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LMS_04 Trial_Alexandra Diggs
LMS_04 Trial_Alexandra Diggs
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You all can see the slides? Yes. Great. So, I'm going to talk to you all briefly about a trial that was published in the New England Journal of Medicine in September of 2024. It's called the LMS04 trial. It was published by the Sarcoma Group in France, and it compared doxorubicin in combination with trabectin, followed by trabectin maintenance, compared to doxorubicin alone, which is standard of care in leiomyosarcoma. And so, just a little bit of background. Sorry, I'm just going to move this. Okay. So, uterine leiomyosarcoma, that we're going to refer to as ULMS in this talk, is a very rare entity. It represents about 1% to 2% of all uterine malignancies, but it is one of the more common sarcomas that we see, and represents about 55% of all the GYN sarcomas. So, when we do see sarcoma, it's most frequently ULMS. It's a very aggressive tumor, and if anyone in Vietnam has seen it, you guys know that it's a very aggressive disease, and even when we are able to resect it surgically, it has a very high risk of recurrence and a high risk of death, regardless of the stage of presentation. So, if you think of the five-year survival of localized disease to be about 64%, 36% for regionally advanced disease, and 14% for metastatic disease. And even in stage one disease, the recurrence rates are close to 50%, so it's a disease that tends to come back. Because it's a very rare disease, there hasn't been a lot of data that's specific to ULMS to help guide the management of this disease, and that's further complicated by the fact that there are genetic variants in this disease. In advanced stage, so stage three and four ULMS, the adjuvant treatment has been chemotherapy for a long time now. It's considered the standard of care, and the first line is largely agreed upon to be a doxorubicin-based regimen, and this has been true since almost the 1970s. There have been many, many studies that have tried to compare combination treatments to the doxorubicin alone, and up until this study, none had shown a real benefit. There's an important trial in 2017 called the Gettis trial that specifically compared gemcitabine docetaxol to doxorubicin and really showed no difference in survival, but it did show worse toxicity for the gem doce group, so doxorubicin remained the standard of care. We think of the overall survival with doxorubicin to be around 20 months, so a little less than two years. This is just a quick review of the Gettis trial because it's kind of what established doxorubicin as a standard of care, single-agent doxorubicin, and as you can see, really no big difference in overall survival between the two groups, but there was more unacceptable toxicity from chemotherapy in the gem doce group, so it was 16% in that group compared to 2% in the doxorubicin, so we really almost always recommend starting with doxorubicin because the benefit is very, very similar. In terms of trabectidins, and it's a relatively new agent for us, not something we use very often in terms of how it works, it blocks the cell cycle at the G2M phase and alters DNA transcription that leads to cell death. It was first FDA-approved in the United States in 2015. It was approved in Europe about eight years earlier as second-line treatment for ULMS or doxorubicin failure. And then there was a trial in the United States, LMS02, that was a phase 2 trial that initially showed some improvement in progression-free survival when you combined the doxorubicin with the trabectin, and so that was the early data that was the basis for this bigger trial. Similarly, this Tdisc trial that's mentioned on this slide was another phase 2 trial that looked at trabectin in maintenance, and so that's what supported the idea of trabectin in maintenance after the combination of the two. So those are the two trials that gave us the early clinical data. In terms of study design, really quickly, the inclusion criteria was either metastatic or relapsed unresectable lyomyosarcoma, and the trial did not include only ULMS, but it did include a big chunk of ULMS, so that's why it's interesting to us. They had to have at least, patients had to have at least one measurable lesion. They had to be 18 years or older, and they had to have an ECOG performance status of zero to one. They could not have received any prior chemotherapy. They could not have a history of any other cancers, and they could not have any CNS, so no brain metastases or spine metastases. In terms of randomization, patients were randomized one to one between the intravenous doxorubicin alone group, which was every three weeks for six cycles, and then intravenous doxorubicin plus trabectin every three weeks for six cycles. The doxorubicin group did not get any maintenance, but could have post-treatment surgery if there was a good response, and the trabectin group did receive trabectin maintenance every three weeks for up to 17 cycles, so 17 cycles was the most that anyone would receive, and they also could undergo post-treatment surgery to resect any residual disease. So randomization for the patients was stratified according to the tumor of origin site, so there were both uterine cancers and soft tissue sarcomas in this study, and then by disease stage, so whether they were locally advanced disease or metastatic. And then they were monitored every six weeks during treatment, every nine weeks during maintenance or follow-up, and then every three months for a year, and every six months until disease progression, death, or end of follow-up. In terms of primary endpoint, the primary endpoint for this initial study was the progression-free survival, and that was reported previously in a Lancet paper that was published in 2022, and the secondary endpoints were disease control, response rate, response duration, overall survival, safety, and second, progression-free survival. So let's look at the results. So this is how many patients were randomized, there were 150 patients that were included in the study, 76 were randomized to doxorubicin alone, 74 to the doxorubicin plus trabectin arm, 67 of the patients that were in the study had ULMS, so that's about 45%, which is important for us, so a big, big chunk of the study. About 54 patients in the doxorubicin arm completed the treatment. In the doxorubicin plus trabectin arm, 62 completed the induction treatment, only 22 completed the maintenance treatment, but really we're comparing the induction because that's what's more comparable between the two arms. So this is the progression-free survival that was published in 2022. So the median progression-free survival was significantly longer in the doxorubicin trabectin group, it was 12 months compared to six months, so double the time, with a hazard ratio of 0.37, so a statistically significant hazard ratio, which is what's important to us. At two years, the progression-free survival was 30% in the doxorubicin trabectin group as compared to 3% in the doxorubicin alone, so the more time you spend looking at this, the more the trabectin was beneficial. Additionally, in the doxorubicin alone group, 37% of the patients ended up receiving