Emerging role of immune checkpoint inhibitors for microsatellite instability (MSI)-high and mismatch repair deficient (dMMR) endometrial cancer

DR LOVE: Welcome to Oncology Today — Current and Future Role of Immune Checkpoint Inhibitors and Other Novel Therapies in the Management of Gynecologic Cancers, a special program focused on recently published and emerging clinical research, this is medical oncologist Dr Neil Love. For this program, I met with Dr David O’Malley from the Ohio State University and The James Cancer Center in Columbus. In addition to this audio podcast, there is also a video component, with Dr O’Malley’s slide presentation.

DR O’MALLEY: Well the original — the original keynote publication with regards to tissue agnostic, we saw approximately about 35% response rate in endometrial cancer in a small number of patients. But with the agnostic approval, obviously there was great excitement to move forward with expanding the endometrial cancer deficient population. And the most recent data that we now see, that the pembro response rate in the deficient endometrial cancer patients, that’s actually about 57%. So one of the most impressive response rates we’ve ever seen, if not — well, the most impressive response rate we’ve ever seen in endometrial cancer.

Now, as we’ve looked at this in further development we continue then to — then go into the deficient group of patients, and that’s when we see the len/pem, so the pan-TKI with pembro in the deficient population. In that patient population, now we’re seeing about 38% response rate, which when we looked at the single-agent IO therapy, or in this case PD-1 inhibitors like pembro, we’re really looking at about 10% plus or minus for response rates.

Now dostarlimab has now looked at endometrial cancer, and we’ve really seen that in both the deficient and proficient. Recently we’ve taken dostarlimab, that was presented at the recent ESMO, and we’re seeing here about a 45% response rate in the deficient population and about a 13% response rate in the proficient. At the same time, we have the confirmatory trials going on, which are looking at moving pembro, or dostarlimab, into really the first-line setting in endometrial cancer.

In addition, we have a very exciting trial looking at len/pem versus standard chemotherapy to see if we have a nonchemotherapy option for patients who are recurrent or metastatic. So an extremely exciting time for endometrial cancer. And we’re going to see these agents becoming part of the treatment in the first-line setting for the advanced and recurrent, but also — also in locoregional disease and potentially high-risk early-stage disease.

DR LOVE: So one thing — I want to kind of get into a few details related to this, but one question I’m curious about is has len/pem been looked at in MSI-high disease? And has the strategy of adding in len to pem in a patient with MSI-high disease who’s progressing on pem been looked at also?

DR O’MALLEY: So very small numbers on the MSI-high patients. And the reason for that is it’s really hard to improve upon that 55-plus-percent response rate in the single agent. In the limited number of patients that have been reported, it doesn’t seem to be making much of a difference in the overall response rate. But you ask a fantastic question, which is how about the patient who has progressed on pembro or another PD-1 inhibitor? And that continues to be an interesting area of study, but we really don’t have any data in that particular combination.

Now interestingly, the cabo/nivo data was recently presented, very small numbers that had previous PD-1 exposure. And the response rate there looked interesting. So we definitely need to explore this treatment option for patients who have progressed on PD-1 inhibitors previously. But that data’s not yet there, Neil.

DR LOVE: So that cabo/nivo paper, I think was presented at ESMO for the first time, correct?

DR O’MALLEY: Correct, and so Dr Lheureux presented that. And it — when we — when we look at those response rates, again interesting, again a pan-TKI and a PD-1 inhibitor, not quite the response rate we saw, but in a much small population than the original KEYNOTE-146 that was presented by Vicky Makker on the len/pem. But again, a much smaller trial, and a very interesting combination. I hope we see more data moving forward.

Incidence of high MSI in patients with advanced endometrial cancer; indications for MSI testing

DR LOVE: Can you talk a little bit about your recommended testing strategy for MSI? What kind of testing? When you do it? And what fraction of patients with endometrial cancer are MSI high?

DR O’MALLEY: So I’m very proud of my team at Ohio State and The James Cancer Center with regards to our emphasis on identifying patients first with Lynch syndrome. We were one of the first centers to report about a 2% rate of Lynch syndrome in endometrial cancer in an unselect population, and that’s been very consistent over time.

Now, the Lynch syndrome patients are much different than the MSI-high patients. So we’re looking at about 30% to 40% of patients will be MSI high, approximately. We now perform IHC testing of the 4 mismatch repair proteins on all patients prospectively.

So even an early-stage patient, they will get mismatch repair testing. We utilize that for a couple of reasons, one of which is if they’re candidates for testing — excuse me — for treatment of PD-1 inhibitors in the future if they recur. But we also utilize it for looking at those who may have an increased risk of genetic predisposition to uterine and colon cancer, or Lynch syndrome. And if we do find those patients with further testing, then obviously that’s a fantastic opportunity for us to intervene and save people’s lives.

