Introduction: Tale of Two Cities — ASCO 2025

DR LOVE: Hi, everybody. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we continue our series with a discussion of gynecologic cancers. We have a great faculty today: Professor Susana Banerjee from the Royal Society of Medicine, the Oncology Section in London and Dr Ursula Matulonis from the Dana-Farber Cancer Institute in Boston.

As with all of our programs, we will be discussing the use of unapproved agents and regimens, so check out the official prescribing information for more.

As with all of our Year in Review series, I met with each of the faculty separately in the last week to record presentations. Those are in the chat room, and we’ll be sending out by email links to them again, along with a link to this program tonight, where we’re going to try to take things to the next level.

Here are the papers that are covered by these 2 fantastic presentations. Today we’re not here to go into the details about the trial but really kind of take things to the next level about what they may or may not mean. But check out these presentations. There’s a lot of great information in that.

Here’s where we’re heading. I want to start out with some reflections on some experiences recently really related to the ASCO Meeting, and then we’ll spend the rest of our time talking about the papers that were discussed in these 2 presentations.

So actually as I worked with both of the faculty I became aware of a paper that we really should have included in the presentation that I’m embarrassed to say I was not aware of. It was published in the JCO last fall, and we’re going to talk about it in a second. I’m going to show you how it came up and what I think it means.

So reflecting back on what happened at ASCO. So at ASCO, as we always do, we were pretty busy. We did 13 different programs in all different parts of oncology, but there are 3 that I just wanted to bring out to you and some thoughts I have now a couple weeks later.

So on Friday night we did a 2-hour program on EGFR-mutant non-small cell lung cancer. Can you imagine that? When that first came out 10 years ago I never imagined it would take 2 hours to go through all the data, and I’ll tell you why I’m bringing that up in a second. We had a great faculty for that, great discussions, so much stuff going on there.

But at the same time, we also did a program on colorectal cancer, and we had a great faculty there. We had oncologists presenting cases by video.

And then the next night we did a program on ovarian and endometrial cancer, something that we’re talking about today, and a lot of the colleagues of the faculty, well known to you all, participated in that program. And the tale of 2 cities is really — the 2 cities are GI oncology and gynecologic oncology because I thought there was some interesting contrasts that came up, and again, a paper that I was not aware of.

So first of all, in the GI program, of course, we were anticipating the plenary presentation, now the first adjuvant IO trial in MSI-high disease, which of course was positive, just as everyone expected it to be, and we spent a lot of time talking about that. But then in the Gyn program we had an interesting case presented that kind of stumped me a little bit, a patient presented by Dr. Gigi Chen who had Stage III endometrial cancer. She actually had Lynch syndrome, so MSI-high, had debulking surgery, complete R0 resection, and then got adjuvant therapy with carbo, docetaxel and pembrolizumab; started out with paclitaxel then switched — pembrolizumab. And I’m like where did that data come from that you’re using an IO adjuvantly? We just saw this colon program, and I wasn’t aware. I started asking gynecologic people and even the faculty. They said, “Oh, yeah, we use adjuvant IO in that situation.”

So Susana, I then became aware of this paper, which actually was a second paper that came out of this CheckMate B21 study, and this actually was an adjuvant trial looking at IO — or chemotherapy plus or minus IO. The initial paper, or the overall paper, the results were negative because most of the patients there were MS-stable, but then this paper came out last fall in the JCO looking at the MSI-high patients. And hey, guess what? Even though there were maybe half the number of patients than the colon study hazard rate 0.31, not a big surprise. Kind of similar. We saw 0.5 with colon. Again, you see here less than 300.

But Susana, to me this looks like a positive trial, and now I understand why Dr Chen used IO. Any thoughts about this? Do you think most people are aware of this study? Dr Slomovitz is right down the road from us at Mount Sinai in Miami Beach, and I didn’t realize he had actually done this. Any comment, Susana?

PROF BANERJEE: Well, I think what you’ve also highlighted is the importance of these meetings, these education meetings and sharing information. I think the story is that we’re used to now over the years, looking at advanced recurrent endometrial cancer, MSI-high, seeing the value of PD-1 inhibitors such as dostarlimab, such as pembrolizumab, and then bringing it more forward in more advanced higher-risk disease, and then given the magnitude of benefit seeing consistently in the MSI-high or MMR-deficient population bringing it earlier.

So I agree. This is impressive. It's kind of what we think and expect biologically. Good to see in this subset preplanned analysis. And equally when we look at some of the other studies that we’ve discussed, like RUBY and NRG 008 and others, some of them do include Stage III disease rather than recurrent disease, so the higher risk, with the populations of MMR and — MMR-deficient and MMR-proficient disease. I think increasingly the recognition that you’d like to treat a woman who you know has an MMR-deficient tumor with IO is quite clear.

DR LOVE: So Ursula, also again thinking about the juxtaposition of this with the colon paper is the question that really goes throughout MSI-high disease, do you really need the chemo. And of course there are trials right now going on looking at just IO alone, both adjuvantly, as well as in the metastatic setting. Other questions. I hear questions all the time in metastatic disease of patients who seem to be responding for a couple years, how long therapy should be continued. Any predictions, Ursula, about eventually are we going to be using chemo plus IO or just IO in these patients?

