DR LOVE: Welcome to this special additional interview to our satellite CME program on the management of gynecologic sarcomas. This is medical oncologist Dr Neil Love.

Dr Suzanne George was initially going to be on the faculty but was unable to attend, so I interviewed her after the meeting to get her take on the management of these patients. To begin, she presented a 56-year-old woman from her practice who had a 20-year history of uterine fibroids and then presented with an 11-cm, high-grade leiomyosarcoma of the uterus. Baseline staging revealed metastatic disease in the lung and liver.

DR GEORGE: I want to take a step back and just give context that I am a medical oncologist that focuses on sarcoma. So what I see are women that have pelvic masses that end up being sarcoma. I don’t see people that have benign pelvic lesions.

So if you go to leiomyosarcoma and think about how women with uterine leiomyosarcoma, or uterine sarcomas in general present, it’s typically with either increasing abdominal pain, pelvic pressure or abnormal bleeding. Now, clearly those are symptoms that can occur in benign conditions as well, but again, my framework is one of which I work within the context of uterine sarcomas.

So this particular patient presented actually quite typically for the patients that I see. The patients I see often present either with abdominal bloating, pelvic pressure, vaginal bleeding. They have a hysterectomy for what is typically thought to be benign reasons. But then in those rare cases that it’s actually not benign and it ends up being a uterine sarcoma, that’s when the patient would get involved in my clinic.

Leiomyosarcoma of the uterus represents only a very, very small, single-digit percentage of uterine malignancies. If one looks at sarcomas as a whole, all soft-tissue sarcomas that can occur in any part of the body, leiomyosarcoma is actually one of the more common histologic subtypes of this rare disease. But it can occur. And it can occur as a primary tumor in almost any part of the body, although uterine leiomyosarcomas are very well described.

DR LOVE: So I tried to become a Talmudic scholar of sarcomas by talking to some of the investigators, but it’s still pretty complicated. Within the whole sarcoma realm, from a biologic and therapeutic point of view, how do you see leiomyosarcomas and uterine leiomyosarcomas? Do they tie into other sarcomas?

DR GEORGE: So we think of sarcomas in general in 2 broad categories, soft-tissue sarcoma and bone sarcoma. Leiomyosarcomas are typically considered a primary soft-tissue sarcoma. It’s one of the more common histologic subtypes, as I mentioned earlier, with liposarcoma actually being another relatively common subtype, although not typically involving the uterus.

Some sarcomas are defined biologically by specific translocations or specific activating mutations. Leiomyosarcoma actually is not one of those. It’s a diagnosis that’s made by histologic criteria together with immunohistochemical (IHC) criteria. And it shares the common concept of being a mesenchymal malignancy. That puts it in the sarcoma category, but it’s a unique histology. It’s its own disease. We know from looking, for example, at retroperitoneal sarcomas in general, if you look at liposarcomas that start in the retroperitoneum, in leiomyosarcoma, leiomyosarcoma has a higher tendency for distant metastases. Less of a tendency for local recurrences than, say, other histologic subtypes. So you do see some differences in natural history.

We also know that looking genomically at leiomyosarcoma that it’s often a complex genotype. You frequently will see p53 abnormalities, Rb abnormalities, abnormalities in the PTEN pathway. But there isn’t a single oncogenic driver. And that’s actually made some of the therapeutic strategies somewhat more complex, because it’s a complex genome, not a single targetable mutation.

DR LOVE: When you look globally at uterine leiomyosarcomas, in total, what fraction of patients are cured?

DR GEORGE: So if you look at uterine leiomyosarcoma that’s limited to the uterus at the time of presentation, and if you look at those women that are treated with hysterectomy alone on block, uterus-limited uterine leiomyosarcoma, it’s estimated that there’s approximately a 50% cure rate with surgery alone and a 50% recurrence rate.

DR LOVE: And what’s the typical stage of presentation? What fraction of patients present like this patient, with metastatic disease?