DR LOVE: So you mentioned dostarlimab, which is not currently approved that I’m aware of. What do we know about this agent and — in general? And you mentioned — it kind of sounds like it’s similar outcomes to pembro with endometrial. Is that your impression?

DR O’MALLEY: Well Neil, I would love you get your impression. You talk to people from all over the — the country, all over the world about PD-1 inhibitors in all different solid tumors. In my experience, the PD-1 inhibitors seem to be more similar than different, both from efficacy and toxicity. Dostarlimab has made a great emphasis on development in Gyn cancers, and I’m thankful for their commitment to move it — this drug forward in both uterine and ovarian cancer. Obviously, we’re talking here about uterine cancer, and we do see some exciting results.

Many of the patients had been enrolled ex-US, and so the experience here is from really throughout the world, that the — the findings are consistent, both from an efficacy, as well as a toxicity that we see in pembro.

DR LOVE: So I want to get into a little bit about the kind of practical issues involved with the use of these therapies. But I am curious for your thoughts about what the potential mechanisms are, I’ve asked a lot of people about this, of antiangiogenics plus IOs. Would you like to take your shot at explaining it?

DR O’MALLEY: I think as we look at can we change the immunogenicity? Does the antivascular therapy change the immunogenicity? Does it — does it somehow allow us that tumor microenvironment? When we look at bev, or the monoclonal antibodies, the results have not been as impressive. But when we look at the pan-TKIs, there’s a different mechanism at play here. What is it? And we look at the preclinical data and there’s a lot of hypothesis.

I really like human data the best, and you cannot argue with the pan-TKI plus PD-1 inhibitor with regards to human data. The — how — why does it happen and what’s the — and why exactly are these patients responding better? Boy, I — there could be about 3 or 4 really good explanations. But I look at the human data, and for me that’s the best data.

DR LOVE: That’s really interesting. So let’s talk about MSI-high endometrial cancer. Maybe you can talk a little bit about kind of how you think through working it into the treatment plan for patients right now. When do you use it and what have you observed?

DR O’MALLEY: So it’s interesting, in an MSI-high patient I currently only utilizing it with cytotoxic chemotherapy in the first-line setting if they’re part of a clinical trial. Obviously, I think in those patient populations that it will be a benefit. But without having data to — to support that definitively I have some concern outside of a clinical trial.

Ultimately, do I think those clinical trials are going to be positive in MSI high when we combine the checkpoint with cytotoxic? Yes. Are we going to see a difference where IO therapy may replace cytotoxic chemotherapy like we’re seeing potentially in lung cancer and other cancers? I think there’s a real opportunity there. Obviously, we’re not there yet in endometrial cancer, but this maybe a real possibility in the future.

DR LOVE: So we saw data at the ASCO Virtual Meeting comparing chemotherapy to IO in colon cancer, MSI high, and the patients on IO did better. And nowadays I think a lot of people are using it first line. Do you think that’s a reasonable strategy in endometrial cancer?

DR O’MALLEY: I do think there, in the future, will be a reasonable strategy. I mean — do I think it’s a reasonable strategy? Right now I would not go there. I think we have great data on combination platinum-based chemotherapy. Do I want to see that question answered in the future? Absolutely. But if I have a patient sitting in front of me, I’m going to go with platinum-based chemotherapy

Saying that, if I had a patient who I did not think was a candidate for chemotherapy or was not eligible for some reason, and we do see those patients based on functional status, would I consider utilizing, for example pembro? Yes, absolutely I’d have that discussion with the patient.

DR LOVE: So yeah, that’s a challenging situation.

Optimal integration of pembrolizumab into the care of patients with metastatic MSI-high/dMMR gynecologic cancers

DR LOVE: What do we know — can you talk a little bit about the outcomes that are seen when you use pembro in MSI-high disease, both in terms of efficacy, but also tolerability? Of course we are getting used to the autoimmune toxicity spectrum that you see. Any difference in gynecologic cancers or in endometrial?

DR O’MALLEY: I don’t think so. When we first started studying this, I was on a panel with you, actually, Neil, and I was much higher in my prediction of those patients who would need to be treated with steroids and/or removed off of immune therapy. But my answer was really based on the literature that was out there.

And early on in our experience, before we had patients who are really maintained on this therapy, I think we were lulled into somewhat of a passive — passivity that we — we should not have been. Meaning these patients have about a 30% to 40% chance of having immune-associated toxicity if they’re maintained. If they quickly progress, like we see in ovarian cancer, after 2 cycles, they’re not going to have immune-associated toxicities, right? We know it really is second — almost exclusively second cycle on.

