Sarcoma: Updates from CTOS 2022

Please note: SARCOMA podcasts are designed to be heard. If you are able, we encourage you to listen to the audio, which includes emotion and emphasis that cannot be grasped from the words on the page. Transcripts are edited for readability. Please check the corresponding audio before quoting in print. SARCOMA CONNECT is an initiative of COR2ED. This podcast is supported by an educational grant from Bayer. The views in this podcast are the personal opinions of the experts. They do not necessarily represent the views of the experts' organisation or the rest of the SARCOMA CONNECT group. For experts' disclosures on conflict of interest, please go to Oncology on www.COR2ED.com. Robin Jones Welcome everybody to our podcast covering clinical practice and patient management highlights from CTOS 2022. The meeting this year was held in Vancouver, Canada, from November 16th-19th. My name is Robin Jones and I'm, a medical oncologist at the Royal Marsden institute of Cancer Research in London, specialising in the treatment of sarcomas. Jon Trent Hi, I'm John Trent. I’m joining Robin Today, as we discuss the important results from the Connective tissue Oncology Society annual meeting and I am a sarcoma medical oncologist at Sylvester Comprehensive Cancer Center in Miami, Florida, U.S.A. I'd like to begin by introducing CTOS so, Connective Tissue Oncology Society is an international group, comprised of physicians and scientists who have a primary interest in tumours of the Mesenchymal and connective tissues. The overall goal of the society is to advance the care of patients with these types of tumours, and to increase knowledge of all aspects of the biology of these tumours, including clinical research, translational research, basic science and even population science, as well as patient, reported outcomes. This year we had nearly 600 attendees for 10 sessions, specific for sarcoma and over 300 posters. Robin Jones The achievement of the year was desmoid fibromatosis, and this is a rare locally aggressive tumour that does not metastasize. It can be challenging to treat, and can cause profound symptoms of pain and also limited movement and limited function. There were a number of very interesting abstracts on desmoid tumours this year, and I'll hand over to John to describe the results of the DeFi trial. Jon Trent Yeah, that's a very great point, Robin. So, Desmoid tumour is not a malignant tumour, it is really a considered a benign tumour, but it's locally aggressive, and can even be life threatening and select cases. Nirogacestat is an oral gamma secretase inhibitor that was developed to interfere with the pathway that's downstream from the activating driver mutations n beta-Catenin or deletion of the gene Apc. When these driver mutations occur, or there's deletion of Apc, theres activation of a downstream pathway including gama secretase. So this inhibitor was developed to interrupt that pathway, kill the Desmoid tumour cells and shrink the tumour, improving patient outcomes. And so in this study, it was a phase 3 study, randomizing nirogacestat to a placebo Patients who received nirogacestat seem to have substantial benefit of those who received placebo in terms of objective response rates, median time to response as well as duration of response. Moreover, nirogacestat was very well tolerated with only really grade one/two toxicity, including diarrhoea, nausea, and fatigue. So nirogacestat was statistically superior to placebo in all of these aspects of efficacy as well as alleviating the tumour burden improving the function and quality of life of patients. Robin Jones Thanks, John, I agree the results at the DeFi trial of very interesting. There were a number of other good abstracts in the desmoid tumour session. Of course it's important to us to highlight that the majority of patients will be managed by active surveillance and pain control, and that only the patients with severe symptoms or progression require a systemic therapy. There were other abstracts focusing on metronomic schedules of chemotherapy. A very important abstract from Tata Memorial Hospital in India, and of course the results of the DeFi trial will lead to a change in our practice, likely for desmoid tumours. The optimal duration of therapy is one thing that remains to be decided, and of course, further follow up with a ovarian suppression is important, which was observed in the trial. And of course it's important in this patient group, because it tends to affect younger women. So do you have any thoughts regarding the side effect profile, and also the other abstracts focusing on surveillance and the more sort of cost effective schedules of metronomic chemotherapy. Jon Trent Yeah, I think those are all really great points, Robin. And so I was impressed by the number of desmoid tumour abstracts the ones that you mentioned, as well as the cryoablation abstract, which is an effective therapy in select patients, that is not a systemic therapy. In fact, it's direct treatment of the tumour through interventional measures. And then certainly low cost is important as well as having a tool that was used in the DeFi trial to really understand the patient’s symptom burden, and the patient's overall toxicity from the medicine versus the toxicity, from the agent nirogacestat. So at our practice at Sylvester, we generally give the patients a period of observation, so at least a serial MRI is performed generally about 3 months apart, before we determine whether there is going to be spontaneous regression or not. There was a lot less spontaneous regression in the DeFi trial than there was, in the prior study of sorafenib in GIST which I thought was interesting, but we all see spontaneous regression, so I do think it's reasonable to give a period of observation, as this is not a metastatic tumour. And then, if the patient does have a progressive desmoid tumour we have to really think about all of these treatment options we have cryoablation, we have sorafenib and we have old-school standard