2026.10.08 | GP | Biotech | Genmab Ovarian Cancer KOL: RAINFOL Data

Primary:

GMAB:CPSE

Associated:

IMNN

AZN:LN

BMY

INCY

MRK

ZNTL

ABBV

CYCC

CORT

VSTM

LLY

Repare Therapeutics Inc.

GILD

PFE

ROG:SW

STRO

IMCR

GSK:LN

Viewpoint:

Academic KOL - Physician Scientist

Moderator: Manushi Shah (MS)

Jose A Rauh-Hain (JAR), Associate Professor of Gynecologic Oncology and Reproductive Medicine in Surgery and Associate Professor of Health Services Research in the Division of Cancer Prevention and Population Sciences - University of Texas MD Anderson Cancer Center

SUMMARY

Overview

The discussion assessed Genmab’s Rina-S following RAINFOL-01 Part C and considered its potential Phase III positioning. The expert treats many heavily pretreated ovarian cancer patients and emphasized that treatment options remain limited, particularly for tumors with low or medium folate receptor alpha expression.

Current sequencing generally begins with ELAHERE for high folate receptor alpha expression, followed by taxane-based combinations, HER2-directed therapy when applicable, chemotherapy, and clinical trials. Biomarker testing typically begins at first recurrence.

Key Insights

Rina-S produced highly encouraging and consistent efficacy in a heavily pretreated population, although randomized Phase III confirmation is required before it can alter practice. Its potential activity across folate receptor alpha expression levels could substantially expand eligibility beyond ELAHERE’s core population. For low or medium expressers, Rina-S could become the preferred initial treatment in platinum-resistant disease if Phase III confirms efficacy. For high expressers, ELAHERE would probably remain first unless Rina-S delivers clearly superior Phase III outcomes. Rina-S may be favored over weekly taxane regimens because it is administered every three weeks and appears to have a more manageable safety profile. The expert viewed a dramatic, practice-changing Phase III result as unlikely, estimating its probability below 10%. Phase III analyses by receptor expression and prior ELAHERE exposure were considered especially important. Payload-related cross-resistance may prevent routine sequencing of multiple topoisomerase-1 ADCs.

Competitive Landscape

10/12/2026 at 06:06 AM UTC

Therapy

Positioning

Advantages

Limitations

Rina-S

ELAHERE

Potential early option for low/medium expressers and after ELAHERE

Broad expression-level activity, three-week dosing, manageable toxicity

Phase III validation pending; neutropenia

Established first choice for high expressers

Proven efficacy and generally tolerable

Ocular monitoring; narrower biomarker population

ROSELLA regimen

Alternative after or instead of ADC therapy

Phase III support

Weekly treatment and taxane toxicity

KEYNOTE-B96 regimen

Similar role to ROSELLA

Competitive efficacy

Weekly dosing, neuropathy, hematologic and immune toxicities

Enhertu

HER2-positive disease

Targeted option

Pneumonitis risk

Emerging ADCs

Future competitors from multiple developers

Early response signals around 50%–60%

Small datasets and overlapping payload resistance

Quantitative and Clinical Insights

Metric

Reported insight

RAINFOL-01 Part C

109 patients; 45.9% response rate; 9.5-month median PFS; approximately 12-month response duration

Discontinuation

5.5%, considered excellent

High folate receptor expression

About 30% of patients

Platinum resistance

Recurrence within 6 months of platinum therapy

Practice-changing scenario

Approximately 55% response, 12-month PFS, and 24-month survival

Chemotherapy benchmark

8%–10% response and roughly 4-month PFS

Rina-S’s main toxicity was neutropenia, viewed as manageable with growth-factor support. No notable ocular toxicity, pneumonitis, neuropathy, or mucositis signal was highlighted.

MS: Hi, everyone. My name is Manushi, and I work with the healthcare team at Guidepoint Insights. Today, we have with us on this call, Dr. Alejandro Rauh-Hain, and we would be discussing Genmab's agent, Rina-S, its recently disclosed RAINFOL-01 Part C data and expectations from Phase III. Before we start with our call, it will be really great if Dr. Alejandro, you can give a brief introduction about yourself. Thank you.