So as we see more patients getting exposed who are going to be maintained on therapy, we’re really seeing those numbers come up to that 30% range that we’ve seen in other solid tumors. So understanding them having that high clinical degree of concern is so important. But it is challenging. It’s not just like looking at an absolute neutrophil count. You really have to talk to patients, get them in, get your hands on them, count on your nurse care, as well as our advanced practice providers, to really utilize their clinical expertise to identify those who may be having the IO-associated toxicities.

DR LOVE: What about the issue of potentially stopping therapy? What’s the typical duration of response? And what do we know about the safety of stopping therapy?

DR O’MALLEY: Yeah, this is such an interesting question to me, and I — and these are the — really questions that we face with the patient sitting in front of us. On clinical trials it’s easy, right? Most clinical trials either continue it or stop it at 2 years, right? But when the patient’s sitting in front of you it’s extremely challenging.

Now, the data is all over the place, and there’s just not enough out there in any of the other solid tumors yet, so I really need to depend on my melanoma and lung cancer and colorectal cancer experts to help me out here.

In my current practice, outside of clinical trial, if the patients have a complete response at 2 years of therapy, I usually end up holding therapy. If they continue to have persistent disease, I tend to continue therapy. And actually one of the cases that we may discuss at a different time is a patient where based on clinical trial I’d stop therapy, and within 3 to 4 months she had progressed. She had — the important caveat is she had persistent disease when I stopped therapy. I have other patients in my clinical practice, both on clinical trial and off clinical trial, who had a CR that I’ve stopped, and amazingly so, we’re seeing cured patients with recurrent cervix or uterine cancer.

DR LOVE: Interesting, your patient that you stopped, did you rechallenge her?

DR O’MALLEY: We did rechallenge her, and she actually — I just saw her yesterday, and she’s doing well. She’s stable and tolerating it fantastic. Because she was on a clinical trial she was restarted on pembro, which was not the agent that she was treated with on the clinical trial, but seems to be stable and tolerating it well.

DR LOVE: What about the role, if any, of PD-L1 or TMB assays in either MSI-high or stable endometrial cancer? Any role? What do we know about it?

DR O’MALLEY: Well we know that most of those with MSI high are also going to have TMB. That — that data is pretty good, right? Testing TMB in addition to MSI high — now we — one thing when we were talking earlier we did not touch on the MSI. And I do tend, if they are proficient based on the IHC, I do tend to try to test MSI to see that small percentage of patients we may pick up. And we don’t really know what that it. It’s probably only 1% or 2%. But boy that could make a huge impact if I’m able to just give them single IO.

DR LOVE: In terms of testing, one of the things that kind of concerns me is I’ve heard about cases that weren’t picked up on IHC I think that were picked up with other assays, maybe PCR. Is there — should you be doing other assays?

DR O’MALLEY: That’s a great question. I don’t think about that enough in my clinical practice. I really have made an attempt, if they are proficient based on the immunohistochemistry, to test the PCR MSI. Now we do see probably a 1% to 2% chance that those patients could be MSI based on PCR even when they’re proficient. But that data isn’t very good yet in endometrial cancer, and we need to develop it further.

Clinical experience with and dosing of lenvatinib/pembrolizumab for patients with metastatic endometrial cancer

DR LOVE: What about in the MS-stable patient with endometrial cancer? Any predictive value of PD-L1 levels?

DR O’MALLEY: That really has not been shown to have a predictive value of PD-L1 levels. Now if we started using higher levels or higher CPS score, up to that 10% or even 20%, would we potentially see that? I think the number of patients who are proficient that reach that level of PD-L1 expression is probably pretty low, and so that’s a challenge to prove it. But at this point I do not check PD-L1, and I discourage people in the current understanding to take that flyer where you’re trying to treat a patient with single-agent pembro or another IO for PD-L1 positive. We have an approved combination of len/pem with very good response rates, and I really would like to see patients go on that combination instead.

DR LOVE: So how do you — you were talking about sequencing with MSI-high disease, what about MS-stable disease? Where do you bring in pembro/len? Always second line?

DR O’MALLEY: So when we look at these patients is second line almost a little bit more challenging in the patient who received adjuvant therapy. In the past, I always went back to a platinum doublet if they had previously received chemotherapy for say an early-stage serous cancer or clear cell.

