Novel Agents Emerging in Pipeline for HER2+ Breast Cancer

Denise A. Yardley, MD

There have been significant advances for the treatment of HER2-positive breast cancer over the last decade, says Denise A. Yardley, MD.

“When we look at the HER2-positive patient, at this point, we have really come a long way with the initial approval of trastuzumab (Herceptin), followed by the addition of pertuzumab (Perjeta), based on the CLEOPATRA data,” explains Yardley, senior investigator, Breast Cancer Research Program, principal investigator, Sarah Cannon Research Institute. “The EMILIA trial has now added T-DM1 (ado-trastuzumab emtansine; Kadcyla), a novel antibody-drug conjugate targeted against HER2.”

While these FDA approvals have made a large impact for patients with HER2-positive breast cancer, there is still more work to be done. “We are really trying to extend the number of novel agents to add to the HER2-population arena,” Yardley notes.

In an interview with OncLive, Yardley discusses 2 novel agents on the horizon for HER2-positive disease.

One agent, MM-302—an antibody-drug conjugate composed of a HER2-targeted antibody linked to liposomal doxorubicin—is being investigated in combination with trastuzumab in the phase II HERMIONE trial versus chemotherapy plus trastuzumab in patients with anthracycline-naïve, locally advanced, HER2-positive breast cancer who were previously treated with pertuzumab and T-DM1.

OncLive: What are the goals of the HERMIONE trial?

What impact could MM-302 have for HER2-positive patients?

Yardley also discusses the oral HER2 inhibitor ONT-380, which is also being explored in several combination trials. According to results of a phase Ib study, ONT-380 and T-DM1 showed early evidence of clinical activity in patients with metastatic HER2-positive disease. Yardley: The HERMIONE trial is really aimed at meeting an unmet need for the HER2-positive patient. It is specifically looking in anthracycline-naïve patients. There is an increasing abundance of those patients who have been previously treated with taxane- and platinum-based HER2-targeted regimens. We are looking at patients with metastatic breast cancer who have been previously treated with pertuzumab and T-DM1 and are anthracycline-naïve. They are randomized in a 1:1 fashion to the new novel targeted agent MM-302 or physician’s choice of chemotherapy given every 3 weeks. Those patients can have any number of prior therapies, as long as they have had pertuzumab and T-DM1. We are looking at a primary endpoint of progression-free survival, as well as the safety profile of the compound against standard-of-care chemotherapies.MM-302 hits a very different target on the HER2 molecule specifically with anthracycline-naïve patients because we have a larger uptake in that group of patients. The phase I data showed that, in a heavily pretreated group, MM-302 was very active.

What other emerging agents in this space are on the horizon?

We are really trying to look in an anthracycline-naïve population and develop another novel agent that will add to the spectrum of treatment available for the HER2-positive patient.One promising agent is ONT-380, which is an oral agent that is actually coming from Oncothyreon. We have had a lot of experience with ONT-380. It is in the class of HER2-targeted oral agents—lapatinib (Tykerb) is probably the one that is most thought of. Lapatinib is fraught with a lot of toxicities, due to the fact that it is not HER2-specific. Therefore, it has some ability to target EGFR, and that is where we see a lot of side effects. However, ONT-380 is HER2-specific; we don’t see a lot the side effects, such as gastrointestinal toxicity and skin rash.

In addition to that, we are very excited about ONT-380’s penetration into the CNS. We have seen patients who have been stable on ONT-380 for 1.5 years and have been through multiple lines of therapy very rapidly with CNS progression, and are now stable, asymptomatic, and tolerating an oral treatment very well in combination with trastuzumab. It is very synergistic with different HER2-targeted agents and it can be given with chemotherapy. It has also been looked at in combination with T-DM1 and also with capecitabine.