10/12/2026 at 06:06 AM UTC

Jose Alejandro Rauh-Hain: Hi, good morning. Thanks so much for the invitation. I'm Alejandro Rauh-Hain. I'm a GYN oncologist by training. So I see patients primarily with ovarian and endometrial, cervical cancer. I work in a large cancer center where we see patients that come for second opinions or third opinions, and we tend to see a lot of patients that are heavily pretreated as well.

MS: Thank you very much, Dr. Alejandro. So I mean, if we can start with the number of ovarian cancer patients under your care and then if we can also get a bifurcation of platinum-sensitive versus resistant and then also like your treatment algorithm and sequencing and the determining factors as well.

Jose Alejandro Rauh-Hain: Yes. So I see, I would say, around 65 patients with ovarian cancer every year. Again, many of them come looking for another options for treatment after they progress. So I would say probably 70% of the patients that I see or 80% of the patients I see already have developed platinum-resistant disease. So I think that is a big part of my practice. In terms of the management for platinum-resistant disease, and we're talking about right now only high-grade, particularly high-grade serous ovarian cancer, but high-grade ovarian cancers overall.

The landscape has changed dramatically in the last four years. I would say, at least — and whatever we discuss today, it might change in the next six months, 12 months just because the field is evolving quite rapidly. And there are a lot of different therapies in the pipeline. So just keep that in mind that, again, it's a rapidly evolving field in which there are a lot of therapies as we're going to discuss in development.

So right now, the way I do it is if I have a patient that has high expression of the folate receptor alpha, and that means more than 75%, I would probably start with mirvetuximab as the first option. If a patient — and keep in mind that we are not curing patients with platinum-resistant disease. So as long as they are alive, patients are going to receive a couple of lines of therapy once they develop platinum-resistant disease.

So if a patient is folate receptor alpha positive, start with mirvetuximab. If they are folate receptor alpha negative, or once they progress on mirvetuximab, right now, to me, the decision is between nab-paclitaxel and relacorilant or the KEYNOTE-B96 regimen of weekly Taxol, pembro, plus/minus bevacizumab. Both regimens are weekly taxanes. So — and if you look at the data, the estimates of PFS, OS are very similar between these regimens of ROSELLA or relacorilant and KEYNOTE-B96.

So in my practice, I usually use nab-paclitaxel, relacorilant instead of pembro and weekly Taxol. But again, I think both of those regimens are equivalent. And we can discuss later if you're interested, whether why I favor relacorilant versus, you know, pembro weekly Taxol.

And then after that, I'll probably — I would also check for HER2 and if they are HER2 positive, either 3-plus or 2-plus at that point, I will probably use Enhertu. If they are HER2 negative or they progress on Enhertu, then I will probably use at that point, chemotherapy pembrolizumab. And along the way, we will always encourage clinical trials.

MS: And so do you do the like biomarker profiling or molecular profiling upfront before starting the treatment? Or at what point does that — yes.

Jose Alejandro Rauh-Hain: Yes. Yes. I mean, I think these days, we try to do, once the patients develop a recurrence, their first recurrence, we do the biomarker testing, understanding that once a patient with ovarian cancer develops a recurrence, we know that it's very hard to cure. And eventually, most of them, or all are — certainly if they're alive, they're going to develop platinum-resistant disease. So we — these days, we try to do it earlier.

MS: And according to some of our other advisors, they were of the view that like for greater than 75% folate receptor expression, like they adopt ELAHERE monotherapy, but like between 25%–75%, they are doing a lot of bevacizumab

10/12/2026 at 06:06 AM UTC

plus ELAHERE. So I mean, I'm just trying to understand, I mean, would you be doing that? Or have you heard about that? Or — yes.

Jose Alejandro Rauh-Hain: Yes. I think that — so I've done it before. That's based on a Phase I study that included patients with platinum-resistant and platinum-sensitive disease that actually showed response rates of 60%, so pretty good response rates. But keep in mind that it's a Phase I study with patients with platinum-resistant and platinum- sensitive in the mix. But yes, I mean, I've done it before, just not very consistently. But yes, I mean, it's definitely in the guidelines, and I would say it's an option.

