HER2+ Treatment Research is Thriving

Although there is no standard of care therapy following second-line treatment for human epidermal growth receptor 2 (HER2)-positive breast cancer, there are a number of options being researched, said Shanu Modi, MD, in a session Wednesday at the 2019 San Antonio Breast Cancer Symposium, titled "Frontiers in HER2-positive Breast Cancer."

Since the approval of trastuzumab nearly 30 years ago, there are now 5 approved therapies for HER2-positive disease, Modi said, which have nearly doubled median survival in the last 2 decades. Currently, the first-line standard of care treatment includes taxanes, trastuzumab (Kanjinti), and pertuzumab (Perjeta), whereas the second-line setting includes ado-trastuzumab emtasine (Kadcyla).

"The real question is what comes next?" Modi said.

Novel therapies in the works include antibodies, antibody drug conjugates (ADCs), potent tyronise kinase inhibitors (TKIs), and promising combination therapies. Many of these options are already in phase 3 or registration trials, according to Modi.

ADCs are a unique class in the field of HER2-positive treatments, comprised of androgen-specific monoclonal antibodies with a connected cytotoxic agent. TDM-1 is the prototype ADC, but newer linker technologies and novel potent payloads are pushing the development forward.

The DESTINY-BREAST01 trial researched trastuzumab deruxtecan, an ADC with a novel payload, high potency, and a high drug-to-antibody ratio. The study results found that it is a very active drug, with an overall response rate of 61% and a disease control rate of 97%. The median duration of response was 15 months and the median progression-free survival (PFS) was 16 months. To put this in context, Modi said the currently available therapies for the refractory setting generally produce response rates of 15% to 30% and a median PFS of 3 to 6 months.

TKIs are also looking promising, thanks to their ability to block the kinase and subsequent downstream signaling cascades, according to Modi. They also have the ability to cross the blood-brain barrier, Modi said, which means they could be active for central nervous system diseases. Current options for TKIs include lapatinib (Tykerb), neratinib (Nerlynx), pyrotinib, poziotinib, and tucatinib.

The NALA phase 3 trial, which studied neratinib for HER2-positive metastatic breast cancer, found a 2.2 month advantage for neratinib over lapatinib for PFS. The study also found a lower incidence of brain metastases in patients receiving neratinib.

Margetuximab is also a much-talked-about developmental treatment with positive study results thus far. It is a HER2-targeted monoclonal antibody with an Fc domain engineered to have greater binding to immune cells. The SOPHIA phase 3 trial compared patients on margituximab plus chemotherapy with patients on the standard-of-care trastuzumab plus chemotherapy, and found a 1-month gain in PFS for patients on margetximab.

Finally, Modi said, there are exciting combinations for refractory breast cancer for which HER2 is not the target, because preclinical data suggest cross-talk between HER2 pathways and cyclin-dependent kinase 4/6 signaling. Ongoing studies in this field include the PATRICIA phase 2 trial and the PATINA phase 3 trial, both of which are randomized.

Modi concluded that, in her opinion, it is possible to get a greater benefit out of targeting HER2.

"In the near future, we should expect to see some very new and exciting options to offer our patients," Modi said. "There are, however, differences in the magnitudes of effects and in which patients benefit, and I think these will be the criteria we will use and will influence our decisions in this space."

REFERENCE

Modi, S. Frontiers in HER2-positive Breast Cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; San Antonio, TX: December 11, 2019.