Ian E. Krop, MD, PhD: There are a number of very promising new agents being developed for HER2-[human epidermal growth hormone receptor 2]—positive metastatic breast cancer, several of which have recent data with strong efficacy profiles. Trastuzumab deruxtecan is 1 of those, but at the San Antonio Breast Cancer Symposium in 2019, we also heard about 2 additional agents. One is tucatinib. This is a tyrosine kinase inhibitor that inhibits HER2. It’s different from other kinase inhibitors that we’ve been using, including lapatinib and neratinib, both of which block not only HER2 but also other HER family members, such as EGFR. By doing that they cause toxicities related to EGFR inhibition, mainly diarrhea and rash.

Tucatinib is different because it blocks only HER2. It has substantially less diarrhea and rash compared with these other drugs. It was recently tested in a study called HER2CLIMB, which enrolled patients with HER2-positive advanced breast cancer that previously progressed on not only trastuzumab and pertuzumab but also T-DM1 [trastuzumab emtansine]. In this study, patients were randomized to capecitabine and trastuzumab with either tucatinib or placebo.

What was interesting about this trial was that it also allowed patients who not only had treated brain metastases but also progressive brain metastases. This is probably the first large phase III trial that allowed patients with not just treated brain metastases but also progressive brain metastases, and the reason it did that is because tucatinib crosses a blood-brain barrier quite well. So it was hoped that tucatinib would be able to prevent the progression of brain metastases. And that was seen very well in the data that were presented at San Antonio, that the addition of tucatinib to trastuzumab and capecitabine led to a very impressive improvement in progression-free survival with a hazard ratio of 0.54, and interestingly, a substantial improvement in overall survival as well.

They also looked at the patients who had brain metastases at baseline, and the benefit in terms of progression-free survival was very impressive with a hazard ratio of 0.48. So this is a drug that clearly has substantial benefit not only in the overall population of HER2-positive pretreated metastatic disease, but also in patients who have brain metastases, which is a common problem in HER2-positive disease. I think this is a drug that looks very promising. And I should point out that the toxicity profile was, as expected, quite manageable. There was a modest increase in diarrhea, but otherwise the toxicities were pretty similar to what was seen with capecitabine-trastuzumab control arm. So there was a big benefit in terms of efficacy, and it’s certainly a manageable increase in toxicity. I think this is a very promising drug for a patient.

We also heard about a study of margetuximab, which is another interesting molecule. This is essentially the trastuzumab monoclonal antibody with the Fc portion, which is a constant region of the antibody, modified so that it binds to Fc receptors better. And this is important because it’s the binding of trastuzumab to Fc receptors that lead to the immune effects of trastuzumab, both through this phenomenon called ADCC, or antibody-dependent cellular cytotoxicity, and perhaps other immune effectors.

Margetuximab was designed to increase the immune effects of trastuzumab, particularly in those patients who have a genetic Fc receptor polymorphism that leaves it to be less effective. And this is actually common in about 85% of patients. The hope was that margetuximab would work better than trastuzumab, but particularly in those patients who have these low-affinity Fc receptors.

The trial, which was called the SOPHIA trial, randomized patients with HER2-positive metastatic disease that had been pretreated to either physician’s-choice chemotherapy with trastuzumab or chemotherapy of physician’s choice with this new antibody, margetuximab. And it did show a modest but statistically significant improvement in progression-free survival. Overall survival was immature when the data were presented at the ASCO [American Society of Clinical Oncology] meeting.

At San Antonio, we had updated data, which showed a modest statistically significant improvement in progression-free survival, and overall survival remains immature. But there is at least a slight trend toward improvement in overall survival of about 4 months that is not statistically significant, but perhaps is even more noticeable in those patients who had these low-affinity Fc receptors. So that fits with the anticipated mechanism of action of margetuximab, that it may work better in those patients with these low-affinity Fc receptors, which make up roughly 85% of the patient population.

Switching to margetuximab really doesn’t have much difference in terms of toxicity profile, with the 1 exception compared with trastuzumab that there are more infusion reactions, but they tended to be mild. So I think this is a very interesting drug with a novel of mechanism of action, and we’re awaiting further data from this trial, particularly to see if the survival benefit becomes more distinct and whether there is a clear difference between the 2 genotypes of Fc receptors, to say that we should be using the drug in only those patients with low-affinity receptors or in all patients.

Transcript Edited for Clarity