DR GEORGE: I don't know the number to tell you specifically. But what I can tell you is that I think most women actually present with localized disease, meaning localized to the pelvis. But recurrences occur, as I said. And about 50% of the patients will recur. And that’s usually within the first couple of years.

Most common sites of recurrence are either in the lung or in the recurrent pelvis, although metastases to the liver, soft tissues, subcutaneous lesions, bone have all been described and are not rare.

DR LOVE: What’s the usual approach to the primary in a patient who’s presenting with metastatic disease? Now, I don't know whether in this case the mets were discovered after she already had the primary surgery or they went ahead and did it for local tumor control.

DR GEORGE: Yes. So in this particular case, the metastases were discovered after the primary surgery had been performed, once they had the histologic diagnosis. So then the patient went on to staging. With that said, in terms of what’s the typical approach to a woman who presents, let’s say, with known metastatic disease and the uterus in place, I think it really varies on a case-by-case basis.

There can be significant morbidity from leaving pelvic disease in place. And frequently, if a woman presents with pelvic symptoms and that’s the most often presenting symptom, whether it be bleeding or whether it be abdominal pressure or pain, in our practice, actually, we will often still recommend that that patient have a hysterectomy just in order to minimize the morbidity of the primary site and then go on to systemic therapy.

When that may not be the primary decision is if the local disease presents in a way that it’s either not symptomatic and there may be distant disease that is symptomatic, then we shift our focus. Or if the local disease may be symptomatic but that the morbidity of surgery due to local extension and involvement of the pelvis would be — that the risks would outweigh the benefit. And so then in that situation, sometimes we’ll start with systemic therapy and then revisit the concept of taking out the local site.

But I think in general, our approach has tended to be to manage the local tumor, primarily because we want to minimize the risk of the morbidity from that tumor continuing to grow in the pelvis.

DR LOVE: It kind of reminds me a little bit about the approach to renal cell cancer. I mean, not exactly, but similar. So let’s talk about the decision that you faced with this woman in terms of first-line treatment of metastatic disease. Now, at that point I’m guessing she was asymptomatic from the disease.

DR GEORGE: That’s right. She had no symptoms. Yep.

DR LOVE: And it’s interesting, because she just presented a few years ago, and yet now, today, her choice would be a little different. We’ll kind of get into that. But maybe you can talk about some of the key clinical trials that have been done to address this issue of first-line therapy and particularly the so-called GeDDIS trial. If you could kind of review what that study looked at and kind of go through it and how it affected decision-making at that point when it was first reported.

DR GEORGE: Sure. So historically, if one thinks about soft-tissue sarcoma in general, our primary first-line standard-of-care therapy has always been an anthracycline-based regimen, so either doxorubicin alone, typically at 75 mg/m² or, in symptomatic patients, perhaps doxorubicin plus ifosfamide. So an anthracycline is really very much the standard first-line approach, or had been historically a standard first-line approach in soft-tissue sarcoma independent of histology, so whether it’s leiomyosarcoma, liposarcoma, synovial sarcoma, et cetera.

But the GOG, as well, really under the leadership of Martee Hensley from Memorial Sloan Kettering, began to look at gemcitabine either as a single agent or in combination with docetaxel. And what those studies showed was that the combination of gemcitabine and docetaxel together clearly have activity in leiomyosarcoma, specifically in uterine leiomyosarcoma, and actually has been extrapolated and is active in other sarcoma subtypes as well.

So based on that work, gemcitabine and docetaxel have been increasingly used in uterine leiomyosarcoma as an early-line therapy. So the GeDDIS trial was a trial that was run in a multicenter fashion in the UK, where they actually tried to say, “Okay. We have this great combination of gemcitabine and docetaxel that’s been showing benefit, and we have our historic standard of doxorubicin alone. Is there an optimal first-line approach in metastatic soft-tissue sarcoma?”