When we really start looking at the response rate, which again, there’s not good enough data out there to really say this definitively. But as we’ve looked at it in the smaller retrospective studies, the response rate for reintroducing a platinum doublet when a patient’s been previously exposed, even in the adjuvant setting, is really not very good.

I now have changed my practice that I’m more apt to go to lenvatinib/pembro even in a patient who’s had a long disease-free survival after previous platinum. If they’ve never seen a platinum doublet, like paclitaxel and carboplatin, I tend to still start with that platinum doublet before len/pem, really on label, right? Previous exposure, and then len/pem. So I really stick to the label in that instance.

If I have a patient, and we have a lot of these patients, especially with endometrial cancer, who have pre-existing conditions like neuropathy, that’s challenging. If I don’t think I can get a doublet, then I may consider len/pem in that instance.

DR LOVE: So you know what the number 1 question is people ask about gynecologic cancers, to me? You can guess — “how to use len/pem. How do dose it. How to prevent side effects.” That’s the first thing everybody brings up, so maybe you can talk a little — we’ve chatted about this before, and there are a lot of practical issues. I hear — I’ve heard people quote you, actually, on how to do it. So can you talk about how you do it in terms of preventing and ameliorating the toxicity?

DR O’MALLEY: Well, let’s start with the most basic, which is how to write the script and get it approved, right? The 20 mg packets are extremely challenging because we know 70% to 80% of people are going to have to be reduced, and with some of the donut hole challenges of Medicare and outpatient prescriptions, getting a new script for this and getting approved is quite challenging. So to dose-reduce somebody, and we know we have a 4 out of 5 chance of dose reducing them, they’re going to have to go down to 10 mg until we can get a new script.

So we’ve looked at all the options as an institution, and I’ve worked with my specialty pharmacy — pharmacist, and we have started at 18 mg. I feel within the 10% recommended dose that it’s extremely unlikely that we’d be hurting the efficacy. But, if the patient then needs to be dose — the 18 mg tabs are 10 and — very easy to drop 1 of the 4 mg, getting down to the recommended first dose reduction of 14 mg, obviously, then going down to 10 mg, which is the second reduction. Very, very easy.

If then they have a bunch of 4s leftover, which happened to me this week. The patient called me, she said I don’t want to pay for — 700 dollars for another copay, what can I do with these 4s? We had her dose at 12 mg. She took three 4 mg tabs. So there’s a very practical option.

With regards to toxicity, our patients are being sent home with prescriptions for antihypertension. And the reason is the hypertension they have comes on quickly and can be hypertensive crisis in a very short time. And it’s always on the weekend, it’s always about 7pm at night, it seems, right after dinner, right before you’re thinking about having a glass of wine. So it’s — it’s that time you get the phone call. I hope my fellows aren’t having a glass of wine. So we — we have that, and they have the prescription there. We say take that first script, and we go from there.

The other is diarrhea. Proactively educating, and I’m sure they have antidiarrheals at home. I don’t mean they know where to get them. I mean they have them at home. And if it’s Grade 1, we manage them as an outpatient, obviously holding therapy if it goes beyond Grade 1. But having those medications, proactively educating the patients, is so important. The fatigue and some of the PPE, those are pretty — we’re pretty comfortable managing those, right, with all the other drugs that we see the PPE in. But those 2, hypertension, diarrhea, proactively have the scripts, be ready to go.

DR LOVE: So checkpoint inhibitors can also cause diarrhea. How do you figure out whether it’s len or pem?

DR O’MALLEY: Well one thing we know with lenvatinib, the diarrhea is going to start earlier on. And we know with pembro that the diarrhea’s going to usually be beyond that second cycle. Now interestingly, when you really dive down the data on len/pem, the most common cycle for dose reduction is actually cycle 2. Which again, time you worry about starting to see your IO-associated toxicities.

This can be one of the most challenging — challenging questions with this combination. Early — it’s easier if it’s earlier on, it being the diarrhea, more challenging if it’s beyond cycle 2. What we usually do is hold lenvatinib. If the diarrhea gets better within 24 to 48 hours, then it’s pretty consistent with lenvatinib. If the diarrhea does not get better, we assume it’s an immune-associated toxicity, and we either start them on steroids, and sometimes we bring them in and get — consult with our GI if we’re really struggling. But usually, if we are comfortable managing as an outpatient, they don’t get better within 24 to 48 hours, we then treat them with IO-associated colitis.

DR LOVE: We had a case the other day where a patient with previous hypertension, who’s on 2 drugs for hypertension when she started lenvatinib, was still having very high blood pressures. I think it was at 10 mg. Would you go down to 5? Or would you go less than 10 mg?

