Treatment Combinations for HER2-Positive Breast Cancer

Mark Pegram, MD

As part of our coverage for the 30th Annual Miami Breast Cancer Conference, we spoke with Dr. Mark Pegram, director of the breast cancer program at the Stanford Women’s Cancer Center and co-director of the molecular therapeutics program. Dr. Pegram will be discussing the potential for novel HER2 combination therapies at the conference.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. Pegram, what are the current HER2 therapies available for treatment of women with HER2-positive breast cancer?

Dr. Pegram: Since 1998, we have had trastuzumab, which has become the mainstay of HER2-targeted breast cancer therapies for both advanced cancer, and since 2005, as an adjuvant therapy for early-stage HER2-positive breast cancer. Trastuzumab is a humanized monoclonal antibody targeting the HER2 receptor and is synergistic with chemotherapy, and has been the mainstay for treatment for HER2-positive early- and late-stage breast cancer for many years.

Subsequent to the FDA approval of that agent, we have had the FDA approval of small molecule HER2 kinase inhibitors, such as lapatinib, which inhibits the epidermal growth factor receptor kinase as well. Lapatinib was approved by the FDA for treatment of advanced breast cancer that is HER2-positive. Studies are ongoing in early breast cancer to interrogate a possible role of lapatinib alone or in combination with trastuzumab in the adjuvant or neoadjuvant setting. The neoadjuvant data have actually already been presented in preliminary form in the Neo ALTTO study, where the drug demonstrated superior ability to achieve pathological complete response together with trastuzumab and chemotherapy, compared with trastuzumab and chemotherapy alone.

Similarly, last year we had a very exciting addition to the HER2-targeted armamentarium, with the FDA approval of pertuzumab, the second humanized monoclonal HER2 antibody to become available in clinical practice. Once again, this has changed the field; it is now the new standard of care for first-line HER2-positive advanced breast cancer or metastatic disease. The drug is currently under active study to decide whether it may have a role in early-stage breast cancer. Indeed, again we have evidence in the neoadjuvant setting that pertuzumab plus trastuzumab and chemotherapy combinations are superior to chemotherapy and trastuzumab alone in the ability to achieve pathologic complete response. We anxiously await adjuvant trials of pertuzumab in combination with trastuzumab and chemotherapy to see if that will move the field forward.

Let me tell you a little bit about the advanced disease [phase III] trial of pertuzumab. The trial involved over 800 subjects that were randomized to receive docetaxel and trastuzumab along with placebo, or docetaxel and trastuzumab along with pertuzumab. It is exciting that the primary endpoint, which was an independently assessed progression-free survival endpoint, demonstrated just over a 6-month improvement in median progression-free survival, with a hazard ratio of about 0.62 and a high statistical confidence. In a preliminary overall survival analysis, there was also a significant trend favoring pertuzumab, and more recently that dataset has been updated at the recent San Antonio Breast Cancer Symposium this past December, where Dr. Sandra Swain presented an update showing a now statistically significant improvement to the overall survival when pertuzumab is added to trastuzumab and docetaxel. Interestingly, the addition of pertuzumab adds little toxicity to the combination of trastuzumab and chemotherapy; however, there is some increase in lower gastrointestinal toxicity and some increase in myelosuppression, but fortunately, no increase in cardiac adverse events with the addition of this second-generation HER2 antibody that disrupts HER2/HER3 heterodimer signaling.