DR MATULONIS: Yeah. I think you’re absolutely correct. I think I really can’t wait to see those trials. Hard to predict, but certainly I think it’s going to be intriguing to see how patients do with IO alone, and can we take away the chemotherapy, which would be such a huge win. I mean, as Dr Banerjee mentioned, studies like GY008 and RUBY in that mismatch repair-deficient group really hitting it out of the park with adding an IO. And I totally agree with the statement said that I also in a node-positive mismatch repair-deficient patient would also use IO as well.

DR LOVE: And again, thinking about what medical oncologists who are hearing both of you another question that come up is what about anti-CTLA4? Ipi/nivo? Maybe the preferred therapy in metastatic MSI colon cancer is ipi/nivo. Are other kind of combinations like going to come into endometrial cancer?

And incidentally, another issue that I think crosses — maybe is going to cross tumor-specific lines, I haven’t heard much about this in gynecologic cancer, but I’m hearing a lot about IOs in MSI-localized disease. Of course, a very — The New York Times even picked up on the Memorial study looking at neoadjuvant dostarlimab. We actually had a patient in the community who was treated with the Memorial regimen with neoadjuvant dostarlimab; hopefully is going to avoid surgery.

And one other just quick comparison just to get your take on it. I’ll come back to you, Susana, when I think about what we talked about in colon and what we talked about in Gyn, we talked a lot about cell-free DNA in the colon program, not only localized but even metastatic disease. There are trials out there. There are intervention trials, randomized trials. There’s a ton of data out there, and medical oncologists are using a lot of cell-free DNA in not just colon cancer but a lot in colorectal cancer.

I don’t hear too much about it in endometrial cancer, but Susana did present this paper from 2024 by Riecio looking at the Signatera assay in Stage I disease. And it was just 101 patients, very small initial study, but 20% — and incidentally, 20% of these patients were MSI-high. They had p53 they looked at. But 15% of these 101 patients had postop MRD positivity, and the recurrence rate of them were 58%, and if they were MRD-negative it was 6%. Now again, 100 patients. This is just the beginning. And I haven’t seen that much data on this, Susana. Any thoughts about where this is going to head? Do you see a lot of research going on in gynecologic cancers or specifically endometrial cancer on cell-free DNA in the future?

PROF BANERJEE: So I think as you point out the concept of measuring minimal residual disease is established, at least in clinical trials and also entering practice in terms of other cancers, but to date I would say in gynecological cancers there hasn’t been the amount of research. And I think that’s probably because when looking at this a number of years ago actually detecting ctDNA has not been so consistent. But as the assays improve, and the limits of detection may well be improving, that’s why it was encouraging seeing the data in endometrial cancer, but also looking DUO-E in endometrial cancer and also in CALLA in cervical cancer, seeing at ASCO effectively 3 important messages about measuring ctDNA in a trial exploratory context. And one of the questions is how are we going to move from this forward and understand more about it and integrate prospectively into clinical trials to learn how it can influence practice.

DR LOVE: Yeah. Actually as we were starting the webinar, before we even started in the chat room, Gonzalo brings up the issue of cell-free DNA from the DUO-E study that we’re going to talk about later. So there’s a lot of interest, as I mentioned, in that.

Ovarian Cancer

DR LOVE: Alright. Let’s talk about ovarian cancer and kind of get an update on what’s been happening. And I’ve got to say, before we get into the data, that I have very fond thoughts about ovarian cancer because our world changed, everybody’s world changed to some extent with the pandemic in 2020, but our world in CME really changed a lot. I mean, our capabilities now are amazing now that we have so much teleconferencing and podcasting. But when I think back to the pandemic, when we shifted our emphasis completely into webinars online, the 2 things I thought a lot about, because they were just peaking around that time, were ovarian cancer — and you can see, August 20^th of 2020 we were doing a program already on ovarian, and we did a lot of programs in the next — during the pandemic. We had cases presented. A very big topic of discussion because of course SOLO-1 was 2018, and then in 2020 it was all happening. And now today I’m just bringing this up because now today things have kind of settled out, but at that point people were trying to figure out what to do, what kind of testing, et cetera.

The other one just incidentally that I think about when I think about the pandemic was CLL, because just at the time the pandemic came CLL had switched from chemotherapy to BTK inhibitors, venetoclax. We did a ton of programs there because it was a common cancer also, like ovarian, where things were dramatically changing. We had so many cases that we talked about. It was really kind of the beginning of what we ended up doing after the pandemic in general so I just have a real soft spot.

And also, as I mentioned, Ursula, it’s been really fascinating to see how things have evolved. We just saw last fall at the ESMO Meeting, Dr Monk presented follow-up data from the PRIMA study of niraparib. You went though this in detail in your talk. We’re not going to get into this other than the fact that they did not see a survival advantage.

Here are the data from the most recent data from the SOLO and PRIMA studies. In the SOLO-1 study it was just BRCA, so whereas in PRIMA they had wild type, they had HRD-negative, et cetera. But in the PRIMA study they did — it looked to me like that’s a significant survival benefit, 0.55 — 0.0004. I think technically, I don’t know, because of statistics or something I don’t know if they clearly said that, but it kind of looks like it, and yet you didn’t see it there.

So I just want to kind of take a step back and ask you both kind of where are we today in terms of making decisions about PARP inhibitors as primary maintenance. So the first questions, Susana, a patient with BRCA or HRD positivity, are all these patients in general going to get a PARP inhibitor from your point of view? Whether or not they get bev are they going to get a PARP inhibitor?

