into play with any of our biological therapies, including pertuzumab and neratinib.
Ruta D. Rao, MD: There are 2 very well-established chemotherapy regimens used in the HER2-positive setting. The first is Adriamycin [doxorubicin] and Cytoxan [cyclophosphamide] followed by a taxane, with trastuzumab and pertuzumab given during the taxane portion of that regimen. The second is a non-anthracycline–based regimen with Taxotere [docetaxel anhydrous], carboplatin, and trastuzumab, to which pertuzumab could also be added.
My preference between the chemotherapy regimens is to use the non-anthracycline–based TCHP [Taxotere/carboplatin/Herceptin/pertuzumab] regimen. This is based on the 10-year follow-up of the BCIRG-006 trial, which Dr Slamon presented. There were no statistically significant differences in this trial between the anthracycline/trastuzumab arm and the non-anthracycline/trastuzumab arm. When the number of events were analyzed, there were only 10 disease-free survival events that were greater in the non-anthracycline arm, but again, this was not statistically significant.
My choice for the non-anthracycline–containing regimen is actually more based on the toxicity. When you look at the toxicities in that trial, there were more cardiac events and more treatment-related leukemias in patients who received anthracycline. So I believe that if we can provide the similar efficacy between the 2 arms and avoid some of the long-term toxicity, that’s the regimen that’s the best for the patient. Either one of these regimens—the AC [Adriamycin/cyclophosphamide] regimen followed by taxane with trastuzumab or the TCH [Taxotere/carboplatin/Herceptin] regimen—can be used in the neoadjuvant setting with pertuzumab.
One of the main toxicities seen from the addition of pertuzumab to chemotherapy/trastuzumab regimen was diarrhea. There was an increased rate of diarrhea, close to 10%. This was during the time that patients received chemotherapy along with trastuzumab and pertuzumab. When the chemotherapy was completed and they were on dual-antibody therapy, the rate of diarrhea was less than 1%.
The APHINITY trial, which is the first one to look at the addition of adjuvant pertuzumab to our current backbone of chemotherapy and trastuzumab, looked at a time of 1 year. At this point, I don’t see any data telling us that using less than a year of pertuzumab would give us a similar benefit.