Eribulin Liposarcoma Approval Advances Precision Medicine in Oncology

George D. Demetri, MD

Soft tissue sarcoma is on the forefront of precision medicine, says George Demetri, MD, professor of Medicine at Harvard Medical School and director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute.

This is particularly evident by the FDA’s approval of eribulin mesylate (Halaven) in for advanced or unresectable liposarcoma, a relatively rare subtype of soft tissue sarcoma which affects approximately 4000 patients a year in the United States.

“It’s interesting that the FDA honed in on just liposarcoma. In some ways, that’s one of the most interesting things about this approval,” says Demetri. “Sarcomas, in many ways, set the stage for parsing cancers into very specific little bins.”

The approval was based on an improvement in overall survival (OS) demonstrated in a phase III study that looked at patients with either liposarcoma or leiomyosarcoma following prior treatment with an anthracycline-based chemotherapy.

In the 143 patients with liposarcoma, eribulin demonstrated a median OS of 15.6 months compared with 8.4 months in those who received dacarbazine (HR, 0.51; 95% CI, 0.35-0.75). Median progression-free survival (PFS) with eribulin was 2.9 versus 1.7 months with dacarbazine (HR, 0.52; 95% CI, 0.35-0.78).

An OS benefit was not reported in the 309 patients with leiomyosarcoma.

OncLive: What is the significance of the eribulin approval?

In an interview with OncLive, Demetri discusses the study, the impact of the eribulin’s FDA approval, what oncologists can learn from studying liposarcoma, and the challenges that come with treating a rare disease.Demetri: The FDA approved this drug in 2010—a long time ago—for patients with breast cancer. Therefore, it is already kind of an older drug. This is a second indication—a supplementary indication in the liposarcoma world.

It’s very interesting because, at the 2015 ASCO Annual Meeting, the study that had it registered by the FDA in sarcomas was presented as a leiomyosarcoma and liposarcoma study. There are several reasonably common types of sarcomas: GIST, which is the most common type, the gastrointestinal stromal tumor, and then leiomyosarcomas and liposarcomas.

Now, their biology is totally different. They simply both start with L. That is what they share. That’s about it. What’s interesting is that the study was really the first randomized prospective study showing that people could live longer if they were treated with a chemotherapy drug. All of the other studies that have been done have never really proven that in any of the soft tissue sarcomas, other than GIST. That is an important consideration.

When the FDA looked at eribulin compared with the older standard drug, dacarbazine— which is from the 1970s—there was not that much of a difference in leiomyosarcomas. However, there was a much bigger difference in liposarcomas favoring the newer eribulin. That is why the FDA approved it for liposarcomas. It is interesting that the liposarcomas were so positive that it drove the whole benefit, despite the fact that there was not an incremental benefit in the leiomyosarcomas.

How will this approval change the treatment paradigm for liposarcoma?

When you mix it all together, the whole study was positive; that tells you just how statistically positive it was for the liposarcomas.This approval helps to dispel some of the nihilism that exists in the field of sarcomas. Although they are hard to treat we now have better tools and new drugs to treat them with, and it’s worth thinking about.

What should oncologists know about using eribulin to treat liposarcoma?

Many practicing oncologists may only see 1 of these sarcoma patients every decade. That is a message that I think we need to get out there. Even though these are rare diseases, the standards of practice and the options for patients are changing because of good precision medicine research. I think that’s important.Every oncologist knows the side effects of eribulin because everybody has used it for patients with breast cancer. It has standard chemotherapy side effects: low blood counts, hair loss, and the risk of neuropathy. Eribulin, if given for too long, can damage nerves, so that is something every oncologist knows to look out for.

Eribulin has a survival benefit, so we should always think about that in people with liposarcoma. It is a modest survival benefit, so that’s the other important thing to know.

What are you most excited about in liposarcoma right now?

For eribulin, on average, the median survival was 13.5 months compared with 11.5 months with dacarbazine (in the overall patient population which included patients with both liposarcoma and leiomyosarcoma). It’s a 2-month OS benefit that, frankly, is statistically significant but modest. It means we still have a lot of work to do.Liposarcomas, although rare, are an area with a lot of emerging research. There are a lot of interesting molecular pathways. It is in some ways, the go-to disease for testing MDM2 inhibitors.

MDM2 is something that neutralizes p53, which is really important to have as a normal gene in our bodies. A lot of cancers get rid of p53, not by mutating it, but by having too much MDM2. MDM2 is, basically, like a stalker that grabs the p53 and takes it out. MDM2 is amplified in liposarcomas, so there is a lot of research going on in that space. It has nothing to do with eribulin, per se, but it’s the type of thing that, as we look toward making the eribulin effect better and making people live longer, is causing us to look at more rational combinations. That’s where a lot of the future lies.

Based on the eribulin approval, do you see the field of soft tissue sarcoma moving more toward a precision medicine approach?

Is working within such a rare disease type a challenge?

It already is. It absolutely already is in so many ways. We’ve got another study with an epigenetic drug that’s specifically targeting a sarcoma that probably happens in 30 patients annually in the whole country—malignant rhabdoid tumors. That’s very rare, so it is important that everybody knows we are looking for those 30 patients. It would be terrible for a doctor in the community to have a patient like this, to have a trial in need of a patient, and not be able to make that connection.The sarcoma community, thankfully, is a very collaborative community. Globally, this was a study that was done all over the world. Many of my GIST studies are done all over the world. We work together. We’re like the pediatric oncology group of adult oncology. We know that because these are rare tumors; we have to work together and our community is very good about doing that. We view the patients as our partners in that.

The challenge is actually disseminating the advances into routine practice. We have to get the attention of oncologists and say, “Hey, this is really interesting.” Many oncologists might say, “Well, I’ll only see that once a decade, so if I ever see a sarcoma I’ll just call somebody at a reference center who knows a lot about sarcomas.”

That’s perfectly fine. I think we have enough reference centers across the country. It doesn’t have to be our center. There are many good ones scattered throughout the country. That is another important thing. The sarcomas don’t necessarily just have to be managed in the community. It’s a shared-care model where doctors who don’t see a lot of them can get collaborative support from reference centers like ours, The University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, or Stanford Cancer Center. That is the great thing.

We encourage community oncologists to reach out to places like ours, not so we can steal their patients away, but so that we can help. The model is that of shared care. We see 1000 sarcoma referrals a year. That’s a lot. For a disease where there are only 12,000 soft tissue sarcomas in the whole country, we see one-twelfth of all the sarcomas in the country here.

We are not trying to beat our own drum here. We are trying to say that experience does matter, and we would like to work with doctors across the country. We want the community oncologist to take care of the patient because we don’t need someone driving halfway across the country to New York or Massachusetts to come here.

However, we want to work together. Many community oncologists are very outstanding clinicians. It’s just an issue that things are changing rapidly here, and I do think it’s probably worth it to reach out. This kind of shared-care model fits well for rare diseases.

Schöffski P, Maki RG, Italiano A, et al. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol. 2015;(suppl; abstr LBA10502).