PROF BANERJEE: Yes. I really think that it’s essential for women with advanced newly diagnosed ovarian cancer with a BRCA mutation to be counseled and offered a maintenance PARP inhibitor.

DR MATULONIS: Uh-huh.

DR LOVE: And Ursula, again, that’s the answer we’re getting. But in the beginning, when the data first came out, people were kind of processing what to do, et cetera, and then it settles out. Anything you want to add to that, Ursula? And then the other question is which PARP inhibitor.

DR MATULONIS: Right.

DR LOVE: Because you’ve got potentially — yeah, go ahead.

DR MATULONIS: No, no, no. So I totally agree with Dr Banerjee. I think in a BRCA-mutated, deleterious BRCA-mutated, BRCA1/2 either somatic or an inherited germline mutation, absolutely a PARP inhibitor is considered standard of care. I think where we’re starting to see perhaps a shift in standard of care would be in the patient population whose cancer is homologous recombination proficient. Despite the broad FDA, at least in the United States, broad FDA use — or approval of niraparib in all comers, all patients, as long as they have — the cancer is sensitive to platinum, the use of a PARP inhibitor.

I think this data from PRIMA from the OS to me is very instructive in how we should be talking to patients and really discussing the risks and benefits of 3 years of a PARP, specifically niraparib, in that HRP population. But I totally agree with Susana that a BRCA mutation is standard of care for our patients, and we also can’t lose sight of all the years of what we learned of using PARP inhibitors in the recurrent setting. I know there are differences in FDA and EMA approvals, but there is a suggestion that the use of a PARP inhibitor in that non-BRCA setting may induce resistance to treatment, which I think is really seen in the HRP population. So I think we just have to remember that in the up-front patient population but also getting back to the endometrial cancer population, as well, and not just jumping on that PFS but also thinking mechanistically how the PARP inhibitor’s working and then also long-term survival and complications from the therapy.

DR LOVE: So one other issue that came up at our ASCO Meeting, Susana, we actually had a patient presented by Dr Lyndsay Willmott, a gynecologic oncologist. It was a patient who actually got treated in 2018, the day after the paper was published in the New England Journal. Dr Willmott took the paper, sent it to the insurance company, and they paid for it, and the lady got 2 years of treatment, did great, and then relapsed about a year and a half later. And this was a patient who was BRCA, and the patient went back on — got chemo again, got olaparib again, still on olaparib a year later. She was raising the question of how long, et cetera. But there’s been a lot of attention to the issue of not using — the FDA issues about recurrent disease. But in this scenario, where you have a patient who’s BRCA or HRD who has prior therapy, maybe a pretty long time off therapy, from your point of view, at least theoretically, is that somebody you would treat again, Susana?

PROF BANERJEE: Treat with a PARP inhibitor again?

DR LOVE: Uh-huh.

PROF BANERJEE: Okay. I wouldn’t actually. I think that the interval that you’ve just said is not as good as I would have hoped in a BRCA-mutated patient who’s been on 2 years of olaparib and then relapsing a year later .of course we see it, but I don’t think that interval is — like some of the patients we see in the trial and also in practice who may well not relapse at all. So I would be giving chemotherapy — well first of all be considering surgery if the recurrence is amenable to surgery.

Also, sometimes I do think if it’s oligometastatic disease, for example, depending on where the disease is, if surgery’s not an option, I do think of radiotherapy. But otherwise I’d be giving platinum-based chemotherapy, and I’d be giving a doublet combination, and I would be following with a maintenance PARP inhibitor. That was looked at in the OReO setting, albeit being more patients in the recurrent — from diagnosis and receiving — sorry — PARP inhibitor in recurrent disease. It is an important question because now we’re getting that population that you described, which is first-line PARP inhibitor, then they recur, could they benefit further from a PARP inhibitor. But to date in clinic if I had a patient in that situation outside of the context of a trial I wouldn’t rechallenge with a PARP inhibitor.

DR LOVE: So Ursula, second opinion to you. Can you envision yourself treating a patient who’s had 5 years or whatever of disease-free survival? And what about the BRCA patient who never had a PARP inhibitor but has recurrent disease or metastatic disease?

DR MATULONIS: I think the answer to the second question is easier. And I think for patients who either didn’t have the BRCA mutation detected, which will still happen, or declined to have BRCA testing, who gets up-front platinum-based chemotherapy then recurs at a second — recurs again, I would for sure consider use of a PARP inhibitor post platinum-based chemotherapy, not using PARP inhibitor along as treatment but using it as maintenance therapy.

I think the only time that I would consider using — and again, this is in a BRCA-mutated ovarian cancer patient, a PARP inhibitor after PARP inhibitor would — and I agree with Dr Banerjee, I’d like to see more than a year and a half disease-free duration. But for those patients who do have oligometastatic disease who either have it surgically resected or radiated, especially in the advanced-stage setting, that may just be a clone of tumor that may just be resistant given the heterogeneity genomically of ovarian cancer, high-grade serous histology, I would talk to the patient about the pros and cons.

PROF BANERJEE: So I agree with you in the oligometastatic disease. I do agree there because in a way you’re just removing that aberrant tumor and continuing. But if I gave chemo again I wouldn’t give maintenance again.