MS: And I mean, in how much time would you know the — like what would the average time be before the patients turn platinum-sensitive — from platinum-sensitive to platinum-resistant? And I mean — or is there like a number of cycles or something before — I mean, when they are categorized as resistant?

Jose Alejandro Rauh-Hain: Yes, very good question. And I'm going to try to explain it because I think this is sometimes something that's confusing. So the definition of platinum sensitivity or platinum resistance, it is based on the time frame since the last platinum-based chemotherapy. So if a patient develops a recurrence within six months of receiving platinum-based chemotherapy, we call them platinum-resistant. If it's more than six months when they develop the recurrence, we call them platinum-sensitive.

So what that means is that it is not that patients are first platinum-sensitive and then immediately platinum-resistant, or by the time they get their third treatment, they're platinum-resistant. It is really that time frame. So there are some patients that might have their first, second, or even third recurrence and still be platinum-sensitive. And there are patients that are just platinum-refractory from the beginning.

What is true, and I think this — I'm trying to answer your question, is that the more lines of chemotherapy you get, the more likely it is that you become platinum-resistant, but every patient is a little bit different. So what that means is that in the first-line, in the frontline, 80%–90% of the patients are platinum-sensitive. So most patients initially for the first line are platinum-sensitive. By the time they develop the first recurrence, around 60%–70% of the patients are still platinum-sensitive.

By the time they develop their second recurrence or their third-line, only around 40% of them are platinum-sensitive. And by the time they develop the third recurrence or the fourth-line, like less than 10% are platinum-sensitive. So as more lines of therapy, yes, that drops quite dramatically.

MS: So according to one of our other advisors, they were of the view that ELAHERE adoption might increase because of penetration into this platinum-sensitive sort of regimen because of like what you just mentioned. I mean, yes, just your thoughts.

Jose Alejandro Rauh-Hain: So there are a couple of studies that have shown that ELAHERE is, you know, can be — could be used in platinum-sensitive disease. There are at least three studies. And the big one is — the fourth one is a randomized — Phase III randomized trial called GLORIOSA, and GLORIOSA is assessing carbotaxol-bev, so standard of care, versus carbotaxol-bev and mirvetuximab only for patients that have high expression of folate receptor alpha. So if GLORIOSA is positive, yes. I mean, I think there's going to be a big shift of patients receiving ELAHERE in platinum- sensitive disease.

MS: And just moving to the Rina-S data that was disclosed, the RAINFOL-01 Part C data, where I think it was 109 patients and showed ORR of 45.9% and median PFS of 9.5 months. Yes, your thoughts on that. And then yes, and then how would you compare — how does that compare with the earlier Part B data that came out?

10/12/2026 at 06:06 AM UTC

Jose Alejandro Rauh-Hain: Yes. You know, I would categorize it as very encouraging, but not yet practice-changing. So I would say that what I'm finding is not only the response rate of 45%, it is that it's very consistent between the response rates, a 12-month duration of response, and nine and a half month median PFS, particularly in heavily pretreated populations. So that makes the efficacy signal very hard to dismiss.

So I think — so I think that — I mean, I would say very, very encouraging results. And you know, hopefully, that's going to translate, and very likely, I would say, it's going to translate in the Phase III RAINFOL-02 study. Sorry, what was the second part of the question? I apologize.

MS: Yes. No. So just how does — like is there anything to read there when — like between the Cohort B data and this Cohort C data, because Cohort B data was 55% ORR. So does that — yes.

Jose Alejandro Rauh-Hain: I mean, keep in mind that in Cohort B, like, yes, you're right. I mean, the response rate was 55%, but it was a small number of patients. So if you look at the 95% confidence interval from that response rate, it was super wide, meaning that, you know, it was just like a lot of variation given the small numbers, right? If you look at the 95% confidence interval of the Part C, it's a very tight 95% confidence interval for the response rate.

So I think it's between 35%–55%, like very, very tight. So I think, you know, I don't think anyone is going to be surprised that the response rate in a larger cohort might be a little bit lower than, you know, in earlier cohorts. I mean, we see this time and time again. So I don't see that as an issue. I mean, I think, again, in a large cohort of patients with platinum-resistant disease, response rates of almost 46% is incredible. It's something that two or three years ago, you know, if you would have asked me, I would think that it was going to be very hard to achieve.