So what this study did was it enrolled patients with eligible histologies, which were most soft-tissue sarcoma histologies, included uterine leiomyosarcoma specifically, included leiomyosarcoma in general. Patients were randomized in a 1:1 fashion to either doxorubicin alone at 75 mg/m² or gemcitabine and docetaxel at slightly lower doses than is considered the US standard. So the gemcitabine was 675 mg/m² and the docetaxel was 75 mg/m². And the gem is day1/day 8, and the docetaxel is day 8 only. And patients were randomized.

And then they were followed. And what that study showed, actually, was that when you look at the primary oncologic outcomes — meaning progression-free survival, overall survival — they were almost superimposable between the 2 arms. And that was not only for the overall group of all soft-tissue sarcomas but also in preplanned subgroup analysis for leiomyosarcoma alone, as well as uterine leiomyosarcoma.

So it’s interesting. Different people have interpreted this data differently. Some people have said, “See. This means that” — anthracyclines — “that doxorubicin remains our first line.” Other people have said, “Look. It looks like the gem/doce is similar to the anthracyclines and it’s a slightly lower dose, so that means that should be the first line.”

And I have to say that in my view, what it means is that we have 2 good regimens that we can offer patients. And I actually do not think that this study alone necessarily answered the question that gemcitabine/docetaxel versus doxorubicin alone — in my mind, there isn’t a single superior agent when you’re talking about these 2 regimens.

Now clearly, we now have newer doxorubicin-based combinations, including a drug called olaratumab, which was recently approved and we may talk about. But that, I think, is starting perhaps to further shape how we could think about first- and second-line therapy in this disease.

DR LOVE: So a couple of other things about this trial that I noticed that I thought were interesting. One was the issue of if you look at treatment withdrawals, they were greater with gem/docetaxel. But it seemed like that was more because of toxicity. Actually, disease progression was more common with doxorubicin. Can you kind of go through that?

DR GEORGE: Yes. I think it’s an important point. So in the GeDDIS trial, there was a significant increase in withdrawals for toxicity on the gem/docetaxel arm compared to doxorubicin alone. And how that influenced the overall oncologic outcomes I think is a little bit difficult to tease out.

But I think it raises important questions. Firstly, gem/docetaxel can be a regimen that can be challenging for some people to manage, for patients. The toxicities of fluid retention, of fatigue, of neuropathy are real toxicities. And I think it’s important that, when using this regimen, that this is a regimen that there’s really close interaction and collaboration between the providers and the patients in order to optimize tolerance for this regimen.

I think most of us who use this regimen a lot were surprised at how high the toxicity dropout rate was on this arm. And particularly because the gem doses were lower than is often used. So I think to many of us, it really highlighted the importance of close follow-up and important communication between the provider team and the patient team.

DR LOVE: I noticed also that they broke the study down based on uterine and nonuterine. Do you think that’s a valid thing to look at? And what did it show?

DR GEORGE: I actually think it’s an important thing to look at for multiple reasons. I think it’s important to do, because uterine sarcomas are really a very unique, rare group of tumors that patients can enter the medical system in so many different places. They can be seen by a general gynecologist and then go through a GYN oncologist pathway all the way through their systemic therapy. Or they may start at a general gynecologist and then be referred into a medical oncology sarcoma practice. And we recognize that medical oncology sarcoma and GYN oncology might look at different studies, because I might be looking as a sarcoma person always at the sarcoma trials. And the GYN team might be really focused, appropriately, on the GYN trials.

So what, increasingly, you’ll see being done in the sarcoma trials is trying to define preplanned analysis at the uterine group so that we can make a distinct statement about the uterine sarcomas that are included in our trials, particularly uterine leiomyosarcoma, because as a subgroup, it’s a significant group.

So I think, practically, it’s an important thing to do, because I think it helps us to be able to answer the question that people ask, “What about the uterine leiomyosarcomas? How do they sort out in this study?” So I think it’s practically an important thing to do.

I think biologically there’s still studies underway and undergoing to try to help us understand biologically how uterine leiomyosarcoma may be similar or different than leiomyosarcomas of other parts of the body.