DR LOVE: So I might not have been clear enough in telling you about the case because the patient actually had a 5-year disease-free survival, had been on the second time of olaparib.

PROF BANERJEE: Okay.

DR LOVE: But in any event I think your thoughts are well received.

So we’re also going to talk about the issue of IO plus PARP in ovarian cancer, and when we get to endometrial cancer we’ll talk about PARP adding into IO. So Ursula, you discussed this in your presentation, the FIRST study that we just saw, and then the prior studies with the ENGOT study looking at IO with pembrolizumab, the DUO-E study as well. Bottom line, Ursula, in your talk was it doesn’t look like IO is here yet.

DR MATULONIS: No. No, it doesn’t. And these trials really corroborate previous trials testing avelumab and atezolizumab. Those are trials that have also been done adding those checkpoint inhibitors to up-front chemotherapy. In some of those trials, especially the avelumab study, there may have been even a detriment to patients receiving the IO, but there’s really no justification for using an IO up front added to chemotherapy with or without a PARP inhibitor.

DR LOVE: So I also want to briefly mention this interesting combination. It’s pretty hard to pronounce. I’ll call it avu and defactinib, avutometinib — I should practice that more.

DR MATULONIS: Avuto.

DR LOVE: Yeah. So again, Ursula, you discussed this. Really fascinating with KRAS-positive disease, low-grade serous cancer. Bottom line — again, I really refer you to Ursula’s talk. But bottom line is this is kind of ready for prime time, Ursula?

DR MATULONIS: Absolutely. 100%, yeah. And Dr Banerjee is really the developer of this, so she’s the expert. But I think this is a very active regimen. It is a win for our patients with low-grade serous ovarian cancer, where we’ve had hormonal therapies and where chemotherapy really does not have much activity. And these are really impressive results; a median duration of response of 31 months for KRAS-mutated ovarian cancer, median progression-free survival 22 months, so it’s a real win.

And these mutations, this is where maybe circulating tumor DNA can also be helpful in kind of trying to figure out what would be next after this therapy. But this is a real winner of a combination, avutometinib and defactinib. And I think these results that were presented by Rachel Grisham at SGO really, again, make sense. Prior MEK inhibition results in a lower response rate, prior bev, prior chemotherapy, just like we’ve seen with other therapies, as well, show reduced response rates. But still, even in the setting of patients receiving those therapies this combination still has very significant efficacy in the RAS-mutated population, and specifically in KRAS-mutated population.

DR LOVE: Yeah, and you wonder about other tumors where you see that so often.

Susana, you’re one of the few people who has experience with this combination. I don’t know exactly what the issues are, but it looks like it has a significant amount of toxicity. What do you see?

PROF BANERJEE: Well, I’ll actually argue otherwise because you’ve got to compare what it would be like with chemotherapy but also with MEK inhibitors such as trametinib or binimetinib, and actually the discontinuation rates in the trametinib Phase III study was over 30%. And I think discontinuation rates are a really important reflection of how well patients may well be tolerating treatment, yet so far in the Phase II study, RAMP 201, and the Phase III is ongoing, the rates of discontinuation are considerably less. So it's class effect of side effects in terms of what we know are familiar with MEK inhibitors, but actually in terms of the rates of discontinuation and indeed dose modifications they appear to be better so far, and that’s certainly what I see in my patients. I had the privilege of participating in the binimetinib and the trametinib study, as well as leading this study, so I can see first-hand how the side effects compare with other drugs.

DR LOVE: Well, actually, I was just kind of looking at dose interruption, but maybe this is more paper toxicity. I see that you see elevated CPK, but I guess is that usually asymptomatic or do they have myositis?

PROF BANERJEE: Yeah.

DR MATULONIS: It is. That’s correct.

PROF BANERJEE: Exactly. It’s asymptomatic. And also, as your probably familiar with, in clinical trials, at least in the beginning, we have very strict criteria for holding drug because these are new drugs, so we need to know how safe they are, so a very conservative dose interruption schedule. And that changed during the protocol once we recognized the safety profile.

DR LOVE: So again I really refer you to Ursula’s talk where she talks about this ROSELLA study. We could spend 15 minutes talking about it. Just such a fascinating concept in terms of looking at the glucocorticoid receptors. This was nab paclitaxel plus... Again, there’s a lot to say about it, but the bottom line is it looks like it’s effective, even a survival benefit.  

Anything you want to — again, you want to say about this? I know in your talk you brought up a number of questions about it, including the fact that nab is not used very much. So you see this coming into practice, Ursula, and how?

DR MATULONIS: Yeah. Neil, I think it’s the beginning of potentially a new therapy. I did discuss it in my talk that it’s a little surprising that Lancet accepted it because it’s really interim results with about a 1-month improvement in median PFS and no OS benefit at the moment. Trend, yes, but not statistically significant. So I think we need more information. I’d love to see a potential biomarker that could distinguish patients who really might have a significant improvement in progression-free survival, perhaps OS.

A lot of the work that was done was done by one of our former faculty here, Jen Veneris, and she really did — was able to quantify levels of expression of the glucocorticoid receptor and that the higher levels of expression predicted poor outcomes, poor responses to chemotherapy compared to tumors that had less. So it would be great to see a potential biomarker come into play as well.

