Clinical Cases in HER2+ Breast Cancer - Episode 17

Case 2: Novel Agents in Late-Stage Clinical Trials for HER2+ MBC

September 11, 2020
Targeted Oncology

Ruta Rao, MD: Dr Tolaney, can you comment on any other novel agents that are being investigated in late-stage clinical trials for our HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer patients, including anything presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2020?

Sara Tolaney, MD, MPH: We’ve touched upon several approvals that we’ve seen this year for HER2-positive metastatic disease, including trastuzumab deruxtecan as well as the HER2CLIMB trial regimen, and we also have approval for capecitabine-neratinib. In terms of other novel HER2-directed therapies, there is an agent called margetuximab, which is a novel monoclonal antibody against HER2 that has an engineered Fc receptor, so it increases binding to CD16A to increase antibody-dependent cellular cytotoxicity. This agent was studied in the SOPHIA trial. This was a randomized phase 3 study for patients who had progressed on 2 prior anti-HER2 therapies, including pertuzumab, and patients were randomized to receive chemotherapy with margetuximab or chemotherapy with trastuzumab. Initially, we had seen data in which there was a modest improvement in progression-free survival [PFS], and the updated PFS data suggest only a 1.3-month difference between the 2 arms, favoring margetuximab. We then saw the second interim analysis for overall survival [OS] at San Antonio [Breast Cancer Symposium] in 2019, which did not find a statistically significant improvement in OS but rather a little under a 2-month difference in survival between the 2 arms.

What was interesting about this agent is that the survival benefit seemed to be dependent on the genotype status. If a patient had a CD16A-F allele, they had about a 4-month improvement in overall survival with margetuximab, although it was not statistically significant. If you looked at those patients who had the V allele, which is a small population with only about 14% of patients, the trend was reversed. Trastuzumab seemed to perform better than margetuximab in the V allele population. This agent is under FDA review, so we’ll have to see if it leads to an approval for margetuximab as an alternative to trastuzumab with chemotherapy in the third-line setting and beyond and whether that approval could be genotype specific. We don’t know that at this point, but it certainly appears to be a promising agent, so hopefully there will be more to come with it.

In terms of other agents in this space, there is a lot of interest in thinking about immunotherapy for HER2-positive disease. We’ve seen some data from the KATE2 trial for T-DM1 [trastuzumab emtansine] plus or minus atezolizumab, suggesting a trend toward survival benefit in the PD-L1–positive subgroup of this study for the combination. There is a registration study in the first-line metastatic HER2-positive setting for THP [taxane-trastuzumab-pertuzumab], plus or minus atezolizumab, being run through the NRG [National Research Group]. That study is unselected for PD-L1 but will have a subgroup analysis looking at outcomes by PD-L1 status. Immunotherapy may have a role in this space in the future.

There are other novel agents that are being explored, including agents like novel HER2 TKIs [tyrosine kinase inhibitors], as well as other ADCs [antibody-drug conjugates] and bispecific antibodies. There is so much going on in the HER2 space, and hopefully all these agents will lead to further improvements in outcomes for our patients.

Transcript edited for clarity.