DR LOVE: And in the GeDDIS trial, what did it show when you specifically looked at just uterine leiomyosarcoma?

DR GEORGE: So when you just look at the uterine leiomyosarcoma, actually those were very similar, no statistically significant difference between the doxorubicin alone versus the gem/docetaxel.

DR LOVE: So it sounds like, what, you maybe try to individualize, at least prior to the new data you individualized the choice based on what?

DR GEORGE: Yes. So personally, I individualize the choice based in part on the patient preference, on toxicity, anticipated toxicity profile, particularly with doxorubicin, meaning prior potential cardiac issues where that may be more challenging versus the gem/docetaxel, if there are any issues where I’d be concerned about edema or neuropathy.

But, importantly, I also really want to emphasize the importance of clinical trials in these rare tumors. And so another factor that goes into my decision-making is, what is the current clinical trial landscape for soft tissue sarcomas? And, if I don’t have a first-line trial available for a patient, I want to be thinking about what do I have for second- and third-line therapy and how does my first-line therapy impact eligibility for subsequent lines of therapy.

In this particular case, actually, I felt comfortable using gemcitabine and docetaxel. It’s a very standard option first line. But I also knew that I had a trial coming that was going to require no prior anthracyclines or minimal prior anthracycline use. So for this particular patient, I wanted to leave the anthracycline door open for clinical trial opportunities.

DR LOVE: So any other important clinical research databases in terms of first-line therapy of uterine leiomyosarcoma that you want to comment on in addition to this trial, other than — we’re going to get to the new stuff. I was just going to ask you, I am curious, culturally, I guess, if you want to use that word, how different people have responded to this choice prior to the recent data. I kind of had the feeling that gynecologic oncologists like the docetaxel/gemcitabine way to go. And maybe oncologists like the doxorubicin. I’m not sure. What was your take on that?

DR GEORGE: Yes. No. I agree with you. I think in the GYN oncology community, gemcitabine/docetaxel is very frequently used as a first-line therapy. And I think a lot of that is because much of the work that was done in the development of this combination was done specifically in a uterine leiomyosarcoma subset, so that answers were clearer in that subset, whereas much of the work that’s historically been done with anthracyclines alone or even with anthracycline-based therapy, let’s say doxorubicin plus ifosfamide, it’s been done in more heterogeneous groups of soft tissue sarcoma. So we would be pulling out leiomyosarcoma as a subset analysis.

And I think that that perhaps has impacted some of the communication or some of the different preferences around these agents. If one looks at the NCCN Guidelines, for example, both single-agent doxorubicin and gemcitabine/docetaxel are listed in the first-line setting. And then there’s a note with a preference towards gem/doce, but again, I think it’s really based on a number of these smaller studies that were specifically looked at uterine leio.

DR LOVE: So can you talk about what happened when this woman received the gem/docetaxel?

DR GEORGE: Yes. So in terms of her disease, she had a wonderful response. She had marked reduction in both her lung metastases as well as known liver disease. And so that was great news from a disease-control perspective.

But then what became really challenging was that she had very significant toxicities from this drug. She had developed really very notable lower-extremity weakness, which we were not sure if it was directly a drug toxicity or more related to the steroids that she was taking around the docetaxel. She had very notable fatigue. She had some lower-extremity edema and profound weakness.

And her overall performance status, despite her improvement on her imaging, her performance status actually declined the longer we kept her on drug. So what we ended up doing in this particular case was — I think it was after 4 or 6 cycles, she was still responding beautifully, but I stopped the docetaxel and I kept her on single-agent gemcitabine alone, almost just like a maintenance therapy. And she tolerated it much, much better. She continued to have excellent disease control. And it was a better fit for her.

