Eribulin Potential Backbone for Breast Cancer Treatment

Eribulin combination strategies are based on scientific evidence, rather than empirical evidence, and could provide a new chemotherapy-based backbone in the treatment paradigm of the malignancy, according to Twelves, professor of Clinical Cancer Pharmacology and Oncology at the Leeds Institute of Cancer and Pathology, St James's Institute of Oncology, Leeds, UK, toldTargeted Oncologyduring an interview.

TARGETED ONCOLOGY:What do you feel is the current status of chemotherapy in the treatment of metastatic breast cancer?

TWELVES:

I still remain interested in the role of chemotherapy in treating patients with breast cancer. In the same way that in the treatment of early breast cancer surgery remains an important element for those women, patients with metastatic disease, cytoreductive chemotherapy will be an important part of how we treat these women. That's an area that I personally continue to be interested in, and in particular because of the clinical trials that I've been involved in with eribulin.

Eribulin is a novel cytotoxic chemotherapy agent, and that's an area that has had some interesting new developments in that it can be used as a single agent, or in combination with other agents in the future.

TARGETED ONCOLOGY:What options are there in terms of combinations with eribulin?

TWELVES:

Over the last 20 or 30 years when we've developed combinations of chemotherapy agents, we've generally done so on an empirical basis. There hasn't usually been a good rationale for combining such agents. What is interesting is that because eribulin appears to have some novel biological effects, there may be a scientific basis for combinations that we might not have otherwise thought of.

For example, we did a trial looking at the combination of eribulin plus capecitabine a couple of years ago. We found that the combination was surprisingly well-tolerated and effective. It was as well-tolerated as many of the palliative treatments are, but as effective as many of the more intense chemotherapies. Since then, we've seen preclinical data that eribulin, in addition to its cytotoxic effects, could also affect the tumor vasculature. This may enhance the accumulation of a partner cytotoxic, so there may a biological rationale for combining eribulin that we weren't aware of some years ago.

TARGETED ONCOLOGY:With these combination treatments, do issues come up with tolerability and toxicities?

TWELVES:

Eribulin is a good agent for combinations because it is generally well-tolerated and effective. It's a drug that patients can continue on for many months and it's a treatment that many patients say they found less difficult to tolerate than other chemotherapy treatments.

When we combine other drugs with eribulin, I think the exciting possibilities are doing so with novel agents where there is a particular rationale. For example, we know from the single agent eribulin studies that eribulin is particularly effective in patients with triple-negative breast cancer. We also know that immunotherapies, such as pembrolizumab, appear to have a role in triple-negative breast cancer.

There are plans for a combination study looking at eribulin alongside pembrolizumab, and it's that sort of rational combination that holds a lot of promise for the future.

TARGETED ONCOLOGY:So do you still see chemotherapy as a backbone in the treatment of breast cancer currently?

TWELVES:

Chemotherapy is going to remain as an important part of treatment for most patients with breast cancer. It's important, therefore, that we have treatments that are more effective and less toxic. We want our patients to live longer and to live better. I think agents such as eribulin that are able to achieve those roles are really fundamental as the building blocks for other combinations.

TARGETED ONCOLOGY:Do you see precision approaches, such as subtyping and looking at genes, continuing in the treatment of breast cancer?

TWELVES:

Precision medicine, in particular breaking down breast cancer into smaller categories, has both challenges and promise. The promise is that we may see individual groups of patients who benefit from a certain treatment, but there is also the challenge that if we look at smaller and smaller groups of patients that it will be more difficult to come up with specific treatments for all those patients.

More importantly, we see within any individual patient that there is great heterogeneity of the tumor. It may be quite difficult to use genetically targeted therapies to treat the bulk of a patient's tumor if, in reality, that patients has many different types of cancers.

In that setting, a cytotoxic agent that is cytoreductive, such as eribulin that can reduce the tumor bulk while being well tolerated, will continue to have an important role.

TARGETED ONCOLOGY:Are there any particularly interesting studies going on?

TWELVES:

The studies that caught my eye around eribulin are those that are starting to confirm initial pre-clinical data that were presented regarding how there might be biologic and phenotypic changes in cancers in response to eribulin. We've known for some years that eribulin is a novel agent, in that it has an interaction with microtubules that is distinct from other microtubule interacting agents. That's how it functions as a cytotoxic.

We have now learned from the laboratory that there are also changes in the biology of the disease. We see changes in the epithelial-mesenchymal transition, so that the cancer is changed from a more to a less aggressive phenotype in the laboratory. We see that eribulin can affect vascular remodeling in the laboratory, and we are now starting to see clinical trials that underpin and start to reinforce this activity.

For example, there is an interesting study from the Spanish Solti Group where patients received neoadjuvant eribulin and their cancers were examined both before and after treatment. There were many interesting aspects to this study, but one that was particularly interesting was that we know luminal A and luminal B tumors are both ER-positive and that luminal B cancers don't respond to endocrine therapy as well as luminal A cancers. In the Solti study, they showed that after treatment with eribulin, luminal B cancers became luminal A cancers.

Looking to the future, it's possible to give patients with luminal B breast cancers eribulin to maybe convert them to luminal A phenotype. This may reestablish them to being sensitive to endocrine therapy.

TARGETED ONCOLOGY:Is there an understanding as to why that is?

TWELVES:

As to why we see these phenotypic changes, I think we're at an early stage there. Having seen those initial observations, the researchers are going back to the laboratory and trying to understand why these changes occur, and the clinicians and clinical trialists are designing trials now to recapitulate in patients what we have seen in the laboratory.

TARGETED ONCOLOGY:What do you think the biggest challenges are in the breast cancer right now?

TWELVES:

These are a number of important challenges in breast cancer. One of them is the notion that because we've seen such advances in HER2-positive breast cancer, breast cancer is sorted. That is very far from being the case. Unfortunately, when women develop metastatic breast cancer, treatment is essentially palliative and the likelihood is that they will die of their disease.

Breast cancer remains a major killer in the western world, and in the coming years as breast cancer becomes more common in other parts of the world, this will become a bigger problem. It remains a huge unmet need.

Another misconception is that it's only triple-negative breast cancer that we're thinking about, and that ER-positive and HER2-positive are somehow sorted. Again, chemotherapy is used in combination with most of the HER2-positive targeted treatments, and once patients become resistant to endocrine therapy, we're left offering them chemotherapy. The era of chemotherapy is far from gone.

Looking to the future, I think we will see a mixed picture of targeted therapies for particular types of disease where there is a single driver. Alongside that, we will see immune response and reduction in the volume of the disease using cytotoxic chemotherapy.