cytotoxic chemotherapy, which is quite effective. and we have increasing number of new agents that are being developed specifically for patients with desmoid tumour, which is a great problem for us to have as treating physicians. We just have to work together to figure out what treatment is best used and most effective and best tolerated by the patients and their specific scenarios. I wonder how the DeFi trial is going to impact your practice at the Marsden, Robin? Robin Jones Yeah, thanks, John, we do have a compassionate access program open for the drugs. So, we have been treating symptomatic patients with this gamma secretase inhibitor. I think, as was discussed at the meeting, the drug will now go through the approval process in many countries including Europe and the UK and we'll just have to see what the decision is in the UK regarding funding approval, but certainly a very effective and well tolerated agent for this challenging disease. One of the other challenging types of sarcoma that we treat is advanced, dedifferentiated or well differentiated liposarcoma. And again, there are a number of really promising abstracts, primarily from phase one trials of mdm 2 inhibitors in a recurrent retroperitoneal liposarcoma, and 2 abstracts in particular led to the initiation of randomized trials. So, the first of BI907828, which has led to a randomized trial versus doxorubicin in the first line, and of course the other abstract was for milademetan, which has been evaluated in a randomized phase 3 trial compared to trevextin. And again, it's really good to have promising data and hopefully more treatment available for this challenging subtype of sarcoma in particular. And I just wanted to do you have any thoughts on those results specifically presented at CTOS John? Jon Trent I'm with you completely, dedifferentiated liposarcoma is a challenging type of sarcoma to treat. They're often retroperitoneal in the peritoneal metastases, and so they're very difficult to operate on for our surgeons and the recurrence rates are very high. And we do treat with chemotherapy, standard cytotoxic chemotherapy like doxorubicin ifosfamide, gemcitabine docetaxel, trabectedin, and even eribulin but you know they're just not that effective, for most patient’s, responses are often transient and so we do need new therapies, and we've known for many years that dedifferentiated and well differentiated liposarcoma are driven by amplification of a certain region in the chromosome, including mdm 2, among other genes. Mdm 2 has the unique capability of binding to wild type p53, and removing it from the cell function similar to a p53 deletion, which is highly tumorigenic in individuals and p53 is one of the most common genes that's impacted in tumorogenesis across all tumour types. So being able to develop a novel agent to target that pathway has been a goal for many years. Years ago early mdm2 inhibitors were developed that just had too much toxicity and not much efficacy. So we are all really delighted to see new agents developed by these small pharmaceutical companies who are interested in developing active agents in oncology, and focusing really on mdm2 inhibitors that are able to bind to that amplified protein, release p53, and allow p53 to actively kill resulting apoptosis of the tumour cells. And so, these two studies were presented at CTOS, and both of these studies showed promising results with reasonably good response rates and pretty good efficacy, and pretty good, fairly few limited adverse events. Now we do have to be cognizant that both of these agents can cause prolonged thrombocytopenia. But it seems like the schedule is being developed in such a way to minimize the risk of thrombocytopenia and still managing to show durable efficacy. And I agree with you, it's very exciting that these agents are already moving into phase 3 registration studies. So, it's quite possible in the next few years that if these studies are positive, we could have new targeted therapies for patients who are affected by de differentiated and possibly well differentiated, liposarcoma. Robin Jones Agreed John, and there were many other interesting abstracts from early-stage clinical trials. I suppose following on with this theme of drug developments and the process from phase one leading to a registration randomized trial. Dr. Van Tine presented the phase one data for the PTC596 or unesbulin tubulin inhibitor in leiomyosarcoma, that has also led to the initiation of a of a randomized trial. And what are your thoughts on this particular drug and the abstract presented at CTOS. Jon Trent Why, I think that this new agent the PTC596 agent is, is quite compelling in its activity, and we do need new agents for leiomyosarcoma. Leiomyosarcoma is a smooth muscle phenotype sarcoma and this type of sarcoma is one of the more common ones and with the smooth muscle features it can arise from blood vessels in muscle, retroperitoneum subcutaneously, and, as I was saying it's very common. And sure we have old-school chemotherapy trabectedin, pazopanib, but we don't really have a good targeted therapy for leiomyosarcoma, because there are many, many different types of mutations, not a solitary driver mutation. But one thing that's emerged over the years is that leiomyosarcoma may have some sensitivity to microtubules, given the responses that we see with eribulin and the responses that we see with the addition of docetaxel to gemcitabine, so I think it is very exciting to see an interest in developing a new microtubule inhibitor for Leiomyosarcoma And in this phase one study patients were treated with this new agent and they may have received dacarbazine in combination with nesbolin and clearly, you know, in the study they showed some efficacy for leiomyosarcoma patients. So, I think it's very exciting time to see a new agent move into the space of the nesbolin. We've had recent approvals with trabectedin and pazopanib fairly recently, but really not the kind of efficacy that we need to be delivering to our patients. So, I'm