Slamon Explores Evolution of HER2-Positive Breast Cancer Treatment

Dennis J. Slamon, MD, PhD

Trastuzumab (Herceptin) was a game changer 17 years ago when it was first approved for patients with HER2-positive breast cancer. Today, the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla) and mTOR inhibitor everolimus (Afinitor) have further advanced the treatment of HER2-positive breast cancer, and transitioned the role of standard trastuzumab.

In the recent phase II ADAPT trial, the pathological complete response (pCR) rate was found to be substantially higher with two T-DM1 regimens compared with trastuzumab plus endocrine therapy in patients with HER2/HR—positive early breast cancer (P <.001).¹ In the T-DM1—alone arm (n = 37), the pCR rate was 40.5%. In the T-DM1 plus endocrine therapy arm (n = 48), the pCR rate was 45.8%. In the trastuzumab plus endocrine therapy arm (n = 45), the pCR rate was just 6.7%.

In addition to the incorporation of trastuzumab into an antibody-drug conjugate, the benefit of the therapy has also been maximized with the introduction of everolimus to the standard treatment.

In the phase III BOLERO-3 trial, patients treated with everolimus in addition to trastuzumab and vinorelbine had a median progression-free survival (PFS) of 7 months compared with 5.78 months in patients who received trastuzumab, vinorelbine, and placebo.²

The study shed some light on the origin of trastuzumab resistance, which is common despite the drug’s success improving outcomes for patients with HER2-positive breast cancer. The mechanisms by which resistance occurs remain unknown, but include the possibility of activation of the mTOR pathway, which everolimus targets.

OncLive: What is the significance of the phase II ADAPT trial data?

OncLive spoke with the oncologist responsible for the development of trastuzumab, Dennis J. Slamon, MD, PhD, who is the director of Clinical/Translational Research and the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center. Slamon, a 2014 Giants of Cancer Care® recipient for Breast Cancer, discusses the impact of the ADAPT and BOLERO trials and how the increased focus on neoadjuvant therapy could transform the treatment of HER2-positive breast cancer.Dr Slamon: The ADAPT trial was very exciting. It is interim data that need to be fully evaluated, but it does show that an antibody-drug conjugate like T-DM1 could have a major impact in the adjuvant setting. The pCR rate, with or without antihormonal therapy for these HER2-positive/HR-positive tumors, is between 40% and 45% for both groups.

The caveat of the trial was that the response rate in the trastuzumab hormone therapy group, which T-DM1 was compared to, was unexpectedly low, given what we have seen historically. However, even if we were to accept that it is low, the pCR still doubled compared with trastuzumab.

The trial will continue and accrue its whole data set number, and we will have a better idea of how big of an impact this will have. By the end of 2015 or early 2016, I would anticipate that most of the data will start to come in.

What have we learned from the BOLERO-1 and BOLERO-3 trials?

Can you further discuss the significance of the PI3 kinase pathway in the HER2-positive setting?

The idea that you can do something for this targeted group with a therapy that excludes an additional chemotherapy is very exciting for women in the treatment of early-stage breast cancer. It allows us to circumvent several side effects that accompany our current therapies that have chemotherapies embedded into the regimen. That is what most people are excited about.These studies looked at the idea of resistance to HER2-targeted therapy and whether adding another drug that targets a pathway—one that that may play a role in causing that resistance&mdash;would reverse it. Thus far, the data from the combined analysis appear to indicate that those patients who are HER2-positive and who have alterations in the PI3 kinase pathway could benefit from the addition of everolimus to their treatment strategy.While we can define it, the HER2-positive breast cancer group itself is heterogeneous. There are other mutations that occur within the group that may dictate how well, or how poorly, patients respond to appropriately targeted therapies—whether that is hormone therapy, HER2-targeted therapy, or chemotherapy.

What is on the horizon for neoadjuvant therapy in HER2-positive breast cancer?

What are some current treatment options aimed at optimizing neoadjuvant therapy for the HER2-positive setting?

A question that came out of the BOLERO trials was: is the P13 kinase pathway playing a role in mediating resistance to HER2-therapy? There are a lot of preclinical data that indicate that may be the case. That got people really interested in looking at this clinically, and that is how the BOLERO trials were designed and developed.The whole idea of neoadjuvant therapy has come to the forefront. The regulatory agencies now see it fitting to approve drugs based on neoadjuvant pCR data and I think that space is going to become very crowded, in a good way. In the HER2 space, it is a quick way to get an answer on whether some of the new anti-HER2 therapies or combination HER2 strategies will work. I expect that T-DM1 agents or the combination of HER2 therapies with other pathway inhibitors will soon be evaluated in the neoadjuvant space. This is a very positive development.In the neoadjuvant space for HER2-disease, the T-DM1 data are the most exciting. This likely will not be the only data to show some excitement. There is preclinical evidence with other pathways, and with the blockade of other pathways. If this were used simultaneously with an anti-HER2-blockade it might really improve our outcomes. The problem with the HER2-positive space is trastuzumab plus chemotherapy has done so well, but there are still patients who are resistant or become resistant. The idea of a simultaneous blockade upfront, assuming the safety profile is good, is truly attractive. We could even push our cure rates much higher than they currently are.

1. Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol. 2015;33 (suppl; abstr 506).
2. O’Regan R, Ozguroglu M, Andre F, et al. Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab- resistant, advanced breast cancer (BOLERO-3). J Clin Oncol. 2013;31(suppl; abstr 505).