And I think that it’s important to note that gemcitabine alone has activity in soft tissue sarcoma and in leiomyosarcoma. There was a very small study done by the French Sarcoma Group that randomized women with metastatic uterine leiomyosarcoma to either single-agent gem or gem/docetaxel. And the outcomes were very similar. There were some methodologic challenges with that study due to some imbalances with prior therapy. But there’s also been single-agent gemcitabine studies that have looked at activity in soft tissue sarcoma that have shown activity, including leiomyosarcoma.

So in my view, it’s important just to remember that single-agent gemcitabine remains an option in the armamentarium, particularly for people that have a poor performance status and that you’re concerned about the added toxicity of the docetaxel. I think people with excellent performance status, yes, the combination, I think, is the standard. But I wouldn’t take off the list gemcitabine as a single agent in people that we might be more concerned about tolerance for.

DR LOVE: What do you think would have been seen in a trial looking at ifosfamide/doxorubicin versus gem/docetaxel?

DR GEORGE: I don't know. That’s a good question. I mean, I think what we know about ifosfamide/doxorubicin in general in soft tissue sarcoma is that you have a higher response rate, objective response rate, when you look at the combination of ifos plus dox versus doxorubicin alone. But when one looks at the longer outcomes, progression-free survival, overall survival, it’s not entirely clear from a statistical perspective that it’s superior. And we know the toxicity is higher.

So by general principles within soft tissue sarcoma, unless someone’s very symptomatic, and most of the standards within the context of the NCCN Guidelines is that anthracyclines alone without ifosfamide are often considered the standard. But if one really is trying to get an objective response rate because of profound symptoms, then the combination is considered.

So I think it’s something in the armamentarium. There have been some old single-agent studies that have suggested that ifosfamide might not be as active in uterine leiomyosarcomas and leiomyosarcoma in general, as it might be in other soft tissue subtypes. And clearly the toxicity is increased. So I think it’s one to consider using but using judiciously.

DR LOVE: So I always love it when someone presents a case where a patient receives a therapy that ends up being approved. And I guess that’s kind of what happened with this patient. Can you talk about what the next step was for her?

DR GEORGE: Yep. So for this particular patient, she was on gemcitabine alone. And then actually I didn’t include all of this detail in the slide, but actually what happened to her was I ended up giving her a holiday from chemotherapy. So she ended up about 6 or 8 months off all therapy. And then coming back from her holiday, eventually her disease regrew. I rechallenged her with gemcitabine initially, actually. She had a nice resumption of response, but it was relatively short lived. Then she recurred, progressed, multifocal, in the lung.

She was treated with dox/olara. And she actually had a really wonderful response. She tolerated the drug well. I think the doxorubicin plus olaratumab is an important study to think about.

Basically what the study design is, olaratumab is a monoclonal antibody that works against PDGF receptor alpha. Exactly the mechanism of action as to improved oncologic outcomes is still being defined, but it’s thought that it might have something to do with tumor stroma interaction. And the study was doxorubicin alone versus dox plus olara. And this was based on an earlier Phase II study with similar design.

And what was shown was that primary endpoints, progression-free survival, there was no statistically significant difference between the arms. But when one looked at overall survival, there was an 11-month improvement in overall survival when one looked at dox/olara versus doxorubicin alone.

DR LOVE: And that was really very striking. I think we should mention that even though, quote, the progression-free survival wasn’t improved, it actually was. I mean, the hazard rate was 0.67, but the p-value was .06-something. So it wasn’t quite —

DR GEORGE: It just missed it.

DR LOVE: I mean, it doesn’t really match up with the degree of survival benefit.

DR GEORGE: Yes.

DR LOVE: But this bump in survival was really interesting.

DR GEORGE: Yes. And I think not only was it interesting, I mean, we haven’t had a drug in soft tissue sarcoma, a non-GIST soft tissue sarcoma, that’s improved overall survival in many, many years. So this was really quite a striking finding. And because of it, it led to the FDA approval of the compound in the fall.