very excited to be participating in this phase 3 study that arose from a phase 1 study, presented at CTOS from our sarcoma community. Robin Jones Great, and some interestingly as well. Dr. McCabe. presented updated results of the rECCur trial. And in many ways this is a completely different trial of evaluating drugs that have been used for a relatively long time in the treatment of recurrence to advance Ewing sarcoma, and again very informative and a very an important trial in terms of clinical practice reinforcing the important role of ifosfamide in this disease. And again, what are your thoughts regarding the results. And how will this impact your practice? in Miami, John? Jon Trent I think that's an amazing trial to be able to do a study that large and such a rare subset of a rare tumour and Ewing sarcoma is really commendable, and I was impressed by the data and also impressed by the study design, really methodically evaluating salvage therapies for patients with Ewing sarcoma. And this is pertinent to all of us. Sure, Ewing sarcoma is one of the more common paediatric sarcomas. But if you do the numbers, there's actually more adults with Ewing sarcoma than there are children. So understanding salvage therapy is critical in our practice. And so these salvage therapies we use most of them, but a lot of times patients don't make it through all of the salvage therapies. And so it's very important to understand which ones are the most active, so that you can have a higher probability of getting a response in patients that have limited treatment options. The use of high dose, ifosfamide is a very common salvage therapy in our practice, particularly in individuals who are under 50 years of age. Older than that, I think it's a little challenging in terms of toxicity. But I feel personally validated, that it measures very well with the practice that we have here at Sylvester. And so I was very excited to see the data presented that, CTOS this year. Robin Jones Indeed, and there were many more interesting abstracts. I’m conscious of the time. But Dr. Loong presented updated efficacy and safety data on entractinib, in patients with NTRK fusion, positive sarcomas again reinforcing the tremendous activity of this class of drug in NTRK fusion, positive sarcomas. And also a very interesting abstract by Dr Kleinerman and colleagues of a novel CD103 + cDC1 dendritic cell vaccine for osteosarcomas . So there were many, many fascinating and interesting abstracts at the meeting this year, and unfortunately we don't have time to present them all. But it was a very, very good meeting, in my opinion. Jon Trent Yeah, I had a I had a great meeting. Perhaps we could maybe just end mentioning briefly some of the abstracts on gastrointestinal stromal tumour, since it's one of the more common tumours that we see in patients with GIST and I thought there was several good presentations. One of the presentations by Steve Bialick and colleagues from our institution, looked at circulating tumour DNA in patients with GIST who were progressive on prior therapies. And really we're starting to tease out which patients benefit from which agents, and so it's been known from pre-clinical data that sunitinib is highly effective against exon 13 mutated GIST and also anecdotes that it's not very effective against exon 17 mutated resistant GIST and conversely, regorafenib is active at exon 17, but not so active at exon 13. And so it was really nice to see clinical validation of pre-clinical models suggesting that perhaps patients with exon 13 mutated GIST should be receiving sunitinib, no matter what line of therapy, if that's the driver mutation as compared to regorafenib. Did you see any other interesting GIST abstracts Robin? Robin Jones Yeah, I think all the abstracts in the GIST session were great, and I particularly liked the abstracts focusing on the analysis of micro GIST following through to larger tumours. Again, giving a fascinating insight into the development of this disease. I'd say, you know one of the things I really like to say, is that there were a number of great sessions. I thought that the retroperitoneal sarcoma session was excellent. Particularly deep discussion on operability, there was an abstract from the UK showing the challenges of actually deeming a retroperitoneal tumour as inoperable which, of course, is important implications in terms of the management of the patient, all the way through to eligibility in terms of clinical trials, if that if a tumour is deemed inoperable. And I say, I thought that the programme committee had done a great job in organizing and selecting all of these abstracts. And suppose with that one of my well, my last questions to you, John is what are your key takeaway message messages or the key highlights from the meeting this year? Jon Trent I agree with you. I'd like to commend the programme committee for really selecting important biological studies, clinical studies, translational research that's helping us not only understand the disease, but really focus on developing new therapies. And so I think the key takeaway is that there's a lot of promise, for new agents for patients with advanced dedifferentiated liposarcoma, which we really need, there's promise for patients with leiomyosarcoma, which we really need new agents there as well. We found active salvage therapy in Ewing sarcoma and also it would be remiss not to mention the ENLIVEN study where confirmation, long-term presentation data from the study confirms that patients with TGCt do get relief of symptoms by taking an oral TKI. I'd like to say that I'm really looking forward to next year's meeting and all of the new advances that are going to be taking place over this year. And certainly, on this this podcast I've enjoyed working with you, Robin, and hopefully we can report out on next years CTOS as well. Robin Jones Fantastic thank you John, and thank you everybody for listening, and I just like to say likewise with a pleasure to work with you. Thanks so much. Jon Trent Thank you.