Learn about the emerging role of CDH6-targeting antibody–drug conjugates for ovarian cancer with Kathleen N. Moore, MD, MS, FASCO, and Isabelle Ray-Coquard MD, PhD, discussing the latest results and implications of studies evaluating raludotatug deruxtecan and other agents.
In this episode, Kathleen N. Moore, MD, MS, FASCO, and Isabelle Ray-Coquard, MD, PhD, discuss the emerging role of CDH6-targeting antibody–drug conjugates (ADCs) for ovarian cancer, including:
Presenters:
Kathleen N. Moore, MD, MS, FASCO
Deputy Director and Cancer Therapeutics Co-Lead
Stephenson Cancer Center at the University of Oklahoma
Professor
Department of OB/Gyn
ASCO BOD
Oklahoma City, Oklahoma
Isabelle Ray-Coquard, MD, PhD
President of the Gineco Group
Centre Leon Bérard
Reshape Lab Inserm u1290
Université Claude Bernard Lyon Est
Lyon, France
Content based on an online CME program supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.
Link to full program:
https://bit.ly/43PXoeP
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Kathleen Moore (Stephenson Cancer Center at the University of Oklahoma): Hi everyone, I am Dr. Kathleen Moore. I am a gynecologic oncologist, Professor at the Stephenson Cancer Center in Oklahoma City, where I serve as Deputy Director. I am excited to be here.
Dr. Isabelle Ray-Coquard (Centre Leon Bérard): Hello, my name is Isabelle Ray-Coquard. I am a medical oncologist working in the Centre Leon Bérard Comprehensive Cancer Center. I am also Professor of Cancer at the Université Claude Bernard Lyon Est. Happy to be there with you and with Kathy to discuss about this so exciting topic of CDH6 and treatment targeting this membrane receptor.
Dr. Moore: CDH6 or cadherin-6 is this transmembrane protein that is overexpressed in a lot of cancers. And I think we will talk at the end of this podcast around other solid tumor opportunities, but it is very overexpressed in high-grade serous ovarian cancer without a clear prognostic sort of role.
It will be important to remember that CDH6 seems to be of particular interest in ovarian cancer, but also in renal cancer, where we have seen an overexpression of CDH6 in this tumor. Also, we do not see overexpression in the normal tissue, which is finally something quite good if we want to anticipate the toxicity of treatment moving in targeting this kind of receptor.
Beyond that, we also do not know exactly what is the role of CDH6 compared to R2, for example, it is not an oncogenic receptor. And this is something that it will be in the future very interesting to continue to explore with the new treatment we have.
This target is not new, although R-DXd, or raludotatug, is the first drug, and I will talk about it in a moment, to show really promising efficacy. We have been here kind of before there was a medication called, it did not really have a name, it was just HKT288 that had a maytansine payload targeting CDH6 in the past.
We are very excited about this medication, but had early and unexplained neurologic events. And so the development of that drug was discontinued, and cadherin-6 fell into the parking lot for a bit of time until raludotatug. Raludotatug deruxtecan, or R-DXd, as we will say from now on, is a very differentiated molecule, though, from HKT288. And I think that is just important to say, I think we all understand this now that these antibody-drug conjugates are basically, there are three components, and they really do create very different molecules based on the antibody, the payload, and probably most importantly and least discussed, the linker.
Technology really does differentiate these agents from one another. So just because this is another cadherin-6 ADC, it is a very distinct molecule. It has a very different payload, a deruxtecan payload.
I think that many listening to this will, of course, recognize that and be familiar from T-DXd. It has a drug antibody ratio of eight, a payload, as we all know with deruxtecan, has a pretty short half-life, a very stable linker payload, and has a bystander anti-tumor effect preclinically and clinically.
So that is the molecule was brought into Phase I in a very typical kind of fashion with a dose escalation that identified initially three doses of interest spanning 4.8-8 mg/kg. The Phase I was done in a select group. There are a number of tumors that express cadherin-6, but high-grade serous ovarian and renal cells are really the two most common. And so, the Phase I was limited right out of the gates to patients that we hope would benefit from this medication.
And then moved into dose expansion with an additional intermediate dose of 5.6 mg/kg, so 4.8, 5.6, 6.4, and 8 mg/kg went to expansion. And so we expanded at those doses, discontinued the 8 mg/kg because of the high rate of pneumonitis, which again shouldn't be surprising based on T-DXd experience, where we saw pneumonitis at the higher dose levels. So the 8 mg/kg was discontinued, and dose expansion continued in the other three doses.
