The phase II MARGOT TBCRC052 trial investigated the efficacy of margetuximab in combination with paclitaxel and pertuzumab (TMP) versus trastuzumab with paclitaxel and pertuzumab (THP) as neoadjuvant therapy for stage II-III HER2-positive breast cancer. While the margetuximab regimen demonstrated a numerical increase in pathologic complete response (pCR) rates, it did not reach statistical significance compared to the trastuzumab regimen.
The rationale behind evaluating margetuximab stems from its unique engineering. Margetuximab is an anti-HER2 antibody similar to trastuzumab but modified with five amino acid differences to enhance immune activity. As Dr. Adrienne Waks explained, "Margetuximab is not an immunotherapy... 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."
The trial randomized approximately 170 patients to receive either TMP or THP for three months in the neoadjuvant setting. The primary endpoint was the comparison of pCR rates between the two arms. The results indicated a pCR rate of 46% with THP and 56% with TMP, representing a 10% increase with margetuximab. However, this difference did not achieve statistical significance within the trial's design.
Subgroup analysis revealed a more pronounced difference in hormone receptor-positive, HER2-positive patients. In this subgroup, the TMP regimen yielded a 19% higher pCR rate compared to THP, although this also did not reach statistical significance.
Despite the negative outcome of the phase II trial, researchers are planning further investigation into the tumor immune microenvironment of the patients. The goal is to identify potential factors that may have contributed to the improved response observed with margetuximab in certain individuals. "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."
