Sarcoma Updates from ESMO 2024: Insights from Dr. Herbert Loong

Herbert Loong, Clinical Associate Professor in the Department of Clinical Oncology at the Chinese University of Hong Kong, discusses key sarcoma updates from ESMO 2024 in this episode of OncoDaily, hosted by Shushan Hovsepyan. Highlights include the EREMISS trial, which shows that regorafenib improves progression-free survival after doxorubicin chemotherapy; the Immuno-SARC2 study indicating positive outcomes for clear cell sarcoma with sunitinib and nivolumab; and promising combination therapies for angiosarcomas. Additionally, studies on GISTs demonstrate the efficacy of lenvatinib and axitinib plus avelumab.

Herbert Loong is the Chair-Elect of the International Affairs Committee, a Scientific Track Member (2022-2024), and the Track Leader for Sarcoma (2023) at the American Society of Clinical Oncology (ASCO). Additionally, he has been promoted to Steering Committee Member at the Lung Cancer Policy Network. Dr. Loong is also the Chairperson of the Asia Pacific Coalition against Lung Cancer, a Board Member of the Connective Tissue Oncology Society, and a Committee Member of the International Association for the Study of Lung Cancer. He is an Associate Professor in the Department of Clinical Oncology at The Chinese University of Hong Kong (CUHK).

Shushan Hovsepyan is the Editor in Chief of the OncoDaily Medical Journal, a pediatric oncologist and an adjunct assistant professor at the Yerevan State Medical University. Currently, she is the Editor-in-Chief of OncoDaily Medical Journal.

She completed her clinical fellowship at the National Institute of Cancer in Milan, Italy and at the St. Anna Children’s Research Hospital in Austria Furthermore, she held a research fellowship position at the European Organisation for Research and Treatment of Cancer in Brussels, Belgium. She is a former co-chair of the SIOP Global Health Network Education and Training Working Group.

Shushan Hovsepyan: Good day everyone and welcome to another edition of the five-minute sarcoma talk on OncoDaily. I’m Shushan Hovsepyan, your host as always, and today I have the pleasure of speaking with Dr. Herbert Loong, Associate Professor in the Department of Clinical Oncology at the Chinese University of Hong Kong and Deputy Medical Director of the Phase I Clinical Trial Center. Welcome Dr. Loong and thank you very much for joining us today.

As you all know, last week Barcelona took place ESMO 2024 and I hope you had a wonderful meeting there. And now I asked Dr. Loong to share updates from sarcoma sessions at ESMO. So now I know that you prepared some slides and I would like to ask you to share the screen and go from there.

Herbert Loong: Sure, that’s great Shushan. Let me just share my screen and thanks again for this invite. The title is five minutes talk. I might go a little over five minutes. There are quite a few good data that was actually presented but in any case let’s just go through this on a whirlwind tour of some of the updates at ESMO. So I’m Dr. Herbert Loong from the Chinese University of Hong Kong and I have decided to break up the talk or this short session into three particular aspects that were particularly concentrated at ESMO 2024.

There were good abstracts in soft tissue sarcomas, good abstract in GISTs, as well as one particular abstract looking at the potential role of using next generation sequencing and molecular tumor boards in sarcomas. So to begin with, the first abstract I’d like to discuss is an abstract or a project known as EREMISS, which essentially is from the French sarcoma group looking at the use of oregoraphanib as a maintenance treatment after first-line doxorubicin chemotherapy.

So essentially patients with prior usage of first-line doxorubicin-based chemotherapy were randomized into one-to-one fashion between the use of oregoraphanib at 120 milligrams per day, three weeks on, one week off, versus placebo.

And the primary endpoint for this particular clinical trial was a progression-free survival. Now you can see here in the bottom is the actual demographics of the patients. The majority of the patients within this clinical trial had leiomyosarcomas as well as some with synovial sarcoma and a mixture of other types of sarcomas that we routinely see in clinical practice as well.

The number of patients who actually had doxorubicin-based chemotherapy or combination chemotherapy seems to be well balanced between the two arms. So to cut a long story short, this is the results indicating the fact that patients who were randomized into the regorafenib maintenance arm actually had a better progression-free survival of 5.6 months versus placebo of 3.5 months. Certainly you would expect the fact that patients who are on the regorafenib arm actually had more adverse events, but if you actually look at the number of adverse events in actual fact, they’re actually quite similar.

Having said that, so there are certainly more grade 3 adverse events in the Regorafenib group versus just placebo. So this potentially is a practice-changing abstract given the fact that now we have a potential role of using a TKI as a maintenance treatment after initial doxorubicin-based chemotherapy.

Another study that was presented by Dr. Martin Broto on behalf of the Spanish sarcoma group is the ImmunoSARC2 study, which actually at this particular juncture is a cohort looking at the use of sunitinib plus nivolumab in patients of clear cell sarcoma. Essentially, this is an open-label phase two study where patients initially are treated with an induction phase with sunitinib first and then subsequently a maintenance phase of sunitinib plus nivolumab.

What you can see is a favorable progression-free survival over what is known in the historical cohorts and a six-month progression-free survival rate of about 51 percent, median progression-free survival of 7.83 months, overall survival of 17 months. Now this is, of course, a non-randomized study, an open-label study, but based on our knowledge of clear cell sarcomas, these are actually very favorable survival results and hopefully we’ll be able to move this particular treatment regimen forward for patients.