And we presented this, it has actually been two years ago now, in just the ovarian population, platinum-resistant for the most part. There are a few patients that were inappropriate for platinum. Many had received prior bevacizumab and prior PARP inhibitors.
So this was in an appropriately treated sort of expansion cohort representing platinum-resistant ovarian cancer. And the response rate was 46%, which, if you think about the traditional benchmarks in this space with monotherapy chemo, you are talking about 15-ish percent. There were complete responses. There were only four patients whose tumors grew during the Phase I participation.
98% of patients who participate saw some reduction in their tumor volume. And again, 46% making that 30% partial response or greater cut point. So it was very exciting to see 55% had what we call the GCIG response. So clear evidence of benefit here with a toxicity profile that really reflects the deruxtecan second class of medication. Common, but low-grade GI toxicities that were high, because cycle 1 in the Phase I, we did not premedicate and could not premedicate. Once you brought premedication in, that came way down.
Some hematologic toxicities, most common being anemia, and of course the rate of ILD in the highest dose range was unacceptable, and that was discontinued. And we can talk a little bit more once we get into the Phase II, Isabelle, about what the final kind of sense of ILD is with this medication.
But that was the Phase I experience. Thus far, there will be some more data coming out on that as we have just finished that up. That will not look too much different, but that really led to the excitement that led to your trial, REJOICE-01.
So I will kind of flip it back over to you, maybe to continue the story of REJOICE-01, perhaps.
Dr. Ray-Coquard: Thank you, Kathy. Effectively at ESMO, we had the great opportunity to present for the first time the Phase II analysis part of the REJOICE-Ovarian01 study, which is finally a Phase II/III trial. We explore the R-DXd, the patient with platinum-resistant high-grade serous or endometrioid carcinoma.
And in the first part, we would like to explore the dose optimization of R-DXd in this population of patients who received between 1-3 prior lines of treatment, including bevacizumab. They were platinum-resistant, not refractory. Mirvetuximab before can be allowed, and the patients were not selected on the tumor CDH6 expression.
In the Phase II, we have included 107 patients. And exactly as Kathy mentioned before, more than 90% received bev before. 51% of the patients received three lines of prior systemic therapy, a little bit less than in the Phase I. 70% of the patients have already received PARP before. And the last primary free interval is between 3-6 months for close to 60% of the patients.
Interestingly, the tumor CDH6 membrane expression was available for 101 patients, and 94%, much more than we anticipated, were positive for CDH6. And in this group of patients, close to 60% were considered to be highly positive, more than 75%. As said before by Kathy, we also see a huge activity with R-DXd in this Phase II, where across all the doses, we have a confirmed response rate of more than 50%, a disease control rate of 77%. And a median time to response very short, about seven weeks.
What is interesting is that in the forest plot, we see a tumor shrinkage for the vast majority of the patients. And when we look at the response rate between the different cohorts, we see that the response rate for 4.8 mg/kg is 44%, 50% for 5.6 mg/kg, and 57% for 6.4 mg/kg. The disease control rate is between 75% for the 4.8 mg/kg to 77% for 6.4 mg/kg, and for 5.6 mg/kg is more than 80%. Interestingly, we also see an activity tumor response across a range of CDH6 expression level, which was determined by a central test where the tumor CDH6 positivity is defined by the percentage of tumor cells positive for CDH6 membrane staining and any intensity. And we really see an activity in all the different percentages of membrane positivity, which is really interesting for the future.
What we also see in terms of safety profile is that we have more treatment-related adverse events and more treatment-related serious adverse events in the 6.4 mg/kg cohort compared to the two others. And considering dose discontinuation, reduction and delay, it was very few dose discontinuations, less than 6%. The dose reduction is below 20%, and the dose delay in 23%. And again, more dose modification in the 6.4 mg/kg. There is also ILD in this Phase II/III, 3.7%, only four patients, only one grade 3 at the time of the analysis in the 4.8 mg/kg, but more frequently in the 6.4 mg/kg cohort. And so, altogether looking to the activity, but also the safety profile, it was considered that 5.6 mg/kg as the optimal dose. And this is the dose which will be explored in the next Phase III step. We will start soon at the U.S. and worldwide level. So we really confirm what is a category revealed for the first time in the Phase I. And also the population is less selected compared to a population included in the Phase I. The results in terms of activity and safety were exactly the same. This is really encouraging, and also gives us the opportunity to think of the drug in the earlier line.
