Esteva Recaps Advances in HER2-Targeted Therapy in Breast Cancer

Francisco J. Esteva, MD, PhD

Although 6 months of adjuvant trastuzumab (Herceptin) demonstrated noninferiority to the standard 12 months in the phase III PERSEPHONE trial, Francisco J. Esteva, MD, PhD, said that it is unlikely to instantly shift the standard in the context of other clinical trials that have failed to demonstrate the same outcome.

In the trial, 4088 patients with HER2-positive early breast cancer were randomized to receive trastuzumab for 6 months (n = 2043) or 12 months (n = 2045). The 4-year disease-free survival rate at a 5-year follow-up was 89.8% and 89.4% with the 12-month and 6-month schedules, respectively (HR, 1.07; 90% CI, 0.93-1.24; P = .01).

Although the 6-month schedule cut the incidence of cardiac toxicity in half, Esteva maintained that “until we have all of the information, 1 year of therapy will remain the standard of care for most patients in the United States.”

OncLive: What are the improvements and advances in HER2-targeted therapy?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Esteva, medical oncologist, New York University’s Perlmutter Cancer Center, discussed recent advances and clinical findings with HER2-targeted therapies across the neoadjuvant, adjuvant, and metastatic settings.Esteva: There are some important data in the adjuvant setting for trastuzumab. [In my presentation], I also touched on some of the new therapies that are being explored in the metastatic setting.

In the adjuvant setting, one of the most important studies was a large randomized trial from the United Kingdom in which patients were either given the standard 1 year of trastuzumab or 6 months following surgery. Over 4000 patients were enrolled, so it was a reasonable sample size. Overall, they showed noninferiority for 6 months of therapy as opposed to 1 year of therapy. The question is how that fits into the standard of care. Should we give less [than 1 year of trastuzumab] based on the results of the trial?

This [question should be answered] in the context of other trials from France, Finland, and other places in which it was not clear that 6 months is as effective as 1 year of trastuzumab. Until we have all of the information, 1 year of therapy will remain the standard of care for most patients in the United States.

There is also interest in the development of trastuzumab biosimilars, which will hopefully reduce the cost of therapy in the future. One of the trials I was involved with compared trastuzumab to a trastuzumab biosimilar. We showed that the pathologic complete response in the neoadjuvant setting was the same for both drugs. We provided additional information at the 2018 ASCO Annual Meeting regarding the efficacy and safety of one of these biosimilars (CT-P6).

I also mentioned an update on the ExteNET trial, which looked at the use of neratinib (Nerlynx) in early-stage breast cancer after completing 1 year of trastuzumab. The ExteNET study showed an improvement in disease-free survival, especially in patients with estrogen receptor—positive disease compared with no additional therapy. At the 2018 ASCO Annual Meeting, there was a poster showing that the earlier you begin therapy, the better the results were in the randomized trial.

What trials have addressed the optimal duration of trastuzumab?

Does the approval of the first trastuzumab biosimilar mark a new era of treatment?

I also discussed some of the results presented in the metastatic setting. There was a randomized study looking at capecitabine, trastuzumab, and pertuzumab (Perjeta) that showed some improvement in progression-free survival compared with trastuzumab and capecitabine. Based on the CLEOPATRA study, the combination of a taxane, trastuzumab, and pertuzumab remains the standard of care in the United States. Following progression, the standard treatment in the second-line setting is ado-trastuzumab emtansine (T-DM1; Kadcyla). Several new antibody-drug conjugates were also presented at this year’s meeting.A French trial compared 6 months with 12 months, but they could not show noninferiority. The HERA study compared 1 year to 2 years and showed that 2 years was not better. Overall, the studies point to 1 year as the optimal [duration of] therapy. The study presented at the 2018 ASCO Annual Meeting from the United Kingdom is the first to show that 6 months is as good as 12 months. The patients who were enrolled in the study were mostly low-risk patients. If you look at the subset analysis, patients at higher risk seemed to benefit more from 1 year of therapy. We need to see the full publication before we change our treatment guidelines and recommendations.The approval of the trastuzumab biosimilar will hopefully give additional options for the treatment of [patients with] HER2-positive disease at a lower cost. [As it stands] only one of them is approved. We need more approvals from different biosimilars to reduce the cost of care, both in the United States and globally.

Is tucatinib (ONT-380) likely to play a big role in treatment?

Is its ability to penetrate the blood-brain barrier its only distinguishing feature?

What is an area of research that you would like to see addressed?

A biosimilar has [to demonstrate] the same safety and efficacy as trastuzumab. There are at least 5 companies that I know of that are working on trastuzumab biosimilars. These are going through regulatory approvals in Europe and the United States. If those studies continue to show similar efficacy, they will be approved. Whether we use them or not is up to the physicians, the patients, and the payers. [As I mentioned] only one of them is approved in the United States and it probably won’t be commercialized until next year.Tucatinib is an interesting small molecule tyrosine kinase inhibitor that seems to be more specific to HER2 as opposed to lapatinib (Tykerb) or neratinib, which inhibits the phosphorylation of both the HER2 and EGF receptor. It has some activity in terms of brain metastases. We need additional therapies for patients with brain metastases, so that is a promising therapy in my opinion. That is one of the main differentiations, but it also seems to lessen the gastrointestinal side effects. There seems to be less diarrhea than with lapatinib because it doesn't inhibit the EGF receptor as much. The toxicity profile seems favorable.I would like to see more research combining HER2-targeted therapies with immunotherapies. Trastuzumab is an immunotherapy in that it enhances the antibody-dependent cell-mediated cytotoxicity. We need to understand in what populations stimulating the T cell and checkpoint inhibitor toward PD-1/PD-L1 might help. We need to continue to explore this area in both the metastatic and neoadjuvant settings for early-stage breast cancer.

There has also been a lot of research testing HER2-directed vaccines, although they have not yet been so effective. Other therapeutic approaches, like PI3K inhibitors, have not been as effective as we would like. The next cycle of research is going to be combining targeted therapy with immunotherapy. [Nonetheless], we have made significant progress in the treatment of HER2-positive disease, both in the neoadjuvant/adjuvant and metastatic settings.

Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2017;36 (suppl; abstr 506).