trabectin as a second-line treatment in subsequent lines. So even within the doxorubicin group, there are a lot of patients that received the trabectin, but they didn't have the same survival benefit as those who received it up front. So one of the important takeaways from this study is that trabectin up front is better than trabectin as a second line. And then there were also promising results in terms of overall survival, which is what this paper showed us, and the median overall survival was 33 months in the combined group as compared to 24 months in the doxorubicin alone group, with a hazard ratio of 0.65, so again, statistically significant. The overall survival at two years was 68% in the doxorubicin-trabectin group compared to 49% in the doxorubicin group. Importantly, the majority of deaths for patients in each group were due to disease progression. That's true for 96% of the patients in the doxorubicin-trabectin group and 97% in the doxorubicin alone, so very similar between the two. This is a nice table here that compares, that gives you kind of all of that information summarized. So it shows you the median progression-free survival that was significantly higher in our experimental arm, and the progression-free survival at 12 months and at 24 months, and you see that it continues to show really great response. The duration of response was much longer in the experimental arm, 12.7 months compared to 5.6 months. We talked a little bit about the overall survival. Dose reductions, importantly, were higher in our experimental arm, and that's because of the two agents, but one of the things that I think we wouldn't all think of necessarily is that a lot more people in the experimental arm ended up having surgery after induction, so more than double the number, so 20% for that experimental arm compared to 8% in the control arm, which means that the combination of the two agents allowed patients to get to a place where the residual disease was resectable. There were more adverse events in the doxorubicin-trebectin group than the control arm, but not enough to kind of go against the recommendation of that combined treatment. In terms of strengths and limitations, what's important and what's really helpful for us as GYN oncologists is that the study had a specific focus on leiomyosarcoma, and so didn't look at any of the other histologic subtypes of sarcoma, so gives us really good information about this disease specifically. It has a large enough sample size to demonstrate a change in outcome for the patients, and it has data to support the long-term use of trebectin. And then we talked a little bit about the inclusion of surgery to resect residual disease. We think that's really important information. In terms of limitations, it's an open-label design without masking, and that's because it's two agents versus one, so it's very difficult to mask in that setting. There is additional grade 3 to 4 toxicity with the combination treatment, and this requires very careful patient selection for the treatment, but given that we don't have good alternatives, it's still a big step in the right direction, and they're already looking into agents that might be comparable to trebectin but have less side effects. Because of this toxicity, there aren't that many people who actually completed the regimen. We talked about 81% completing induction but only 28% completing maintenance, and I don't know if you remember, but at the very beginning, we talked about a total of 17 cycles of maintenance. On average, people only received 10.5, so not very many got close to that 17. And then one of the other things that the authors mention is that the patients did not have any early cardiac protection from the doxorubicin, and that's something that could have really improved outcomes for the patients, so something to keep in mind for patients getting doxorubicin. So in conclusion, combination therapy with doxorubicin-trebectin induction followed by trebectin in maintenance is associated with improved overall survival and longer progression free survival among patients with metastatic or surgically unresectable uterine or soft tissue leiomyosarcoma. This supports a change in first-line therapy for advanced or metastatic ULMS, given that there's now clear data to support an improved overall survival. And it's very important to note that trebectin up front is better than trebectin in a second line, which is what it was previously approved for. The study also establishes a new median overall survival benchmark, which we mentioned earlier in this talk was 20 months previously for doxorubicin alone is now 33 months for the combination. This is just a slide that shows the guidelines that are used in the United States, the NCCN guidelines that have now updated their recommendations for first-line treatment and the preferred regimen, including doxorubicin-trebectin specifically for ULMS. I think I'm over time. Sorry about that. This is, these are a few questions that we kind of discussed when we discussed this paper. And so I'll leave them here for you all. One of the things we talked about was where did patients get the benefit from? Is it the initial addition of trebectin? Is it the, is it the maintenance? Is it the surgical resection? I think some of the data supports that that upfront initial addition is very helpful. How feasible is this regimen? It's only 28% of the people actually completed maintenance therapy. Is that because of toxicity? Could we find alternative combination treatments with less toxicity? And there are studies that are looking into a comparable agent called lurbinectadin that might have less toxicity than trebectin. So that's an interesting thing to keep in mind. And the last point is really, is a little bit more specific to the United States, but refers to how insurance companies will agree to pay for trebectin and how that might affect how we do studies. Because if we're not getting funding from certain, from the company, the pharmaceutical companies that are making the agent, then it's harder to, to fund trials with the, with these agents. All right. That's all I got. Well, thank you.
Video Summary
The LMS04 trial, published in September 2024, focuses on treating uterine leiomyosarcoma (ULMS), a rare and aggressive sarcoma. Conducted by the Sarcoma Group in France, it compares the efficacy of doxorubicin alone, a standard treatment, against a combination of doxorubicin and trabectedin with trabectedin maintenance. The study involved 150 patients, primarily with ULMS, showing that the combined treatment offers superior outcomes. Specifically, progression-free survival doubled from 6 to 12 months, and overall survival increased from 24 to 33 months compared to doxorubicin alone. Despite higher toxicity and challenges in completing the regimen, the trial indicates a potential shift in first-line therapy for ULMS, emphasizing that upfront trabectedin is more beneficial than its use as a second-line treatment. The trial results have informed updated US guidelines and suggest exploring alternative treatments with fewer side effects.
Keywords
uterine leiomyosarcoma
doxorubicin
trabectedin
progression-free survival
first-line therapy
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