Adrienne Waks, MD, on MARGOT/TBCRC052: Phase II Trial in HER2-Positive Breast Cancer

This was a trial for patients with stage II to III HER2-positive breast cancer who were being treated in the neoadjuvant setting. And in the trial, we were comparing two different regimens. We were comparing a regimen of paclitaxel, margetuximab, and pertuzumab, so that's the TMP regimen, versus a control arm of the THP regimen, which is paclitaxel, trastuzumab, and pertuzumab. So essentially, we're comparing three months of neoadjuvant treatment in two different regimens that are using different anti-HER2 antibodies, the margetuximab or the trastuzumab. And the primary goal of the trial, a primary objective, was at the end of the day to compare the PCR rates, the pathologic complete response rates, between the two arms. Our hypothesis going in and what we hoped to see was an improvement in PCR rate with the margetuximab. So backing up, the reason that we did this trial and the reason that we were interested in studying margetuximab here is that margetuximab is an anti-HER2 antibody. It's very similar to the standard antibody trastuzumab, but it was engineered very specifically with just five amino acids different from trastuzumab in a way that was biologically meant to basically improve the immune activity of the margetuximab antibody. So I always tell my patients, "Margetuximab is not an immunotherapy. It's an anti-HER2 antibody," but it was specifically designed to really build on the immune responses that you see with any antibody therapy like trastuzumab. So it's really an immunologically-optimized trastuzumab. And so what we hypothesized is that in the early stage patient setting, when patients are being treated in the neoadjuvant setting for a HER2-positive breast cancer, that they would have good anti-tumor immunity and maybe we could capitalize that by using the margetuximab in place of the trastuzumab. So we randomized about 170 patients in this trial and at the end of the day, what we found is that there was not a statistically significant difference between the two regimens in terms of their PCR rates. There was a numerical difference, so the PCR rate with the THP regimen was 46% and the PCR rate with the TMP regimen was 56%. So there was a 10% bump up if you used the margetuximab antibody, but that wasn't statistically significant within the design of the trial. When we looked in different subgroups to try to see if maybe we could find a subpopulation of patients who did benefit more or less from the margetuximab, interestingly among the hormone receptor positive and HER2-positive patients, there was a more substantial increase in PCR rate with the margetuximab. There was a 19% higher PCR rate with the margetuximab compared to the trastuzumab that trended towards statistical significance. But again, didn't meet statistical significance. So at the end of the day, this was a negative randomized phase II trial. We didn't show the superiority of the margetuximab over the trastuzumab. But again, we're definitely interested in the numerical increase that we saw, and we're absolutely planning to do a careful evaluation of the immune microenvironment for all of these patients, trying to understand if the patients who did have a better response to the margetuximab might've had something in the immune microenvironment of the tumor at the outset that led to that improvement, because that's something that we could potentially capitalize on in selecting those patients who are really most likely to benefit from the drug.