DR LOVE: There are a number of examples of this kind of research finding in oncology, not maybe exactly the same, but where either you don’t see a PFS advantage and a survival or it’s not very impressive. And people always struggle to try to explain. Sometimes people say maybe the trial was too small — it’s some kind of statistical fluke one way or the other. Others bring in biologic hypotheses. What’s your take on it?

DR GEORGE: I think we don’t know. Part of it, I think, could be related to the study size. I think part of it could be related to we don’t have good data yet on how people were treated postprogression. I think on studies like this, where overall survival is the secondary endpoint, PFS is the primary endpoint, you can’t control for postprogression treatment. So there’s potential sway or variability in there.

DR LOVE: It looks like the trial design is that the control group could receive olara on progression. Did they?

DR GEORGE: Yes, that’s true. So patients could receive olaratumab as a single agent on progression. That’s right. And they did. I don’t have the numbers in front of me, but I think it was around 40% of the patients in the single-agent arm did receive olaratumab as a single agent upon progression.

DR LOVE: Now, is this a randomized Phase II?

DR GEORGE: That was a randomized Phase II.

DR LOVE: And is there going to be a randomized Phase III? I would guess it’s very hard to get big numbers in this disease.

DR GEORGE: Oh, yes. So the FDA approved the drug as an accelerated approval. So it requires a confirmatory Phase III. The study’s already been accrued. And hopefully it will read out sometime in the next couple of years.

DR LOVE: Interesting.

DR GEORGE: To see if it is, indeed, a true finding, a reproducible finding.

DR LOVE: What about tolerability and side effects when — of course, you have both doxorubicin as well as the olara. I note that in your case report, you brought up the issue of nausea and anaphylaxis.

DR GEORGE: Yes. So because it’s an antibody, there’s always a risk that people could have a reaction to the antibody. And actually, Dr Van Tine, who’s from the Midwest, talked about how that’s a different challenge, perhaps in different parts of the country. What I think is actually one of the biggest differences between the 2 arms was myelosuppression, as well. It seems that the olaratumab may increase the degree of myelosuppression compared to doxorubicin alone. But I think that, again, will be something that will be better sorted out in the confirmatory Phase III. The patient population will be a little bit more homogeneous. And I think impact of numbers of prior therapies and things can also help sort out the myelosuppression issue.

DR LOVE: It’s interesting, too, kind of the discussion that went on about how do you put this all together in terms of taking action, because you don’t have a comparison of doxorubicin and olara versus gem/docetaxel. So you have to kind of do indirect adding it up. And I’m curious about what your take is.

DR GEORGE: I think it’s important to note that in the randomized Phase II that led to the accelerated approval, it was not limited to first-line patients. So I think that’s really important. So my take on it is, again, I think gem-based therapies with gem/docetaxel are an important tool in the toolkit. I think doxorubicin plus olara is an important tool in the toolkit. For many patients, I am starting doxorubicin plus olara first line, primarily because of the survival advantage.

But with that said, if for a patient preference or a toxicity concern I choose or together with the patient we jointly choose to use gem/docetaxel first line, I think that’s fine, because I know I can come in with dox/olara as a second-line option. So right now, based on the data we have, it’s not approved only in the first line. The confirmatory study’s looking for first-line therapy, but the approval was not based on first-line data.

DR LOVE: So I guess you would have to kind of look at the, like, the GeDDIS trial and say to yourself, “If those two were about the same and you’re adding on 11 months" — of course you’re not supposed to do that, indirect comparison, Phase II, et cetera. But that’s, I guess, the hope.

DR GEORGE: Right. I mean, one could do that. But again, the study didn’t say that we could only add those 11 months on if we did it first.

DR LOVE: Yes. That’s a good point.

DR GEORGE: Now, with that said, the confirmatory Phase III will be looking at specific line of therapy as the first line. So I think that will give us more information. But I think yes. So this is a conversation personally that I have with patients. I describe to them the survival advantage. I describe to them what we do with the gem/docetaxel. And then we go from there.