DR LOVE: I want to move on in a second and talk about HER2-positive gynecologic cancers, but first, as always, we see press releases come out that are intriguing. We thought that IO was not going to be part of ovarian, but here we have actually in platinum-resistant disease chemo plus or minus pembro. Supposedly there’s a positive study out there. I don’t know. Maybe we’ll see it as ESMO, but we’ll see how positive it is and whether it’s even worth thinking about.

Just to mention, we saw survival data on the MARISOL study looking at the antibody-drug conjugate mirvetuximab now clearly entrenched.

I want to ask you about this new ADC. I feel like we talk about ADCs every day, Ursula, here when we talk about solid tumor oncology. This is an interesting target, CDH6, raludotatug deruxtecan. We know deruxtecan is in a number of ADCs and of course T-DXd that we’re going to talk about in a second. Pretty interesting-looking waterfall plot, Ursula. Any thoughts about this, how it’s tolerated and where it’s heading?

DR MATULONIS: Yeah.

DR LOVE: And also the relationship to the CDH levels, which you also see seemed like it worked in everybody.

DR MATULONIS: That’s right. I think the raludotatug deruxtecan I think is a really interesting drug. It’s in Phase III testing right now in platinum-resistant ovarian cancer, and it has several benefits, as you showed with that waterfall plot, which is pretty impressive. And I think also if you’re a biomarker believer or not believer this is a drug that allows you to use the drug seemingly regardless of the levels of CDH6.

So for patients where the tumor gets lost, which happens, tumors get destroyed after 10 years in some hospitals, and sometimes it’s really hard to do tissue biopsy, so there is an advantage of not having a biomarker, and I think Dr Moore had a very nice presentation really showing that there was responses regardless of the biomarker being present or not. And I think we’re seeing here in terms of the toxicity profile very compatible with a TOPO1 payload. And we’ve got mirvetuximab in the folate receptor alpha-positive platinum-resistant setting, up to 3 prior lines, with a microtubular DM4 payload. So I think this drug is going to be interesting, and we’ll see how the Phase III moves forward.

DR LOVE: And here, again, Ursula’s talk went through all these Phase III in platinum resistant. It wouldn’t be a big surprise if we start seeing other ADCs coming into ovarian cancer. You already have 2, and we’re about to talk about the second one. We already talked about — we referred to mirv — mirvetuximab.

HER2-Positive Gynecologic Cancers

DR LOVE: But let’s talk about HER2-positive gynecologic cancers. We actually did an entire CME program at the SGO Meeting just on HER2-positive gynecologic cancers. It was incredible because a couple years ago I couldn’t find any cases where people had used T-DXd. All of a sudden I went out, and they were there. They’re using it, and it looks like it’s working in community practice the way it’s billed. Of course there are issues about HER2 testing. Obviously right now, at least if we’re talking about T-DXd, of course trastuzumab has, also has a role, but the new story is T-DXd. And of course T-DXd has a pan-tumor approval for IHC 3+, but also in the trials you see patients included in these trials with T-DXd who were 2+. Some of them had reflex FISH testing, some of them didn’t. This is something that’s going to get more attention, even in breast cancer, looking at better HER2 measurements.

But Susana, can you talk a little bit about what we saw in the DESTINY-PanTumor program, where there were several gynecologic cancers, but also biliary tract cancer. But cervical, endometrial and ovarian all were looked at, fairly small numbers, but you see a pretty consistent story. Very good-looking waterfall plots and response rates. Any thoughts about T-DXd, Susana, in terms of where you think it’s going to — where it is right now in terms of when and how to use it in gynecologic cancers?

PROF BANERJEE: Well, first of all, I think, as you’ve highlighted, this has changed practice. I think it is — or it’s changing practice. I think it was fascinating based on actually small numbers of patients in each of the cohorts, but it brings to the head really this tumor agnostic indication. And along with that brings other questions because what’s clear also is that not all responses are as deep or as durable just because of a biomarker when you look at different tumor types, and the efficacy may well vary. But coming to Gyn cancers, for example ovarian cancer, mucinous ovarian cancers often may have HER2 expression, overexpression, and are notoriously refractory to conventional treatments that we have. And we don’t have PARP inhibitors that situation, for example.

So I think in particular in rarer cancers, also cervical cancers that are HER2-positive, this really may give an option for patients, an effective option. Treating women in this trial I really could see some aggressive, rarer cancers with HER2-positive disease could see first-hand the benefits here.

So I’m very encouraged by this. I do feel that we do need more numbers. We’re reading a lot into small numbers in terms of breaking it down into 3+, 2+, for example, local central testing. But you can see consistency, and I’m really looking forward to more studies with a larger number of patients in HER2-expressing gynecological tumors, not only with T-DXd but potentially other HER2-directed ADCs.

DR LOVE: Absolutely. And of course, Ursula, your colleague at Dana-Farber, Sara Tolaney, who we work with all the time, gave the biggest presentation in breast cancer in many years at ASCO, now putting T-DXd as first-line therapy in metastatic breast cancer. Very positive results, and of course in breast cancer you’re even using it in HER2 low.

Interesting here in endometrial cancer, I know there’s a small number of patients, but IHC 3+ 85% response rate. Probably not exactly that. Any comments about the types of benefits? What we saw in breast cancer and we’re starting to see in gynecologic cancers, Ursula, are pretty significant benefits, fairly long-lasting. What have you seen?