DR O’MALLEY: I just — this patient I told you had a bunch of 4 mg left, I did — I did — a similar story, actually. I did actually say that we’re doing to do some 8 mg if her blood pressure goes up. So would I normally? Probably not to 5, but maybe 8, particularly if her disease is being maintained, but also go with that third agent for the antihypertension. We’ve gotten pretty comfortable managing that. I — when I go to the third agent, I’m usually involving some of my internal medicine colleagues or cardiology to help with the management.

DR LOVE: So in terms of future directions in endometrial cancer, particularly as it relates to IOs, but also new agents, anything that you’re excited about?

DR O’MALLEY: I think you’ve really touched on them, Neil. We have a lot of different agents which are just coming into the marketplace in some of the molecular targets. Antibody-drug conjugates are — are starting to make some headway into endometrial cancer, uterine cancer patients. So I think as we look at that, further development of cabo/nivo, there’s a lot of other options out there. There’s also a pan-TKI they call “luci.”

There is some really exciting options out there, and the laundry list is probably 10 or 20. And we’ll see as we get more data.

Activity and FDA approval of pembrolizumab for patients with PD-L1-positive metastatic cervical cancer who experience disease progression on or after chemotherapy

DR LOVE: So let’s go on and talk about cervical cancer, not only IOs, but a new agent that you’ve done a lot of work on, and we just saw some new data presented at the ESMO meeting that I’m wondering whether is actually going to lead to approval, and that’s the, you mentioned antibody-drug conjugate tisotumab vedotin.

But let’s start out with the issue of checkpoint inhibitors in cervical cancer because I thought it was real interesting when pembro was approved, given the fact that the data aren’t that tremendously exciting. Can you kind of go through that, what we know about checkpoint inhibitors in cervical cancer? And also why they don’t cause better responses with all — viral etiology?

DR O’MALLEY: I think it’s — it gives the sad state of affairs in recurrent cervix cancer when a 14% response rate not only leads to approval, but we all immediately start using the drug because we know nothing else works. So when we really look at checkpoint inhibitors in cervix it’s about 15% plus or minus 5%, and it’s across any checkpoint that’s been studied. It’s pretty consistent. Why isn’t it better? I don’t know. We get back to that immune microenvironment. What is going on at that microenvironment which doesn’t allow the body’s own immune system to fight this disease off?

When KEYNOTE-158 received — led to approval of PD-1 positive, and again, a CPS score greater than 1% PD-L1 expression, that we really see, in 77 patients, there was this 14% response rate. Now when we look at those that were less than 1% PD-L1 expression, there was a 0% response rate.

Now one thing that’s not talked about in this group of patients, that only 2 of the 77 — excuse me, 2 of the responses — 2 of the responses of the 77 patients, had received prior bev. So in that patient population you’re looking at about a 3% response rate with the prior bev. So we’re getting — we’re starting to figure out more subpopulations of patients that may or may not be responding.

Activity of the anti-PD-1 antibody balstilimab alone and in combination with the anti-CTLA-4 antibody zalifrelimab for recurrent cervical cancer

DR O’MALLEY: Now, it’s interesting, I just presented the data from 2 new agents at this past ESMO, and there — we call them bal and bal/zal, a PD-1 inhibitor and a CTLA4 inhibitor. And we presented 2 independent Phase II trials, one with the single-agent bal, and one with the combination. Once again, we’re seeing a response rate right about 15% on the single agent and about 22% response on the combination.

So as we look at those patients, you say well that’s not that much different, what’s interesting is the complete response rate went from about 2% up to about 5%, 6%. So are those complete responses actually cured? Well, that’s way too premature to say that. But we’re also seeing longer duration of response. Of course it’s at the expense of a little bit higher toxicity.

We were all excited about nivo/ipi data last year, presented by Wendel Naumann at ESMO. Unfortunately, it doesn’t look like further data is really being developed moving forward, and we really need better agents and combinations of these agents for these patients with recurrent cervix cancer.

DR LOVE: Right, so I mean we should be clear that bal/zal is like ipi/nivo anti-PD-1 and anti-CTLA4, and I know I’ve seen a couple cases that were treated by either you, and another one by I think a doc in practice who consulted with you, of people with good responses with cervical to that kind of strategy. Is it your thought that that’s where things are heading maybe?

DR O’MALLEY: Absolutely. It’s very hard to get excited about a 15% response rate, but when you have nothing else, we were all excited. Can we get up to that 20%, 25% response rate, and could we potentially get curative intent in recurrent cervix cancer in these patients? I never thought I would even be saying something like that out loud, but this is the world we’re living in, Neil. You see it in these other solid tumors. It’s amazing. The combination immune therapy plus or minus cytotoxic or an antibody-drug conjugate is absolutely where we’re going and where we need to go.