DR LOVE: In a weird way, it kind of reminds me of some of the reactions in breast cancer —  we work with your colleagues, Drs Winer, Burstein, et cetera — to the CLEOPATRA study in HER2-positive metastatic disease, where they saw this huge bump in survival when they added in pertuzumab. And nobody quite understood it, but everybody wants to get it in, so to speak. I don't know.

DR GEORGE: Right.

DR LOVE: Maybe we can just finish out with what happened to your patient, because, as you point out, she then went on to get more therapy. And that actually kind of brings out some of the other issues that are involved in the management of the disease.

DR GEORGE: Yes. So she had dox/olara. She had a great response to that. And basically the way that the drug is given — you had alluded to it earlier — is you will give 8 cycles of doxorubicin. Cardio protection is important, because fundamentally — I mean, I think it’s important to talk about. The study pushed the doxorubicin cumulative doses higher than I think many people are typically using in practice. It was 75 mg/m² times 8 cycles, so 600 mg/m² cumulative dose. Now, some people chose to stop after 6 cycles or there might be dose reductions in there, so I just want to caution people to think about that.

Some sites would use dexrazoxane early on. Some would start at cycle 5. So some degree of cardio protection and thinking about cardiomyopathy is important.

This patient did fine, did not have cardiomyopathy. Single-agent olaratumab is then a standard, assuming that you’re remaining in disease control at the time that you max out on your anthracycline. Then people can go on to single-agent olara.

Single-agent olara, it’s important to note single-agent olaratumab is not approved itself other than in this maintenance. But I would not use it by itself. I would not combine it with other therapies, other cytotoxic chemotherapies. Those studies are underway but have not yet been reported out.

DR GEORGE: And then this patient, actually she’s still on that therapy.

DR LOVE: How long has it been now?

DR GEORGE: Gosh. So she’s been on olara for — I started her on the regimen — she was the first person I treated on label, so I probably started her last November.

DR LOVE: Right. So it’s been less than a year that, but she’s still on it. What’s her quality of life now that’s she’s just receiving the olara?

DR GEORGE: Oh, it’s good. Much better. Myelosuppression is a challenge, but that’s manageable. But the quality of life has actually been very good, high quality of life, functioning well with family. She was already retired, so not working, but taking trips and I would say her performance status is a 1.

DR LOVE: So that’s really interesting. So you see actual myelosuppression just with the olara? She gets, what, drops in her white count?

DR GEORGE: Yes. Yes. Not to the same extent that she did on the combination, but still just slight drops — she had a lot of gem/docetaxel, a lot of gem alone. Her bone marrow’s always been sensitive even without all that prior chemo.

DR LOVE: That’s really interesting that she’s been on it and she seems like she’s doing well at this point.

DR GEORGE: Yes. She’s doing great.

DR LOVE: Maybe you can talk a little bit about some of the other options down the line, including trabectedin.

DR GEORGE: Yes. So trabectedin is a drug that has been used in clinical trials in the United States for over 15 years. It’s derived from a marine sea squirt. It’s a DNA minor groove binder, so it interrupts cell division. And it has shown, over a number of different earlier randomized Phase II trials, showed benefit in soft tissue sarcoma, particularly in the subtypes of liposarcoma and leiomyosarcoma.

And based on those earlier data, the drug was actually approved in Europe for leiomyosarcoma and liposarcoma. Actually, not just Europe, but basically everywhere in the world except for the United States and some places in South America. And, subsequently, there was a Phase III trial done here in the US that randomized patients with leiomyosarcoma, either metastatic leiomyosarcoma or metastatic liposarcoma, to either trabectedin or dacarbazine. And dacarbazine is a standard active agent, later line, in soft tissue sarcoma.

So patients were enrolled. The study accrued very quickly. And ultimately the drug was approved for both of those histologies based on an improvement in progression-free survival of 3 to 4 months between the 2 arms. This also had preplanned subgroup analyses for leiomyosarcoma as well as uterine-only leiomyosarcoma — uterine primary leiomyosarcoma. And the benefit held. So I think this is a drug that really adds another tool to the toolbox for patients with advanced uterine leio.