Dr. Moore: I do feel compelled to say, I've been very involved in this medication from the beginning. I am really proud of this particular Phase II that was led by Isabelle and my partner, Debbie Richardson, because it really did take dose optimization very seriously. Three doses randomized with stratification factors, looking at pharmacokinetics, safety and efficacy, really trying to identify the most effective and safest dose to move into a Phase III, in a manner that took maybe longer than we normally like.
So I am really just proud of that because I think it is a really patient-centered program.
I want to talk about the biomarker a little bit, Isabelle, because with this panoply of antibody-drug conjugates coming at us in ovarian cancer, many of which, at least the topoisomerase one inhibitors, most of which do not have a biomarker. They are all coming in all-comer situations with these response rates of 50%, which is great.
I do wonder, though, whether or not the benefit of the biomarker is not so much in the initial response rate, which you showed in the nice presentation, did not really seem to vary, but whether we will see duration of response or PFS being tied to the level of the biomarker. And I am just wondering, what do you think in the future with R-DXd? Do you think that it is going to matter, the biomarker, or do you think it is just really biomarker agnostic with this medication?
Dr. Ray-Coquard: This is a big question. And I agree with you today, it is not clear how we will see the results. Why? Because in the response rates, as I mentioned, and you said, we do not see a difference, whatever the expression is. But considering the duration of response, the PFS, and perhaps the OS, we will see a gradient of activity. And in this case, perhaps we will be in a situation where the level of expression could impact not on the response, but on other outcomes, which is at the end, something important, and perhaps will be impacted on the design of the future clinical trial, for example, if we want to explore this drug in the early setting, but also as a treatment versus as a maintenance therapy, which can be both a situation where the drug would be interesting, but the activity and the range of activity can also impact this decision.
And I agree with you, the biomarker is not finalized. Also, we report the response rates, whatever is the level of expression, we need to have more data to clearly conclude on this topic.
Dr. Moore: Yes, and I think we will get that, you know, we will get that with continued follow‑up of the Phase II. And certainly with the Phase III, we will certainly have more data, which, I think we can anticipate having multiple of these topoisomerase 1 ADCs make it across the finish line. I mean, just statistically, there are so many, there are going to be a few that that make it across the finish line, and understanding the relevance of the biomarker beyond response rate may really be helpful in picking the right medication for each patient or each patient's tumor in the future beyond response rate.
I think the other thing to anticipate from your study that I am excited about is the fact, and really grateful to the patients who participated, because they all agreed to biopsy, coming on the clinical trial to be compared to the archival tissue to really sort out temporal and potentially spatial, but mostly temporal heterogeneity of the biomarkers. So we still have a lot to learn from this ongoing program. And the patients who participated, you know, you cannot say enough about the generosity of participating and providing a biopsy so that we can really understand how to better take care of patients in the future. So it is going to continue, I think, to provide a lot of data to us moving forward.
Can you remind us what is the activity of R-DXd in the platinum-sensitive population? I know that there are very few patients in the Phase I, but it will be interesting to see what you report at ESMO for this population with platinum-sensitive relapse.
We did study, and many of the programs have pulled out these patients who participated in Phase I trials with tumors that were technically platinum-sensitive by virtue of a platinum-free interval greater than six months, but platinum-ineligible for a number of reasons, you know, maybe because of a platinum allergy, more commonly because of really not having a sense that the tumor was really platinum-sensitive, like maybe the prior platinum, there wasn't a response, but they just did not progress for eight months. You know, there is this group of tumors that we recognize are not likely to benefit from platinum, but yet they have this platinum-free interval that kind of pigeonholes them in these platinum-sensitive populations. So fortunately, we have been allowed to put them on more effective therapies with Phase I.
So 18 patients who participated in the Phase I had disease recurrences that we would consider platinum-sensitive by virtue of a PFI greater than six. They, about 80% of them, had received prior bevacizumab. 80% of them had received prior PARP. So this was a really pretreated group of tumors. 80% of those that had received a prior PARP progressed on the PARP. So, a high-risk group of tumors. I think we're starting to recognize this group of tumors as perhaps different than those we would truly consider sensitive to platinum.
And when we looked at response rates in this group of tumors, it was 72% with a confidence interval that went from 47% to 90%. So the confidence interval was wide, but still the lower limit of that confidence interval was still a really pretty good response rate.
We did look at CDH6 expression, just high versus low, just to get a sense. And it really did not matter. 18 patients, so take that with a grain of salt, but we saw deep responses in both those with high and low CDH6 expression.