DR MATULONIS: Absolutely. I think the antibody drug conjugates have changed absolutely 100% for certain gynecologic cancer treatment. It opens up for ovary, endometrial cancer, cervical cancer. You mentioned the pan-tumor accelerated approval by the FDA for 3+, but the NCCN Guidelines also list for 2+, so we can use these drugs in 2+ and 3+.

And I was talking with a patient yesterday who has a uterine carcinosarcoma. There’s a trial called the STATUS trial that was published in the JCO a couple of years ago in 1+ or higher uterine carcinosarcomas with response rates as well.

So I do think that now that we have antibody drug conjugates in our armamentarium, we’ve talked about mirvetuximab, we’re talking about T-DXd, these drugs are being used. These 2 drugs, they’re different payloads, they’re different targets. Mirvetuximab can be used for up to 3 prior lines of treatment, and T-DXd you can use the trial. The PanTumor02 allowed unlimited number of prior lines, so it’s a therapy that we can even use in a more heavily pretreated patient with efficacy.

There are toxicities, absolutely, especially lung toxicity. As per the FDA package insert you really have to follow patients closely. I check CT scans every 2 cycles and definitely pick up pneumonitis, so that is a challenging toxicity besides some of the hair loss, bone marrow suppression, and then GI toxicities as well.

DR LOVE: So we could spent a long time talking about prevention and management of toxicity of T-DXd, but just a couple things, Susana. Ursula referred to the ILD, which of course is a great concern, has led to very, very close monitoring of patients, but also the algorithm, at least in breast cancer, that if you pick patients up with ILD before they’re symptomatic, Grade 1, you can hold the drug, give steroids, and then treat. Whereas if you wait until picking up on symptoms, and you can hear Ursula screens early because of that. Any comments on that, Susana?

Also, another kind of thing you hear a lot about in T-DXd, first in breast and then outside of it, was the acute GI effects. The breast people love olanzapine with T-DXd. I’m curious what your experience is both with acute GI effects, Susana, as well as your thoughts about retreating for asymptomatic Grade 1 ILD.

PROF BANERJEE: Yeah. So Ursula, I think I really liked your paper because you discussed a study from multiple institutions, I think, with regard to rechallenging with T-DXd, and I think that’s an important message that you can rechallenge if Grade 1 and treated appropriately. But I do think we are picking up more Grade 1 pneumonitis because we know what to look for now, and our radiologists know what we’re looking for, and we’re looking out for it more so picking up more. So I think that’s an important point, but it’s important to manage early in order to keep patients on treatment safely for longer.

In my experience, and my experience has only been within the trial setting because I work in the UK, and we don’t have the FDA approval or the NCCN Guidelines, but what I can say in the context of the clinical trials I didn’t note so much problems with diarrhea, actually, or acute toxicities. It was more the concerns about pneumonitis for obvious reasons because untreated that can lead to — well, ILD can lead to death. But I’ve seen the relevant guidelines. I think that’s what’s really important, to follow the guidelines early and learn from the experience of others in terms of instituting measures early because these drugs can be effective and have durable effects, so we want to keep patients on safely for as long as possible.

Endometrial Cancer

DR LOVE: So this is just kind of a tasting menu. We could talk a lot about all these topics, but I want to get into endometrial cancer. And as Susana said in her presentation IOs have revolutionized the treatment of endometrial cancer, and certainly they’re now a primary issue in the first-line metastatic setting. We talked about the use in the adjuvant setting. But we have the RUBY trial that has very impressive results that Susana went through in terms of the benefit of dostarlimab, as well as the NRG study looking at pembrolizumab, again first-line therapy.

Just to kind of summarize right now, Ursula, any situations right now where you’re not using an IO as part of first-line therapy in metastatic disease? And also how do you choose which IO?

DR MATULONIS: Yeah, no. Good question. All good questions. Well, for mismatch repair deficient I think it’s uniformly yes, we would use it up front. In the mismatch repair proficient setting I definitely have a conversation with patients talking about the risks and benefits. My tendency is to choose pembrolizumab because it’s a shorter duration of therapy with seemingly — relatively comparable impact as dostarlimab. I do think that checkpoint inhibitors when they do have toxicities are potentially life altering for patients, so I think we need to just be careful.

I think RUBY has presented some subset analyses of the 4 different types of patients were molecularly defined. And I think the 1 patient population where the benefit in mismatch repair-proficient cancers may be more limited is the nonspecific molecular profiler ­— NSMP — so in those patients I do think that there are potentially other therapies that could be used adjuvantly that are undergoing testing right now. But those are the patients that I’m really having a very serious conversation and maybe leaning away from them, but I also look at the — obviously the IHC MMR status, but I also look at the tumor mutational burden and making sure that those patients also — what that TMB looks like and also whether or not they have a POLE hypermutated state that may not be picked up on the MMR IHC.

DR LOVE: So I’ve got to tell you that at the ASCO Meeting, again we had all these cases presented by community-based docs, Dr Kellie Schnieder presented the first case we ever had presented in our conferences of POLE, a patient who interestingly had been on lenvatinib/pembro for 5 years, and she was about to stop it, probably related to the fact that she had POLE. But I thought that was really — had a TMB of 92.

Again, Susana, not much of an issue about MSI high. What about first-line IO, MS-stable? And if you don’t use it are you using lenvatinib/pembro second line or something else?

