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In this final of four exclusive episodes, 口袋女优 brought together three expert leaders for a virtual discussion on antibody-drug conjugates (ADCs) in ovarian cancer.

Moderator Susana Campos, MD, from the Dana-Farber Cancer Institute in Boston, is joined by Richard Penson, MBBS, of Mass General Cancer Center at Massachusetts General Hospital in Boston, and Elizabeth K. Lee, MD, also from the Dana-Farber Cancer Institute.

Our experts break down new data on mirvetuximab-soravtansine (Elahere), raludotatug deruxtecan (R-DXd), and trastuzumab deruxtecan (T-DXd; Enhertu), including new findings presented at the International Gynecologic Cancer Society (IGCS) annual meeting. Click here to watch previous episodes from this roundtable discussion.

Following is a transcript of their remarks:

Campos: So we've touched base on uterine cancer, cervical cancer, and we're going to move on to ovarian cancer. And there are very interesting things happening in ovarian cancer in the last several years. We've had very interesting trials -- the , we've had the SORAYA trial, we've had most recently the MIRASOL trial presented by [Dr. Kathleen Moore], SORAYA presented by Dr. Ursula Matulonis.

The MIRASOL trial showed us both the progression-free survival and overall survival [benefit] with an ADC. In this particular case, mirvetuximab in patients that are folate receptor α-positive, defined as greater than or equal to 75%. And these ADCs are not confined simply to mirvetuximab. There's some very interesting new ADCs that were also reviewed by Moore. And I'm going to ask Dr. Elizabeth Lee to maybe touch a little bit on the first, if you wouldn't mind.

Lee: Absolutely, and I completely agree. I think this is right now the era of targeted therapies, and I include within that antibody-drug conjugates. These are a class of agents that's just exploding across gynecologic cancers -- ovarian cancer, as well as endometrial cancer. I know we haven't really touched upon this, but with the in endometrial cancer, I think that's another area that's developing the folate receptor α-targeted ADCs in endometrial. As a class, this is just an exploding field.

R-DXd, also known as DS-6000, is a novel agent that's targeted to CDH6 (cadherin 6). This is using a payload -- that's DXd -- we're familiar with from Enhertu (trastuzumab deruxtecan). And so this was a biomarker-unselected trial in which R-DXd was administered to ovarian cancer patients. And what was reported out were those ovarian cancer patients.

I think, as we expected, they were heavily pretreated, some received [bevacizumab] some received PARP. What I thought was interesting was that they did seem to have looked at retrospectively the H-score for CDH6 expression, but that actually wasn't reported, as far as I'm aware, in correlating to response rates.

But regardless, across all of those patients who were enrolled, there was a very striking waterfall plot. There was an overall response rate of 46%, a vast majority having had at least some reduction in their targeted lesions by RECIST, an overall disease control rate of 98%. And this extended even down to those with the lower ranges of the doses that they were exploring, went down to the 4.8 mg/kg range.

I do think it's worthwhile to mention that 8.0 mg/kg was the highest dose, the 8.0 mg/kg dosing was associated with a number of ILD [interstitial lung disease] events. As we have seen for Enhertu (trastuzumab deruxtecan), it seems they have also have seen for R-DXd.

But I think overall this is a very exciting antibody-drug conjugate. Not only was there a really great response rate in a biomarker-unselected population, but the duration of response is over 11 months, with a great disease control rate. What I'm really looking for is to look at those H-scores for CDH6 to see whether there are certain brackets of expression that correlate with improved response or less response, improved duration of response or not. I think that will be really important.

What I'm seeing from the folate receptor-α testing, and for the approvals for mirvetuximab, is that there may be a differential in response based on positivity. On these newer generations of ADCs, they may be more potent -- higher DAR [drug‐to‐antibody ratio], better bystander effect, we may be able to get down to very low expression levels of the target antigen.

Campos: No, it is. Dr. Morris's presentation -- granted it was, I believe, a first-in-human phase I study -- it was striking, the actual efficacy. In terms of toxicities, I do believe, and correct me if I'm wrong, but she mentioned there was a case of basically pneumonitis that one has to be very cognizant of and very attentive to very, very early on.

Penson: Two deaths, two deaths from pneumonitis.

Campos: Bigger dose if I recall, and so they're scaling back clearly.

Penson: You have to remember these have a really narrow therapeutic window. And so at 7 mg/kg of mirvetuximab, we had patients who couldn't see for a week. So 6 mg/kg is great, only half the patients get blurred vision. These are really targeted agents.

Campos: Yeah, absolutely. And not to be undone, because we were all very intrigued -- I was going to say blown away, but intrigued is a better term -- with the DESTINY-PanTumor02 trial, and that was with [trastuzumab deruxtecan], and that was updated most recently at IGCS. Richard, do you want to talk a little bit about that?