Interestingly, the group of tumors that had progressed on a prior PARP, which was 12 of the 18, so now we're getting to very small numbers, but the response rate there was 58%. Again, just giving us this sense that tumors that have progressed on a prior PARP may be different, and we may need to think about them a little bit differently. The median duration of response was overall about 5.7 months, although we are still following them. Median PFS was 8 months in this group of tumors, who were not first platinum-sensitive occurrence, by the way. These were heavily pretreated. So it is a signal that something we want to follow up on.
It is very consistent with other small case series of tumors that were technically platinum-sensitive, but have received an antibody-drug conjugate. And I think points us to some opportunities for the future to use this and/or other medications maybe instead of platinum in those tumors that are really definitely high-risk for an attenuated response to platinum. Maybe we could use this instead of, perhaps this is a maintenance, although I think we need to talk about that, but it does open the door for maybe moving this antibody-drug conjugate up in lines of therapy into more biologically selected group of tumors. And I think that just needs to be studied a little further.
What are your thoughts on ADCs in the platinum-sensitive setting, Isabelle? Like, are you ready for that, or …?
Dr. Ray-Coquard: Honestly, after what you report at the ESMO Gyn for the platinum-sensitive and what we see particularly for the patient who progressed during PARP, also it is retrospective data coming from a large Phase III as part of one. I think we have a great opportunity to consider this drug alone or in combination with bev, for example, in this group of patients. And I hope that we will see clinical trials to make the demonstration.
Now, I agree with you, the maintenance could be something relevant for a population where we know that at the end of the chemotherapy, the patient will relapse shortly. And we know that there is a poor prognostic population in ovarian cancer. Also, we have PARP inhibitors in the first-line. It is not enough. So trying to use this drug for a large population in the high-grade ovarian cancer is something important. I would also like, you know me, mentioned raludotatug, if we see some activity, will be something relevant.
This population did not bring the same opportunity than high-grade ovarian cancer or breast cancer. So exploring this drug largely in gyne, I would be very happy to have this kind of treatment and others. And definitively, with the piece of data we have built together, we can say today that CDH6 is an important topic in ovarian cancer.
And working on this target and exploring new treatments, including raludotatug deruxtecan is something that we definitely have to provide for our patients with ovarian cancer in the near future.
Dr. Moore: Yes, I agree. I think, to your point, there is a study, it has not resulted yet, but called DESTINY-PanTumor, which enrolled a whole cohort of non-serous epithelial ovarian cancer, clear cell, mucinous, low-grade endometrioid, etc. So that cohort is enrolled. We are just waiting for it to mature along with endometrial and cervical cancer. There are maybe a couple other examples of that out there, but that will be our first peak specifically at the activity of these topoisomerase 1 ADCs in a non-serous, designated cohort. I think that that is the first study to look at that. So that is going to be an important readout that hopefully we will see maybe in 2026.
And then the other thing I would just mention is that just with everything, once you have a successful drug, there is more development. So there are other cadherin-6 antibody-drug conjugates in development that are worth noting.
They are distinct molecules. There is CUSP06, which has, of course, a different linker and an exatecan payload. It has presented very early Phase I data in high-grade serous ovarian cancer with a response rate that was 36%, but in the dose escalation. So I think we need to see what they look like in the expansion cohorts once they get to their recommended Phase II dose. The efficacy and the side effect profile here may be quite different than R-DXd. And I think we can anticipate that with an exatecan versus deruxtecan payload, which is better efficacy-wise and safety-wise.
So it is important that we have another molecule in development. And then there is another one, SIM0505, that has not reported out yet, but is in Phase I dose escalation. So there are others coming that we are going to need to weigh the risks and benefits of to optimize which one we select for our patients.
So it is exciting. I mean, I think you want to have kind of the best drug coming forward. So I think we will kind of wait and see, but it is good to have options.
But I think with that, other things you wanted to mention about the space, Isabelle?
Dr. Ray-Coquard: We can perhaps mention that today there are a lot of clinical trials available for patients with ovarian cancer. We are speaking about REJOICE-Ovarian01. The Phase III will be open soon for all these patients. And I think that it is important that our colleagues are aware about that and can also participate or addressing the patients. This is something that patients will appreciate, I think.
Dr. Moore: Agreed. Yes. It is kind of overwhelming right now, the number of antibody-drug conjugates in the space. So it is a bit of a tension of really great opportunities for patients, but also making sure that we're designing the studies that are very patient-centered and are trying to optimize the right drug for the right patient at the right time for the right duration. And we are learning as we go and trying to pivot as we learn.
So it is a fun time, but also there is a little bit of tension to get it right. And I think, really, congratulations to you, Isabelle. I think this is just an exemplary study. It has already taught us a lot. It is going to teach us even more, and hopefully we will get the Phase III up and running soon.