DR LOVE: What about tolerability/side effects issues?

DR GEORGE: Yes. It’s an important thing to think about. So this drug is given by 24-hour continuous infusion. So that in and of itself has its own logistic and tolerability issues associated with it. It’s important to note that the drug can have vesicant-like properties. And so if there’s any needle dislodgement or a concern for extravasation, that should be managed. In our center, we manage it as an extravasation of a vesicant.

Other side effects are, it’s hepatically cleared. And it can certainly cause transaminitis. The dose modifications guidelines are actually defined around the midcycle LFTs, particularly the alk-phos and myelosuppression. Nausea can be an issue, but usually up-front management of steroids, which are required actually to try to help manage some of the liver potential toxicity, can help with the nausea/vomiting. Fatigue is an issue. There’s no hair loss with this drug. People like that there’s no hair loss. So that’s good news.

There are rare reports of capillary leak syndrome, but that’s uncommon. So the big ones I always talk to people about are the importance of the extravasation risk, myelosuppression, liver abnormalities, nausea/vomiting and fatigue.

DR LOVE: How about rhabdomyolysis?

DR GEORGE: It’s reported. It certainly is reported that people can have CK. So this is a drug that, through its development, had CPKs being drawn as part of the safety profile. And we certainly saw CPK elevations. I think the incidence, however, of clinically significant or meaningful rhabdomyolysis related to renal dysfunction is really very, very low.

DR LOVE: So what about other nonprotocol therapies that you utilize in patients that get beyond that, including eribulin?

DR GEORGE: Yes. So eribulin is an interesting drug. Eribulin is a drug that was originally looked at in soft tissue sarcoma in Europe in a multicohort Phase II trial. So basically what happened was there was a leiomyosarcoma subgroup, a liposarcoma subgroup, a synovial sarcoma and other different sarcoma subgroups to try to parse out the different histologies that are fundamentally biologically different.

From that Phase II study, there was some suggestion of activity in leios and lipos. And again, this includes leiomyosarcoma of uterine origin and nonuterine origin. That led to a Phase III trial being performed, again compared to dacarbazine as the standard arm. So dacarbazine versus eribulin in leios and lipos was the study design. There was no statistically significant difference in progression-free survival, but there was a modest overall survival advantage. But it was limited to the liposarcoma-only group. So eribulin subsequently has been approved by the FDA for advanced liposarcoma.

Now, the important thing to note about this study is that, if you look at the PFS and the survival curves with eribulin and the control arm, which was dacarbazine, which is a drug that we think of as active in leiomyosarcoma, the curves are almost superimposable. And so actually in the NCCN Guidelines, eribulin is endorsed as a Category 2A recommendation for other sarcomas, including leiomyosarcoma, although it did not achieve the overall survival advantage. Now, that is a finding that’s actually a 2A recommendation in the soft-tissue guidelines but is not a 2A recommendation in the uterine guidelines.

DR LOVE: So 1 final question I wanted to ask you is, we had sent you the transcript of this meeting that unfortunately, because of the snow storm, you weren’t able to get to. Anyhow, I’m just kind of curious what you thought about what was said, because it was kind of an interesting dynamic going on between Brad Monk, kind of representing the gynecologic community, and Brian Van Tine, medical oncology. And I kind of got the feeling that Brad was rethinking — he was kind of not all that excited about olara and all that. And I kind of had the feeling that after he heard Brian talk a little bit, he was rethinking it. But I’m kind of curious what you thought about, reading about this interaction.

DR GEORGE: Yes. No. I thought it was really interesting. And I think it just highlights the needs and the opportunities for collaboration. And I think that they both said that in the meeting, which I think is really great. I think we all bring something slightly different, different perspectives, to the table. And I think coming to the table, to be able to collaborate around these very rare tumors is a great opportunity for us to improve the care for the patients.