DR LOVE: So you mentioned the low response rate, but when you see responses do you ever see really triples or homeruns, where people have prolonged — even though the rate of response is lower, do you see good responses?

DR O’MALLEY: Well that’s what’s amazing. If you really look at the duration of response in the cervix cancer patients, we — we see prolonged, prolonged responses. And we even see those who don’t have official response as defined by RECIST who have benefit with — with disease regression, and then prolonged disease control. I have now a handful of patients in my practice that continue to be maintained with recurrent cervical cancer going on years.

DR LOVE: So let me tell you about — I have this graphic in my mind. It’s one of our poll questions we like to ask people. So we ask people what their approach was to second-line therapy of cervix, investigators, and almost all of them said test for PD-L1, if positive give pembro, except 2 people. So Mike Birrer said he gives pembro to everybody, doesn’t even test their PD-L1, and Ignace Vergote, and we’ll talk about his in a second, said he’d give tisotumab.

So let’s talk about Mike’s response first. Do you think that’s — I thought it was kind of weird that the same thing happened in bladder cancer, I don’t know if you know this story, where the FDA kind of decided what was enough benefit to justify an approval. But Mike’s point is there was no other options, I mean I didn’t know there were no responses that have been seen with KEYNOTE-158 and the PD-L1 negative.

DR O’MALLEY: Yeah, so in the PD-L1 negative there was no responses.

DR LOVE: But you said there were only 2 patients?

DR O’MALLEY: No, so — so let me clarify. So in the 77 PD-L1-positive patients, so the 14% response rates we’re looking at, whatever that is, 11 patients, there was only 2 of those 11 patients that had had previous bev. So when you do the math, that response rate with previous bev is even worse. So bev probably changes the microenvironment. This comes back to our earlier discussion of what is — is — are the antivascular therapies helping the checkpoint inhibitors? I’m bringing up a different question, are previous antivascular therapies making it so there’s a less chance they respond to immune therapy, okay?

DR LOVE: Interesting.

DR O’MALLEY: Now if we look at that 17% — 17 patients that — I think it was 17 that were PD-L1 negative in the original KEYNOTE, there was no responses in those patients. And we know how the FDA loves biomarkers. Now very interesting, the trials which I presented of bal and zal are the single largest experience in IO therapies in cervix cancer reported thus far. We had 2 trials, again independent, that were reported. What we found is looking at the histology was probably a better predictor of response than the PD-L1 status, meaning patients with squamous cell had that higher response rate, about 20-plus-percent, okay? Patients with adeno or adenosquamous was down to about 5 or less.

Now, if you use Mike Birrer’s theory here, just treat all the squamous and test the adenos. Because you have that — if you have that rare patient who is PD-L1 positive who is an adeno or an adenosquamous, in that scenario I’d definitely want to give them pembro.

DR LOVE: That’s really interesting.

Mechanism of action, activity and ongoing investigation of the antibody-drug conjugate tisotumab vedotin for metastatic cervical cancer

DR LOVE: So let’s talk about the other options that’s coming — may be coming to this disease, which is the antibody-drug conjugate tisotumab vedotin. First of all, can you talk a little bit about what it is?

DR O’MALLEY: Well if you can teach me how to pronounce it. You know I refuse to say it now after struggling now how many times in the public forum, so I’m going to call it TV, Neil.

DR LOVE: Okay.

DR O’MALLEY: You’re a better person than me, my friend. So TV is an antibody-drug conjugate against in tissue factor, which is expressed in most women with cervix cancer. We know tissue factor’s expressed throughout the body. Now it’s really interesting, it is the active compound is MMAE, which, as we know, is an antimicrotubule. So we talked about other antibody-drug conjugates, these are antimicrotubules, like paclitaxel, with a more directed therapy with the — with the antibody-drug conjugate against — against tissue factor with the payload of MMAE.

DR LOVE: So what do we know about it in cervical cancer? We had seen some data previously, and then Dr Vergote — no, it was Rob Coleman actually, presented I think the data at ESMO. Can you talk about what we know before ESMO, and what we learned at ESMO, and where do you think this is heading?

DR O’MALLEY: Before ESMO we were talking about pretty small numbers. Their Phase I trial with expansion. I think we were talking about 20-some patients before that. Rob Coleman did a beautiful job of presenting about 100, 102 patients, I think, at the — at ESMO. And what he found and reported, what we found, was a 24% overall response rate. Now Ignace is a brilliant man, and has probably seen some of that data, and he was probably the one outlier there. If you don’t say there’s limitations in approvals, which your questions often are framed, that a 24 response rate — 24% response rate is better than the 14% response rate.

