Expert Highlights Evolving Options in HER2+ Breast Cancer

Tiffany A. Traina, MD

The treatment landscape of HER2-postive breast cancer went through an exponential shift in 2017 with 2 new FDA approvals and the emergence of encouraging novel therapeutic options.

In July 2017, the FDA approved neratinib (Nerlynx) for the extended adjuvant treatment of patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin). The approval followed a 12-4 recommendation from the agency’s Oncologic Drugs Advisory Committee, stemming from the results of the phase III ExteNET trial. Even though the drug is approved, many clinicians are hesitant to adopt it, due in part to the success observed with adjuvant therapy with pertuzumab (Perjeta).

The approval for pertuzumab in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer came in December 2017. This regimen is indicated for those at high risk for recurrence, and is based on findings from the APHINITY trial. Results from that phase III trial reported that this regimen demonstrated a 3-year invasive disease-free survival rate of 94.1% versus 93.2% for those who received trastuzumab plus chemotherapy and placebo.

Considering this indication for pertuzumab, experts such as Tiffany A. Traina, MD, say that they are unsure of where to place neratinib in the sequence of treatment. This hesitancy is due in part to the early trials of neratinib, which did not include patients who had prior exposure to pertuzumab, Traina explained.

Other agents in the pipeline include DS-8201, which Traina believes will fit well into the HER2-positive landscape if approved, as it is both well tolerated and highly effective.

OncLive: Can you discuss the trepidation that we are seeing with neratinib?

In an interview with OncLive, Traina, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed her experiences with using neratinib and pertuzumab, and shared her excitement on the direction in which the HER2-positive breast cancer field is moving.Traina: Neratinib’s approval is for an extended adjuvant scenario for HER2-positive early-stage breast cancer. It’s in a unique position because so much has evolved in the treatment of HER2-positive early-stage disease. We now have much more use of neoadjuvant pertuzumab in combination with trastuzumab and an anthracycline-taxane—based neoadjuvant regimen. We recently saw the data from the APHINITY trial showing that 1 full year of adjuvant trastuzumab and pertuzumab was associated with improved survival outcomes. Now trying to integrate the FDA approval of neratinib is just a bit more challenging. The early trials with neratinib did not have patients who had prior exposure to pertuzumab. Therefore, I am not quite sure where its place will be.

How would you go about determining treatment for early-stage HER2-positive breast cancer?

I know there is a lot of debate and discussion of whether patients who receive preoperative pertuzumab and fail to have a pathologic complete response should continue on their pertuzumab, which is supported by the APHINITY trial. That might be a place for trying neratinib where it may not be cross-resistant, but it is a big unknown. I don't think the European Union’s decision is going to impact the US provider's use of neratinib—it’s just more of matter of the clinical trial data not guiding what current practice really is.In practice, I favor using pertuzumab in patients who have tumors larger than 2 cm in the setting of node-negative or node-positive disease. I do still incorporate a bit of neoadjuvant therapy, so anthracycline-taxane—based trastuzumab and pertuzumab and then, following surgery, continuing the trastuzumab and pertuzumab for a full year. For tumors that are smaller than 2 cm and are node-negative, we can de-escalate treatment. As opposed to incorporating pertuzumab, regimens supported by Dr Sara Tolaney's work showed that weekly paclitaxel for 12 weeks with trastuzumab may be sufficient.

How could an agent such as DS-8201 fit into the treatment landscape?

I struggle to figure out where to place neratinib. Perhaps, for patients who are extremely high risk, however you define that, maybe those who are estrogen receptor-/progesterone receptor-negative and HER2-positive with a lot of residual disease and bulky adenopathy even after preoperative therapy. I might try to give those patients the benefit of the doubt and finish the full year as supported by APHINITY, and then maybe think about neratinib after that.This antibody-drug conjugate in HER2-positive advanced breast cancer is really a remarkable agent. We participated in the clinical trials of this drug and I have treated patients with it. Patients who have had advanced disease previously treated with chemotherapy and trastuzumab combinations, pertuzumab, ado-trastuzumab emtansine (T-DM1; Kadcyla), lapatinib (Tykerb)—pretty much our full armamentarium—have gone onto this antibody-drug conjugate and have had tremendous, palpable, durable responses.

It is incredibly encouraging and I would love to see where things go with the next trials. It is both well tolerated and highly effective. Hopefully, we will see an approval so that we can get access for our patients.

Are there any other therapeutic options that look promising?

Looking ahead, do you foresee any other big changes in the field?

Another piece that is interesting about that drug is that there have been some recent data to suggest activity in weak HER2 expressers. In IHC 1+ or IHC 2+, which we do not traditionally call HER2-postive breast cancer, [there] has [been] some preliminary data showing benefit with this antibody-drug conjugate.The landscape is changing and it makes us really wonder, can we revisit certain cytotoxic therapies that were too toxic to deliver, or seemed ineffective? Now with conjugating a few molecules to a very specific targeted antibody, it could open up a whole new therapeutic opportunity. We've already mentioned DS-8201, which is very exciting. For advanced disease, hopefully that will become one of the tools that we will have to treat patients with HER2-positive breast cancer. We are still trying to figure out how T-DM1 will have a place in early-stage disease, and we would like to see what the results of the ATEMPT trial are, which randomized patients to paclitaxel and trastuzumab versus T-DM1. We may be able to risk stratify better, de-escalate for the lower-risk cancers, and then potentially add in more [therapy] for our higher-risk patients. I do think it is an exciting time.

von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122-131. doi: 10.1056/NEJMoa1703643.