Another interesting study was presented by Dr. Breelyn Wilky on behalf of her colleagues looking at a combination of a CTOA4 as well as a PD-1 inhibitor in patients with sarcomas. This is the combination study of botansilamab as well as balstilamab, and in actual fact she has presented prior data of this combination previously, but this is a larger cohort now with 52 sarcoma patients where we’re seeing an overall response rate of 23 percent, and specifically in the patients of angiosarcomas there’s actually a response rate of up to 39 percent.

More interestingly, in actual fact, specifically in the angiosarcomas group where we do expect that there is going to be some response to checkpoint inhibitors, the response were not only in patients with cutaneous angiosarcomas but also in patients with visceral angiosarcomas, and this was somewhat unexpected based on previous clinical trial findings.

Moreover, it does seem as though the duration of response for the responders have been very, very good. Another interesting study, and now shifting gears, is on GISTs, and this is the LEVA-GIST study, which is the use of lenvatinib in patients with advanced GISTs. Essentially, patients who have had prior treatment of both imatinib and sunitinib were randomized in a one-to-one fashion between lenvatinib versus placebo, both together with best supportive care, where the primary endpoint was progression-free survival.

This was presented by Dr. Leserne on behalf of his colleagues at the French Sarcoma Group as well, and what you can see here is the median progression-free survival, again, for patients treated with lenvatinib and best supportive care was better than placebo. However, in terms of overall survival, there is benefit as well, and certainly this may be an option for patients who are refractory to the first two generations of tyrosine kinase inhibitors for GIST. Another GIST trial that was presented was presented by essentially the Polish Sarcoma Group, looking at the combination of exitinib and avelumab, exitinib being a VEGF inhibitor, avelumab, of course, meeting a PD-L1 inhibitor in combination.

In patients with metastatic or advanced unresectable GISTs, again, have to have had prior treatment with imatinib and sunitinib, and patients in this open-label study actually had a three-month progression-free survival rate of 57.1 percent, median duration of response of 18.5 months, and a median progression-free survival of 4.6 months.

What’s more interesting about this study is they recruited patients of various types of GIST, which carries different types of mutations, and interestingly enough, the patients with wild-type GISTs seem to do just as well as patients with the typical kit exon 9 or exon 11 mutation, and there, in actual fact, may open up a treatment option for patients who don’t have molecularly driven GISTs and being able to have a good survival with this particular combination treatment. So we do look forward to more expansion of this particular trial later on as well.

Lastly, I just want to talk about the potential role and the use of next-generation sequencing and molecular tumor boards in sarcomas.

This is a report, again, from the French Sarcoma Group, looking at a project that they’ve been doing known as the Multi-SARC Study, really highlighting the role of NGS in patients with soft-tissue sarcomas.

As you know, the French Sarcoma Group is a very large national group where referrals for sarcomas are all centralized, and in actual fact, in this particular clinical trial, it is patients with newly diagnosed soft-tissue sarcomas where they’re randomized to either get NGS upfront or no NGS, and in the patients who actually have NGS also have their NGS reports brought to a molecular tumor board, and then to identify whether or not there are potential targetable mutations, either through clinical trials or from off-label use of some of the drugs that’s actually registered in France.

And this is to compare, of course, patients who, after the molecular tumor board, did not identify any alterations and then continue with standard of care.

In the recruitment of this particular trial, in actual fact, it’s a very large trial. You can see on the bottom right-hand corner, the demographics, there are about 220 patients in each of the arms, and the most common histology, again, is leiomyosarcoma, followed by liposarcoma, as well as undifferentiated leomorphic sarcoma. And in terms of the molecular alterations that’s been found in these patients, these are typical alterations that we do see in sarcomas.

Certainly, TP53 would be something that’s most common. But in terms of some of the potentially targetable mutations, of course, we’re looking at MDM2 or CDK4, predominantly probably driven by the liposarcoma patients, but we also know that there are other sarcomas which carry these alterations and potentially also targetable with clinical trials of these particular agents. Overall, 47% of the NGS patients had at least one targetable mutation identified, and in actual fact, 36% of the NGS patients received targeted therapy based on next-generation sequencing.

So, with this, that’s really a quick snapshot and summary of the latest results that were presented at ESMO, and I’ll be happy to discuss further.

Shushan Hovsepyan: Thank you so much for sharing the updates. It was very productive and helpful for our audience, and it is fascinating to see how these studies open up new possibilities, particularly how we can individualise this treatment for different sarcoma types, and the challenge now lies in how quickly we can translate this into practice, and what are your thoughts about where is the future of sarcoma research is going?

Herbert Loong: Yeah, I think there’s been a lot of interesting ideas, as well as preliminary evidence of all these approaches, but I think one of the difficulties with sarcomas is it’s still relatively rare. These are relatively small patient numbers, and I think what needs to be in steps really is to harness or hone down on one or two of these ideas and really make it more international, have more involvement by the international community, and then see whether or not we could expand based on the number of patients that we have globally to try to really establish the prospective evidence of some of these trials.

Shushan Hovsepyan: Yeah, I completely agree. Collaboration is the key for sarcoma research, and yeah, thank you, Dr. Loong, for this comprehensive overview, and for our audience, I would like to thank everyone who joined, and until next time, stay well and stay tuned. Thank you.