PROF BANERJEE: So again, a lot of our use is driven by what we can access and what’s approved and what’s reimbursed. So I completely agree there’s no doubt with the MMR-deficient patients. With the pMMR I share the concerns that Ursula’s highlighted, as well, because side effects can be limiting, in particular in endometrial cancer, where patients may have multiple comorbidities already, and so that’s a really important point. And that brings us — so in terms of what I would do if I’m not using IO in the first-line setting we use lenvatinib and pembrolizumab, which is approved and funded in the NHS at relapse. So that’s the option, and I’d use immunotherapy later rather than in the first-line setting.

DR LOVE: So Ursula, we talked before about adding IO to PARP with ovarian cancer, and now we’re going to talk about adding PARP to IO, which as you both described really has now become a standard part of, if not first-, of second-line therapy.

So we have RUBY PART 2 that looked at adding niraparib to dostarlimab, and then we also had the DUO-E study looking at adding olaparib to an IO, in this case durvalumab. And we’ll talk in a second about particularly from DUO-E what was seen there, particularly in the MMR-proficient patients. But bottom line from your perspective, Ursula, where do we stand in terms of adding PARP to IO in endometrial cancer, again, particularly in the MS-stable patient with metastatic disease?

DR MATULONIS: Yeah. I really think it’s premature to do this. I know some of my colleagues are saying that you should do that, but I really do think it’s premature. I think we’ve learned a lot in ovarian cancer. It’s taken us decades to learn this, but you really have to be — understand mechanistically in endometrial cancer, where it’s different than ovarian cancer. Ovarian cancer is much more BRCA driven, much more driven on DNA repair problems. And endometrial cancer is not ovarian cancer, and I think that though there is a nominal PFS benefit it is there, I don’t want to say it’s not, but I do think that looking at survival, long-term survival, and understanding mechanistically how a PARP inhibitor might work here and specifically in which population.

So I think it’s premature at this point, and I think for DUO-E there’s just — there’s not a — there’s 3 arms here, durvalumab, olaparib/durvalumab and the control. It’s really hard to separate out the olaparib only so there probably should have been a fourth arm of an olaparib maintenance-alone arm.

DR LOVE: So Susana, I guess there’s a lot more research to come, but I’m also curious about some of these additional analyses. Actually, Dr Westin ran our program at ASCO, and of course she did a lot of this work. And she and Katie Moore presented data at the SGO looking more in DUO-E in terms of ctDNA and what they saw there, which also is a question of whether ctDNA is now going to start fitting into trials like this. Anything you want to say about some of the more detailed sub analyses that are being done in these studies looking at PARP added to IO, Susana?

PROF BANERJEE: So I think the DUO-E is a really good example of how — the use and the exploration of translational endpoints. So I think it’s really good the way that quite quickly the team have looked at potential biomarkers, including circulating DNA. I appreciate the exploratory nature and the post hoc analyses, but I think it does provide helpful information how we can go forward in future trials.

And I was really interested in the fact that ctDNA positivity could be measured and also seeing risks of progression across treatment arms. A very interesting sub-study here, where you’re actually looking in the pMMR patients and seeing changes, looking at clearance of ctDNA with durvalumab and also changes with olaparib. So this doesn’t change what I would do in practice in the use of the drugs, but it may give us some indication of how the mechanisms may be working and which groups to target. And I think in terms of the trial team and investigators it’s really good to be able to not just look at the clinical data but actually have translational work going on, as well, to help bolster things up.

So the main message I have here, as well as with the CALLA study, and we talked about the uterine Stage I paper, is that perhaps we should be looking more in trials as our techniques get better at measuring other biomarkers, not just in the tumor but in the circulation, and the longitudinal changes, but also recognizing how will that then impact on treatment decisions.

DR LOVE: So Ursula, I’m curious about your thoughts about whether you see a future in not only the presence or absence of cell-free DNA but the amount. Here we saw that decrease quantitatively, but also the data that looked at specific other biomarkers. I would have thought, although I don’t know if it’s that simple, that HRD-positive — or HRD mutations might have correlated with benefit from olaparib. I’m not sure if it’s 100% that clear. But any thoughts about these translational studies that are going on right now, Ursula?

DR MATULONIS: Yeah. I mean, I think Dr Banerjee said it perfectly. I do think that incorporating these translational studies into the trials is just vitally important, and as we are amassing more treatment options for our patients just thinking about RAS mutation, where we talked about avutometinib and defactinib. But there are RAS inhibitors now, and being able to really with accuracy predict patients who are going to benefit from the treatment, and then at progression really pinpointing what the next therapy is going to be doing, just like so many other cancers have done so beautifully. And we’re behind, but we’re definitely catching up, and I think it’s vital to have these translational studies, and especially circulating DNA. I think it’s going to be really important.

Cervical Cancer

DR LOVE: So I want to finish out with a couple words about cervical cancer. Again, I refer you to Susana’s talk, where she goes into much of it, including some updates on therapies that have come into practice … issue of chemo/IO with chemoradiation therapy.

And Susana, we have the ENGOT KEYNOTE-A18 study that combined pembrolizumab with chemoradiation therapy. We saw a benefit with pembro with progression-free but also overall survival. And then we have the CALLA study looking at durvalumab in a similar situation. And here maybe you can talk a little bit about what was seen here and also, again, the further analysis they did on cell-free DNA, Susana.