And what’s amazing about that data — nobody’s talking about this, the waterfall plot, about 80% of patients benefitted. It’s a lot like len/pem in endometrial, almost everybody benefitted. Though that response rate, that 30%, is a different bar, which is important for regulatory, but in clinical care, if you have disease regression it’s a win, as you know.

DR LOVE: Well we’ve been asking poll questions about this situation, and it’s interesting because if you present a patient who’s symptomatic and requires second-line therapy, then you start to see people thinking about tisotumab. I guess if they’re not symptomatic, I think a lot of people lean towards checkpoint with the hope that they’re going to get this prolonged response. I don’t know that you see that with tisotumab, so maybe that’s a logical thought.

But how do you see sequencing these 2 strategies moving forward, assuming tisotumab becomes available?

DR O’MALLEY: We’ve really seen quite a change in the way we treat these patients. We use what we call the GOG 240 regimen, some platinum. If they haven’t had cisplatin before we use cisplatin. If they’ve had cisplatin before most of us use carboplatin for tolerance. Paclitaxel with bev if they don’t have a contraindication to bev. The trial GOG 240 treated until progression or toxicity.

But we know, once we start seeing about 8 cycles of platinum, people start to get really beat up. It’s been a very interesting change in the treatment paradigm around the country. We’re using a recurrent metastatic cervix cancer, now we’re treating it a lot like ovarian cancer, where we get to that 6 to 8 cycles, even if they have persistent disease, we back off the cytotoxic, and we maintain them with bev. Zero data to support it, zero data.

I actually just saw the first paper published in Gyn Oncology in the last few months talking about this maintenance strategy in cervix cancer. But it was really interesting, the patients did very well. Again, retrospective, single institution, but that’s really been much of our experience, where we keep them away from the cytotoxic, allow them to recover. If they start then progressing, do we then go back to cytotoxics? A very reasonable option, especially if you’ve had a length of treatment. Or do you go with the more tolerable immune therapy? TV, wonderful drug, but has some toxicities, okay?

Now, if you have a patient who progresses after that 6 to 8 cycles, they’re feeling beat up, they’re not very symptomatic, I absolutely am going to go to the immune therapy. A little bit better tolerated, as long as they don’t have a bad toxicity, and you have that potentially 2-plus-year duration of response, or disease control would be a better way to say it, that we can be maintained. So the homerun we’ll go for, with pretty low risk from a toxicity standpoint, and then go back to the cytotoxic, once TV’s available to us, and we hope it is here shortly, go back to the cytotoxic with TV.

Now, we’ve completely negated talking about where we are on utilizing the checkpoint inhibitors plus cytotoxic chemotherapy plus/minus bev, and that’s really the ongoing Phase III trials right now. So some of this will be a moot point in the future as we expect many of these trials, both in metastatic recurrent, but now — hypothesis testing in locoregional high-risk disease. Meaning they’ll get chemotherapy/radiation plus/minus pembro. We know the recurrence rates, even those locoregional disease in the high-risk patient population, approach 50%, and if they recur, they’re noncurable.

So we’re going to see, I suspect, almost all patients who are at a higher risk of recurrence get some sort of IO therapy in the upfront setting.

DR LOVE: So we’ve been doing a lot of programs on bladder cancer, a lot to talk about there, but they’ve got an antibody-drug conjugate too, enfortumab vedotin, and they’re all excited about combining that with a checkpoint inhibitor.

What about tisotumab plus checkpoint inhibitor?

DR O’MALLEY: Absolutely being looked at. We have a multi-arm trial utilizing TV in — both with bev, as well as pembro. So it is absolutely an option — absolutely an option in the future. But as we move those checkpoints into the first line, it may be a moot point unless we have the option of replacing paclitaxel with TV. That may be an option, and you know how I like the ADCs, the antimicrotubules — ADCs, in — to replace paclitaxel. But we’re not — nowhere close there yet, excuse me.

DR LOVE: So that model actually is happening right now in Hodgkin’s disease upfront, where brentuximab vedotin is being combined with chemo, and that’s where they’re seeing the best response rates.

Prevention and management of tisotumab vedotin-associated ocular side effects

DR LOVE: So let’s talk about the tolerability/toxicity issues with tisotumab. We’ve been hearing all kinds of strange things with all these new novel agents in oncology. Now there’s a whole bunch of ophthalmologic things. And the story with tisotumab is absolutely fascinating. Can you talk about what we’ve seen there?

