Review of the ExteNET Trial and the TRAIN-2 Trial

Experts in the field of breast cancer management review the data from the ExteNET and TRAIN-2 Trials.

Jacob Kettle, PharmD, BCOP: Another drug I want to cover, moving out of the IV [intravenous] space and into the oral spaces, is neratinib. These data were released a few years ago, so it’s been on the market for a while. This will be an oral HER2 [human epidermal growth factor receptor 2] inhibitor continued for a year after completing chemotherapy and trastuzumab. Their results are fairly similar to pertuzumab and chemotherapy with trastuzumab, showing a 5-year invasive disease-free survival of 90.2% versus 87.7%; that’s about a 3% window of difference. Where does this drug fit in your treatment algorithm?

Allison Butts, PharmD, BCOP: The ExteNET trial will talk about looking at extended anti-HER2 therapy with a year of neratinib following a year of adjuvant trastuzumab.

Just like the APHINITY trial, with such modest results, patient selection is key. Looking at the data in the adjuvant setting, the benefit you mentioned was largely confined to patients who are triple positive or hormone receptor positive and HER2-positive patients. That’s an important consideration when you’re looking at whether you should or shouldn’t you include this. Another factor to consider here is its toxicity. Neratinib causes some significant diarrhea for our 1 patient. Full disclosure, we at the University of Kentucky have used this only once. The patient’s diarrhea with neratinib was far more significant compared with pertuzumab, for which it is also a pretty major toxicity.

You need to find a patient who is likely to benefit but also able to tolerate the diarrhea and what that means for their quality of life. Again, this trial brings about unanswered questions just like the APHINITY trial did. These patients were enrolled from 2009 to 2011, so the landscape of HER2-positive breast cancer has changed dramatically in that time. How does this play in with how we currently practice? Pertuzumab didn’t exist then in the neoadjuvant or adjuvant space.

Does neratinib provide any benefit at all in patients who were already treated with pertuzumab, or is the benefit of additional therapy already tapped out with the addition of that drug? The KATHERINE data were not out during that time period as well. If a patient gets adjuvant ado-trastuzumab emtansine, are they tapped out? Do you get anything from neratinib or not? Those trials just haven’t been done, so it’s difficult to find a solid place in therapy for neratinib at this time.

Jacob Kettle, PharmD, BCOP: In addition to these new molecules we’re talking about, can we replace a HER2 target with another HER2 target? Can we add a HER2 drug and make things better? I want to talk about the TRAIN-2 trial, where there’s a different scope. Can we exploit these biomarker therapies to allow us to subtract therapy? The TRAIN-2 trial looked at combination HER2 therapy, in this case trastuzumab and pertuzumab, and compared 2 groups of patients: 1 that did and another that didn’t get anthracyclines. Their overall results were that there didn’t seem to be an additional benefit by adding the anthracycline in these patients. I’m curious: what are your thoughts, Allison, on the TRAIN-2 trial and what that means for practice, particularly in the United States?

Allison Butts, PharmD, BCOP: This is a trial I was excited about coming out because we’ve been toying with this question for a while. Do anthracyclines retain their benefit in the setting of dual anti-HER2 therapy? It’s important to recognize that this trial was completed in Europe, so the regimens they use were slightly different than we’re used to seeing. They used FEC [fluorouracil, epirubicin hydrochloride, cyclophosphamide] followed by a taxane and carboplatin or the paclitaxel-carboplatin regimen, of course, with the dual anti-HER2 therapies. But here in the United States, we see more of the AC [doxorubicin-cyclophosphamide] followed by taxane with H and P [trastuzumab-pertuzumab] or the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimens.

It is important to keep in mind that there is still a window of opportunity to look at this data in the United States and how it applies to our standard-of-care regimens. Regardless, it is key that this study did come out and show that there was no improvement in any of the outcomes studies when an anthracycline was included in the regimen. As we know, anthracyclines carry the risk of long-term cardio toxicity and secondary malignancies. There is a lot of motivation to try to justify getting rid of that anthracycline chemotherapy if we can.

The other point that we need to make rather than taking these results completely to heart is trying to figure out who benefits. There are patients who would benefit from anthracyclines, perhaps patients who have a borderline HER2 FISH [fluorescence in situ hybridization] ratio or patients who have a significant amount of positive lymph nodes. They’re young.

There might be a niche there for the anthracycline-containing regimen with dual anti-HER2 if we could find the right patients. All in all though, it justifies the current standard of care in the United States, which tends to be doing the docetaxel carboplatin with HP [trastuzumab, pertuzumab], rather than an anthracycline-inclusive regimen.

Jacob Kettle, PharmD, BCOP: That’s a good way to look at it. Does the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab]—type regimen tend to be the most commonly used in the United States? If nothing else, the takeaway from this trial supports that as a reasonable approach, but I’m with you: We’re probably never going to reach the point where we can totally eliminate the potential need for anthracyclines.

There aren’t enough patients to tease out every little minute high-risk feature to totally rule out that there may not be some gain from that anthracycline. For some patients, as you said, those who are high-risk, maybe those who may be younger, if you can just increase percent survival by some, it’s worth the risk for that particular patient.