Debu Tripathy, MD: I do think that some patients could get both of the additional therapies: pertuzumab at the time they’re getting trastuzumab and then, after they’ve completed their antibody, neratinib. I would reserve that for the high-risk patients, obviously. I think patients who have a lot of positive nodes, 4 or more nodes, would be candidates for that. I think having 1 to 3 nodes denotes a pretty high-risk group, as well, particularly if they’re accompanied by other high-risk features like a high-grade disease, large tumor size, or hormone receptor negativity. I think that the benefits are independent of each other. We don’t have clear data to say that we should only use neratinib when trastuzumab has been used without pertuzumab, since that was the study population. We don’t have any a priori biological reason to believe that the benefit you would get with neratinib is any different depending on what the patient has received.

It is true, though, that the degree of benefit, the absolute reduction in risk, is going to be smaller if you get more effective antibody therapy, so you have to factor that in. I just think that in someone who has really high-risk features like multiple positive nodes, you’re still left with residual risk. The key word here—or the key operational phrase, I should say—is residual risk. What is the residual risk that the patient has at that point in time that you’re making a treatment decision? At the time you’re making a pertuzumab decision, of course, their risk is just based on surgery or whether they’ve had neoadjuvant therapy or whether they have residual disease. You can make that decision. But even with pertuzumab, you can calculate, based on the APHINITY trial and hazard risk, what their residual risk might be. If it’s still in a range where you could impact it, then you could use additional neratinib. The formula you should use is where you take the hazard rate at 1 minus the hazard rate, and you multiply that by the residual risk. That’s going to be the absolute benefit that a patient might get. So you can numerically calculate this and present that to the patient.

Ruta D. Rao, MD: The role of neratinib for a patient who has completed a year of adjuvant trastuzumab and pertuzumab has not yet been studied. Based on the APHINITY trial, it seems that the patients who were hormone receptor—negative got the largest benefit. This was in contrast to the ExteNET trial in which the hormone receptor–positive patients seemed to benefit the greatest. Based on that, I think we can conclude from the data that we have that a patient who has a high risk of recurrence may receive an additional benefit from neratinib, even if they received adjuvant pertuzumab.

I would potentially consider giving both regimens in a patient who had locally advanced inflammatory breast cancer or a lot of positive nodes and who is also hormone receptor—positive. If one were to use all the possible adjuvant therapies we have, I believe that chemotherapy with the monoclonal antibodies, trastuzumab and pertuzumab, should be given in the neoadjuvant or adjuvant setting. Neratinib could be considered after the patient has completed their year of adjuvant monoclonal antibody therapy.

Transcript Edited for Clarity