Novel Agents in Early Trials for Breast Cancer

Sara Hurvitz, MD

Following up on the 2012 annual meeting of the American Society of Clinical Oncology (ASCO), CancerNetwork speaks with Dr. Sara Hurvitz, director of the breast cancer program at the University of California in Los Angeles. Dr. Hurvitz is actively involved in translational phase I/II breast cancer clinical trials as well as in research to better define distinct types of breast tumors to better design novel targeted therapies.

-Interviewed by Anna Azvolinsky, PhD

CancerNetwork: Dr. Hurvitz, you were involved in the phase II program for trastuzumab emtansine (T-DM1) and presented the phase II efficacy results of treatment-naive patients at the European Multidisciplinary Cancer Congress held last year. T-DM1 is a next-generation trastuzumab compound. Can you explain what is unique about this compound?

Dr. Hurvitz: This is a novel molecule called an antibody–drug conjugate and what makes it unique is that it is stably linked to a very cytotoxic chemotherapy. So the trastuzumab, which is a HER2-targeted monoclonal antibody that is relatively nontoxic on its own, is linked to a derivative of a drug called mertansine.

Mertansine is a therapy that was developed in the 1980s and was so toxic they had to shelve it in terms of a regulatory pathway. What has been done is scientists have figured out how to link the trastuzumab to the chemotherapy so that the chemotherapy is not released until it is inside the cancer cell that bears the HER2 on the outside of the cell. The trastuzumab portion of the molecule will bind to the HER2 extracellular domain and the entire T-DM1 molecule is taken up inside the tumor cell and once inside the tumor cell the linker releases the emtansine or derivative of mertansine chemotherapy, which is then activated so that the cell is killed. So it is a beautiful targeted delivery of the toxic payload to cancer cells.

There have been other antibody–drug conjugates that have been developed in the past that have not been nearly as successful and that is because the linker released the chemotherapy prior to getting inside the tumor cell. So that is probably what makes this compound so unique for breast cancer, and the technology of the linker is being exploited for other molecules that are in development for both breast cancer as well as other tumors.

CancerNetwork: The results of the phase III EMILIA trial with T-DM1 in patients that were previously treated were presented at the plenary session at this year’s ASCO. The data showed that T-DM1 improves progression-free survival as compared to lapatinib plus capecitabine and has fewer side effects. There is also a phase III trial called the MARIANNE trial assessing T-DM1 as a first line of treatment that is still ongoing. If the MARIANNE trial results are positive, what do you envision to be the main role for T-DM1? As a first- or second-line agent?

Dr. Hurvitz: The MARIANNE study is actually comparing T-DM1 alone vs T-DM1 plus pertuzumab vs standard of care trastuzumab plus a taxane. If the combination of T-DM1 and pertuzumab is the winner I think that there is going to be a lot of enthusiasm among oncologists to use the two together in the front-line setting to give patients the highest chance of a good response and durable remission. We do see durable remissions especially in HER2-positive disease in the front-line setting. I think most oncologists have a handful of patients that treated in the front-line setting with aggressive upfront therapy achieve a complete response and have years in remission with that therapy, so I think there is a sense that if we treat a little more aggressively upfront, patients may have a chance at a longer time of disease control by doing so.

I think though that there would still be a role for a second-line setting, which was studied in the EMILIA clinical trial. There would still be a role for T-DM1, because for many patients who are treated in the adjuvant setting and have a relapse in a relatively short period of time, or have already had front-line therapy and their disease progresses, T-DM1 offers them a relatively nontoxic approach that’s able to improve progression-free survival. So I think realistically speaking that oncologists would be eager to use it in both types of settings.

CancerNetwork: Could you highlight any drugs in development or maybe specific clinical trial data that you are particularly looking forward to in the next year or so?

Dr. Hurvitz: Yes, in addition to T-DM1 there are multiple other agents being evaluated in HER2-positive breast cancer and that is what I am focusing on right now. We know that we have lapatinib which is an oral tyrosine kinase inhibitor that targets the intracellular portion of HER2 as well as HER1 or EGFR. This is an FDA-approved agent and it is useful in the trastuzumab-refractory setting but it is still associated with a fair amount of toxicity in my own clinical experience with diarrhea and rash.