PROF BANERJEE: So this study, the CALLA study, was … presented the results, before this final analysis, before the pembrolizumab study. And I think many people were disappointed. So I don’t treat locally advanced cervical cancer, I treat metastatic or recurrent cervical cancer. But it’s very clear that this was a surprise given the success of immunotherapy in the recurrent and metastatic disease setting. But again, a bit like DUO-E, the benefits have been looking more at translational research within the studies, what can we learn to try and identify prognostic but also potential predictive factors.

And you’re seeing a theme here with the ctDNA that high levels were associated with increased risk of progression, yet if ctDNA was not detected that correlated in this analysis with reduced risk of progression and death. So I think with immunotherapy, in particular with earlier stages or locally advanced, it’s important to have a long follow up in order to see changes like in survival, for example, and also selection of patients as well. Because we’ve talked about ovarian cancer, endometrial cancer, and Ursula’s mentioned that they are — and you’ve mentioned it, they’re different diseases, and that’s probably why IO may work better in certain cancers like endometrial cancer and cervical cancer, yet the PARP inhibitor story works out better in high-grade serous ovarian cancer. So I think that’s really important that although we may be giving carboplatin and paclitaxel as our backbone for everything traditionally that we understand a lot more now that gynecological cancers are separate entities, and that will be relevant in terms of efficacy with our targeted treatments.

DR LOVE: So we’ll talk about 1 more topic, which is another antibody drug conjugate in cervical cancer, tisotumab vedotin, Ursula. I’m excited to tell you that we’re planning right now a CME program on ophthalmic issues in oncology, particularly with ADCs, which is where we’re really seeing it. I’m really excited. I’m learning more and more about this as I study it. And of course one of the first ADCs where I heard about ophthalmic issues or ocular issues was with tisotumab. We’ve seen now follow up data with the innovaT 301.

Anything you want to say about the global efficacy that you’ve observed in metastatic cervical cancer with this agent? Is it similar in terms of duration of response, types of response to what you see with other ADCs? I’m really curious about your experience with the ocular. Do you use the icepacks on the eye for example?

DR MATULONIS: Yeah, no. I think it’s great that you’re having a program on eye toxicities because this will be important not just for oncologists but also for ophthalmologists as well. I mean, I think tisotumab is certainly an interesting drug. It’s been studied. It’s now FDA approved in cervical cancer in the United States for metastatic disease; don’t need a biomarker. I think it’s the first step, hopefully, of other agents, other specifically antibody drug conjugates, and obviously now we have T-DXd that we can use in the US as well.

But tisotumab certainly has a response rate. Is it huge? No, but there’s a response rate there, 20, 25%. And I think the drug — the toxicities can be managed, and I think really telling patients that they have to put the icepacks on to avoid the conjunctival changes and the eye swelling, really educating ophthalmologists about the eye toxicities, but I do think that the toxicities are manageable, yes.

DR LOVE: Susana, any comments? What’s your experience with this agent?

PROF BANERJEE: I’ve again been part of the study, and you can see that the response rate, albeit relatively low compared to many other cancers, so around 20%, is far better than what we have as standard of care in terms of chemotherapy. And so when burden of disease can be high having shrinkage can make women’s lives much better in terms of symptom control.

So I think this is a great step forward. I think what’s important in some of the other tisotumab Phase II studies is actually looking at combinations, for example combination with tisotumab vedotin and pembrolizumab. And I’ve certainly had some patients really have quite profound benefits and durable benefits with the right combination at the right time. So I think this is a space to build, ADCs, but also with tisotumab vedotin in cervical cancer, potentially with combinations.

DR LOVE: So a final comment from you, Ursula. There’s been a lot of excitement about combining IO with ADCs. In bladder cancer that’s first-line therapy, enfortumab vedotin plus pembrolizumab, which beat cisplatin-based combination. We’re seeing that in all types of studies. And actually again your very prolific colleague Dr Tolaney presented a trial, first-line therapy of triple-negative breast cancer. It looks like it’s going to be ADC plus IO — sacituzumab. Any thoughts about that strategy as it relates to gynecologic cancers, Ursula?

DR MATULONIS: I think certainly in endometrial cancer and in cervical cancer it absolutely makes sense given the activity of checkpoint inhibitors in these cancers. Ovarian cancer I think it’s a little bit unknown at this point just because of the lack of benefit of single-agent IO or even now that we’re seeing with chemotherapy with PARP inhibitors. But certainly in endometrial cancer and cervical cancer, and that’s just 1 question of looking at that combination.

But as I think Dr Banerjee alluded to before, how do we sequence? All cancers have these issues, right, in terms of target. Does the target continue? Does the target go away? Which target do you need? What’s the payload? Can we reuse payloads with different targets? All these questions are still up in the air at the moment, so a lot of work to do, and it’s a very exciting time in Gyn cancer drug development.

DR LOVE: So Susana and Ursula, thank you so much for working with us today. Actually, reflecting back on those ovarian cancer programs we did in 2020 there wasn’t much else to talk about besides PARP inhibitors. Today we’ve been talking about a lot of other things in ovarian as well as other gynecologic cancers.

Audience, thank you for attending.

Be safe, stay well and have a great night. Thanks so much, Susana. Thank you, Ursula.

DR MATULONIS: Take care. Thank you, Neil.

PROF BANERJEE: Thank you.

DR LOVE: Have a good one.