DR O’MALLEY: So what’s really interesting about the ADCs are most of these problems have been corneal problems. And so we have to partner with the ophthalmologist. I don’t even know what some of — what most of these words are, that when they’re describing. Microcysts, and what are we going to do? And we can’t see it. They complain of blurred vision or some visual changes, but it’s not an uncomfortable feeling for these patients. But TV, we actually see inflammation of the conjunctiva. So they get these red, beefy eyes, and it’s really irritating for them.

So some of the mitigating strategies that have been instituted are putting cold packs over the eyes, what we’re trying to do is, in theory, decrease the drug delivery to these aspects of the eyes. What else are we doing? Lots of eyedrops, making sure they’re not wearing contacts, nothing to irritate the eyes. We’re also using intermittent steroid eyedrops to try to decrease the overall inflammation.

With those mitigation strategies we’re seeing improvement of the Grade 3. We’re seeing improvement overall of the occurrence. We still do see some of these side effects.

DR LOVE: So yeah, the icepacks, or cold packs, are really fascinating. It’s kind of like what you do for alopecia, when you’re trying to kind of get rid of the circulation. I know Dr Vergote was telling me that he thinks it really works well. Beyond the eye problems, any other major tolerability issues?

DR O’MALLEY: Well I tell you, Dr Vergote is — I’m a cynical Irishman, he’s a Belgian. I think there’s something about that. But no, it does work. I say that tongue in cheek. But there’s still issues. We need to get better at it. We need to change the icepacks more frequently. We really need to educate the patients.

Research experience with and ongoing evaluation of anti-PD-1/PD-L1 antibodies in combination with chemotherapy or targeted therapy for advanced ovarian cancer

DR LOVE: So let’s finish out talking about ovarian cancer. Unfortunately, a lot less exciting, particularly in terms of checkpoint inhibitors compared to say endometrial cancer. We did see some recent trials being presented. It seems like you’re trying somehow to figure out a way to get IOs into the story there with ovarian, but so far kind of seems like it hasn’t happened. We saw the IMagyn-50 study, the TOPACIO study, the MEDIOLA study, were some of the more recent ones. Can you comment on those papers, and also just in general what we’ve seen with IOs in ovarian cancer?

DR O’MALLEY: IOs by themselves in ovarian cancer have been disappointing, to say the least. We have the JAVELIN 100/200 trials all negative. Now what are we — we are learning — we are learning that there may be a biomarker with the PD-L1 expression. The problem in these trials is to get that higher level of PD-L1 expression the numbers get much smaller. So 1%’s probably not enough. Is 5% or is 10% really the number? But you start to really limit your population. And we definitely see trends, particularly in the recent IMagyn-50, where there may be a signal there. We need to see more of that data.

Now when we start to look at the combination of IO plus PARP, IO plus antivascular, you get a bit more of a signal, and maybe a little bit better duration of response. But these are not synergistic, they seem to be additive. Now what’s the one exception to that that I’ve seen that’s really blown me away? MEDIOLA, in the nongermline BRCA, which was just presented at ESMO as a mini oral. In the patient population of — of non — non-BRCA we saw an 88 response — 88% response rate; granted, only 33 patients.

But this was all 3 classes of drugs. We had antivascular bev, we had IO, we had PARP. All 3 drugs together in a treatment setting, so platinum-sensitive patients who were treated with 3-drug combinations, no cytotoxic, only the 3 drugs, with an 88% response rate, with some very sustained duration of response. Small trial, 33 patients, but to me, utilizing the — approach is probably where we need to be in ovarian cancer. Or, in a biomarker-positive patient population, but higher than 1%. Is it 5%? Is it 10%? Is it 20%? That’s really the question.

DR LOVE: What’s the connection between the genomic status and this? You said these people were, I guess BRCA negative. Was that just for the purpose of research or do you expect BRCA-negative patients to respond better to IOs? Or to this combination?

DR O’MALLEY: Well this a follow up — yeah, this is a follow up cohort. The original MEDIOLA trial looked at BRCA patients, started with germline and expanded to all BRCA patients. So this was the non-BRCA cohort, and so we looked at PARP/IO, okay? With PARP/IO we saw modest, modest improvement — excuse me, modest efficacy, again looking additive not synergistic. So when we compare, we know that there’s modest gains with IO plus PARP. We know there’s modest gains with PARP/antivascular. We know there’s modest gains with PARP/antivascular. Maybe the key is the triplet.

DR LOVE: This concludes our program. Special thanks to Dr O'Malley, and thank you for listening. This is Dr Neil Love for Oncology Today, a special edition on the current and future role of immune checkpoint inhibitors and other novel therapies in the management of gynecological cancers.