Penson: This is really exciting, the trastuzumab deruxtecan -- the TOPO1 [topoisomerase I inhibitor] payload and hitting HER2 -- but this was the sort of non-gastric/breast cancer groups. And so the DESTINY-PanTumor02 presented by Jung-Yun Lee, and what was fabulous was they presented the [immunohistochemistry (IHC)] 1+ and the zero [HER2 IHC expressors]. So for example in ovarian cancer, the response rate (small numbers) in 11 participants -- a 64% response rate with a HER2 3+ [IHC expression], a 60% response rate in five participants with immunohistochemistry-negative tumors.

So this is a really interesting drug and 60% [response rates] in endometrial, 50% in cervical, 60% in ovarian with HER2-negative tumors. So this is potentially really quite a potent drug where we originally thought that there was twice the response rate in the HER2 3+ as opposed to the HER2 2+ groups. Now we know that there's actually broader activity, which is quite exciting.

Because it's been controversial to use the breast or the gastric staining, they compared those and there's quite a lot, but only about 10% variation. So you get discordance in about 10%. So they are using, I think, the gastric staining system for the study.

Campos: And Dr. Lee, you've had a great deal of experience with this particular drug in phase I. What's your experience with this drug?

Lee: No, I completely agree. As we're seeing borne out in the trial data, it is a very effective, very potent drug for many, many patients, including some with a significant durability of response as well. I think this is now probably bringing to mind incorporating HER2 testing now into our routine practice and standard of care, seeing these really excellent results and seeing if we are able to reach for trastuzumab deruxtecan in cancer settings in which it was typically not yet FDA approved, but it is very effective, very high efficacy for this drug.

I think it's still something to bear in mind that the pneumonitis risk is still present, still about 10%. This is pretty much in keeping with what we've seen in the previous trials in the non-gynecologic tumors leading to trastuzumab deruxtecan's approval. I think the ILD is something that as we are exploring many, many more ADCs -- and as we think about using ADCs sequentially, and multiple ADCs in the treatment course of any one person -- that we do have to be very careful about the pneumonitis risks and the ILD risk as well.

I think this is something, the HER2 testing, that we'll bring more and more to the forefront for these endometrial cancer patients -- and we certainly already think about HER2 testings for uterine serous carcinoma, high-grade endometrial -- but also thinking about it for cervical and ovarian as well. I think the data and the efficacy of HER2-negative cancers really speaks to: are there mechanisms of action of this drug that we aren't fully understanding or is it just the limitation of our IHC, the limitation of our testing as it stands for these HER2-negative patients that we're still seeing effect for HER2-targeted ADCs.

Penson: Betsy, can I ask, and I don't know the answer to this question, so it's not like to try to make me look good. I'm not going to be able to say what I think, but they suggested there were these three mechanisms: the direct sort of payload delivery, the bystander effect in adjacent cells that sort of get the payload, and what they called serial payload toxicity. That never really, I couldn't really understand what that was. Do you have any better idea about that?

Lee: I'm not really sure about that last one, but I still struggle to understand that for HER2 IHC 0 patients -- 0! -- how a HER2-targeted ADC is actually exerting its mechanism of action, because they're really just pre-payload at that point that is hanging around long enough and is causing some cytotoxicity dissociated from payload. I'm not sure. Or is there actually truly HER2 present and it's just a limitation [of testing]?

Penson: I think so. The idea is that they think it's important -- rapidly going cells use HER2, whether there's very little or it's amplified or just overexpressed. That's the theory. But it is interesting, some of these drugs like the try to biologically get sort of an edge on the tumor when they are so tight in terms of therapeutic window. I think it's really interesting, the chemistry is fabulous.

Campos: And just a quick food-for-thought considering that we have these two fabulous ADCs, trastuzumab-DXd and R-DXd. They have the same payload -- topoisomerase I -- but they have a different target. Just out of curiosity, obviously we don't have the answer to this. If the patient progressed through one ADC, would you consider using the other ADC, considering that it's the same payload but a different target? Assuming that there's no toxicity with interstitial lung disease, pneumonitis. Betsy, what would you say?

Lee: I personally would maybe not favor that of a sequential TOPO1 inhibitor payload, one right after the other. I see a little bit more rationale, for example, going from mirvetuximab -- which has an anti-mitotic payload -- over to, for example, R-DXd, as the payload's different. I worry a little bit about potentially overlapping mechanisms of resistance. For example, upregulating DNA repair mechanisms if you use a TOPO1 inhibitor followed by another TOPO1 inhibitor.

Campos: And Richard yourself, would you use one after the other, simply because they have a different target?

Penson: Yeah, I'm sold on ADCs. I just think that, a bit of blurred vision, it's a lot of effort with lubricant and steroid eye drops and great quality of life. That's an easy trade with hair loss and neuropathy and just the misery of chemotherapy. So yeah, I'd have no problem from going from one to another.

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