Lastly, just this past week, another HER2-targeted therapy was approved by the FDA. Again, an exciting phase III development on which I was fortunate enough to participate in. This is the trastuzumab emtansine (T-DM1) antibody-drug conjugate. This is, really at its core, a combination of chemo and trastuzumab. However, it is in contrast to giving the two types of agents alone, where we still have to endure the toxicity of chemotherapy. In this case, T-DM1 is a covalently linked cytotoxic moiety directly to the trastuzumab antibody backbone, so the trastuzumab is being used as a delivery vehicle to deliver the cytotoxic payloads specifically to tumor cells. The beauty of this is that it appears that T-DM1 maintains all of the efficacy of chemo plus trastuzumab, but without any of the chemo toxicities-no significant gastrointestinal toxicity, no myelosuppression, and we don’t see alopecia with T-DM1. There was also no cardiac toxicity in the pivotal trial; there was just 1.7% incidence or so of cardiac adverse events in the T-DM1 arm, which matched the control arm. The control arm was a combination of lapatinib and capecitabine, which is one of the FDA-approved lapatinib regimens. In this T-DM1 trial, there was also superior progression-free, and now overall survival benefit, compared with the control arm in patients who have had prior taxanes and prior trastuzumab exposure. Again, this is exciting indeed because this molecule is now poised to move into the first-line setting for metastatic disease. A large pivotal trial to study T-DM1 in that clinical setting is already completed its accrual. More importantly perhaps, is the prospect of using T-DM1 in the adjuvant setting for early-stage HER2-positive breast cancer. The planned adjuvant studies are being written now and will be launched this calendar year. Again, this is a breakthrough in technology because of the linker chemistry that allows this cytotoxic to be exquisitely and precisely delivered to the tumor site in the T-DM1 molecule. It was this revolution in chemistry and new technology that allowed this antibody-drug conjugate to become a success.

Cancer Network: That is a lot of advancement in terms of HER2 therapies. Are there any other HER2 therapies that are in development?

Dr. Pegram: There are still a range of HER2 molecules in various pipelines. There are FC-domain engineered antibodies that are in preclinical development and some in early clinical development. These antibodies have enhanced immune effector function, so they are more potent in eliciting antibody-dependent, cell-mediated cellular toxicity compared with trastuzumab. It will be really interesting to see if these represent a step forward. In addition, there are HER3 antibodies that are in preclinical and early clinical development that may be of interest in this field. There are new antibody-drug conjugates targeting HER2 that have different cytotoxic moieties that distinguish them from T-DM1. This may be an interesting avenue to explore in the future. It would appear that there are few limits to further development of HER2-targeted therapeutics in the near future. These molecules show great promise. I think the analogy that comes to mind in this instance is the therapeutics that target the estrogen receptor-there are multiple ways to hit that target, and we are finding and learning the same lessons in HER2-targeted agents. And in this case, the approaches taken can be complementary when used together.

Cancer Network: You mentioned some of the combinations that are already being tested. Is there any scientific rationale for combining two HER2 drugs?

Dr. Pegram: There sure is. In the case of pertuzumab and trastuzumab, each of these antibodies binds to a different epitope on the HER2 receptor target. But you can give both simultaneously and they will both bind, and pertuzumab has activities that trastuzumab does not; only pertuzumab can disrupt HER2/HER3 heterodimers for example, That was the scientific rationale for combining the two, which is now a standard of care with FDA approval. Moreover, there is strong scientific rationale to take that one step further and combine T-DM1 with pertuzumab. Because as I mentioned, at its core, T-DM1 is simply chemo plus trastuzumab; they just happened to be chemically linked. Therefore, presumably, adding pertuzumab to that construct may also be synergistic, and we might expect to see similar improvements in outcomes by adding pertuzumab to T-DM1 as we did to adding pertuzumab to chemo plus trastuzumab.

Cancer Network: Are there any other combinations of HER2-targeted agents that you would like to highlight that we have not touched upon yet?

Dr. Pegram: We haven’t really discussed the concept of combined receptor blockade, which is also a success and has won FDA approval. I participated along with many of my colleagues in the field in a trial targeting HER2 and estrogen receptors simultaneously using aromatase inhibition and lapatinib. In HER2-positive, ER-positive advanced breast cancer, the combination proved to be successful and has led to FDA approval; it is now routinely available for our patients in the clinic as a nonchemotherapy treatment option for HER2-positive, advanced disease. I think that is a very important advance for patients, not to have to endure the toxicity of chemo while they are on that particular regimen. I think that is another good example of how integration of HER2-targeted therapies with other targeted therapeutic approaches may hold more promise. I think we will see more of that with other molecularly targeted agents added in with HER2-targeted agents down the line.

Cancer Network: Great. Thank you so much for joining us today, Dr. Pegram.

Dr. Pegram: Absolutely! Looking forward to seeing everyone at the Miami symposium.