There are a number of other molecules being evaluated. One is called neratinib and that is an oral therapy that is similar to lapatinib. It has some interesting data relating to its efficacy. An exciting molecule that I am really looking forward to seeing data on is afatinib, which is a molecule made by Boehringer Ingelheim, and this is a pan-HER potent inhibitor of the HER1, 2, 3, and 4 with very exciting early preclinical and phase I data. There is a large phase III randomized study called the LUX-Breast 1 study-that is an international study evaluating afatinib plus vinorelbine compared to trastuzumab with vinorelbine in trastuzumab pretreated breast cancer in the second-line setting.

Another target that is being pursued in the trastuzumab refractory setting are mTOR inhibitors and PI3K/mTOR inhibitors. PI3Kinase/AKT/mTOR is a pathway that has been shown to be activated in trastuzumab-resistant cell lines. There is early phase I data with the molecule everolimus which is an mTOR inhibitor that looks promising in trastuzumab- and taxane-refractory disease. There is a large phase III, international, randomized study that is looking at the use of everolimus with trastuzumab and paclitaxel vs paclitaxel and trastuzumab alone for patients with HER2-positive first-line metastatic breast cancer and that study is called the BOLERO-1 study. BOLERO-2 has recently been published and presented and that was looking at everolimus in the ER-positive/HER-negative setting. This is the BOLERO-1 study and we expect results to be presented within the next six to twelve months. So those are just some interesting, upcoming, studies that are being evaluated. There are other molecules that are being designed that target PI3Kinase and mTOR at the same time and those are also very promising and exciting.

CancerNetwork: Just to switch gears, there has been a lot of progress in terms of defining new breast cancer subtypes using genomic tumor data, particularly for difficult to treat and aggressive triple-negative breast cancers. How do you see this sort of data being used currently? And do you think it will facilitate new drug targets and biomarkers in the short, two- to three-year time frame?

Dr. Hurvitz: I think the hope is that understanding molecular pathways that drive tumor biology will lead to more targeted therapies. I think that is how this data is currently being used, sort of in an exploratory fashion that is then used to create hypotheses about tumor biology and test new therapies. So we are sort of in the beginning stages of using this genomic data. In a clinical sense it is still highly research-based at this time.

I think that one of the things that turned out to be a very exciting in BRCA1- and BRCA2-mutated breast and ovarian cancer is PARP inhibition. I think we all got quite excited when there was a molecule that was supposedly a PARP-inhibitor that had very promising phase II data in triple-negative breast cancer and this was the BiPar Sciences molecule, and then when the phase III data came out and it was negative there was a collective sigh of disappointment. Unfortunately that drug was not truly inhibiting PARP, it was inhibiting many other targets and PARP was one of them, but it was not strongly targeting PARP whatsoever. So I think we still have to see whether PARP inhibition is going to be useful in the basal-like breast cancer in the future.

Right now there are several companies that are exploring highly potent PARP inhibitors. We have Clovis Oncology, AstraZeneca, Abbott, and BioMarin, which is a small company in northern California. Data regarding these inhibitors continues to come out and hopefully we will find something that helps these rather aggressive and difficult to treat tumors for which we do not currently have targeted therapy.

CancerNetwork: So as a last question, what do you think has been among the biggest advances in breast cancer over the last couple of years?

Dr. Hurvitz: To me, actually, trastuzumab emtansine has been among the most exciting advances. Not only because the drug is targeted delivery of chemotherapy and yields much lower toxicity but still with impressive efficacy results, but because the technology that was utilized to develop this targeted agent can be utilized for other tumor types and so really may have a ripple effect and affect many patients in the very near future in a beneficial way. So that has sort of been the most exciting data that I have seen come out recently and also I think the mTOR inhibitor story in ER-positive breast cancer is incredibly exciting. We haven’t had a lot of news in ER-positive breast cancer, and yet the most common breast cancer is ER-positive and patients die of ER-positive metastatic breast cancer. It is very high incidence and so the fact that the BOLERO-2 study came out with positive results for everolimus in combination with an aromatase inhibitor is very exciting and very promising.

CancerNetwork: Thank you so much for joining us Dr. Hurvitz. That was really informative.

Dr. Hurvitz: My pleasure.