MS: So you mentioned that it is not practice changing, if I heard that correctly.

Jose Alejandro Rauh-Hain: It is not practice changing yet.

MS: So I mean, if you can elaborate a bit on that, I mean yes.

Jose Alejandro Rauh-Hain: Yes. I mean, it all depends on the results of the Phase III. And that's what I meant. Like if the results of the Phase III turn out to be very, very impressive, then I would say, yes, I mean, there is a potential that it's going to be practice-changing, and a lot of people would use it. But all of that, you know, really depends on the results from the Phase III randomized trial.

MS: So I mean, just your thoughts or if you have any expectations from Phase III trials based on whatever data we have till date, I mean, how plausible is this 45% sort of ORR and nine months sort of PFS? And then would that be — would you consider — would that be considered as practice-changing? Or — yes.

Jose Alejandro Rauh-Hain: Yes. I mean — and I think this is where — if you ask 10 oncologists, they might give you 10 different answers. But I can tell you what I think to me, what would mean practice changing. And what I think — and also, I can tell you what, you know, more or less I think might happen. So if you think about right now, the landscape, right, in terms of response rates and PFS and OS compared to other therapies. So we start with ELAHERE. In ELAHERE, response rates in the Phase III randomized trial were like 42%.

The PFS was five and a half months and overall survival was around 16 months. So that's ELAHERE in high expressions of the folate receptor alpha. If you look at nab-paclitaxel relacorilant, PFS, very similar five and a half months, overall survival, similarly 16 months. And KEYNOTE-B96, so weekly Taxol, pembro, plus/minus bev, PFS was a little bit longer, eight months and overall survival also a little bit longer, I believe, was 18 months. So the reality is that all of them are similar, right?

10/12/2026 at 06:06 AM UTC

No one — with these cross-trial — issues with cross-trial comparisons, no one would say that of the three regimens that I — sorry, that I mentioned, no one — I don't think we are going to be able to say that one regimen is better than the other. Even that numerically, weekly Taxol, pembro seems to be slightly better, like I mean, there are so many issues that with cross-trial comparisons in terms of patient populations and selection bias and so forth, right? So if — and this is where like we are trying to do — this is a thought experiment.

I'm not saying this is what's going to happen, but this is how I think about it. If Rina-S has a PFS in the Phase III randomized trial similar to all of these data, let's say it's like seven months and overall survival is 17 months, right? And response rate is 45%, right? I would say it would be, in my mind, very similar to what we have available right now. And then the decision is going to be how you decide which one you're going to use first because at the end of the day, you're probably going to use all of them, right? So that is kind of the base case scenario, ok?

Now the — to me, the practice-change scenario, let's say, if they come out and say response rates are 55%, the PFS, we double, they double what they've done with mirv or ELAHERE. So let's say the PFS is 12 months, and the overall survival is 24 months. That to me is practice-changing, right? I mean, those results would be outstanding. Most likely, I think the results are going to be in between what I say the best-case scenario and the super outstanding results of like practice-changing.

MS: So say, in a hypothetical scenario, if it is like in between, say, for example, 47% or 48% and nine months sort of PFS, then how would — I mean, how would it be — if it's — like if it's not the best-case scenario, I mean, how would the positioning or your use differ, I mean, between best case and the other scenarios?

Jose Alejandro Rauh-Hain: Yes. And again, how physicians will see the data and how they're going to practice, it's — there's other variables that come into play. But what I can tell you how I think about my practice is that if it's that kind of the middle of the ground, I would say probably if a patient is folate receptor alpha positive, I will probably start with ELAHERE.

And then after that, I would use Rina-S as long as they show the activity in post-ELAHERE patients, and we can talk about that. And then after that, I would use nab-paclitaxel relacorilant. And then after that, I would probably use just chemo plus bev. That's how I think about it.

MS: And just two follow-ups on that. So firstly, the pembro combination, I mean, you seem to use it — I mean, you seem not too excited about it. You can correct me if I'm wrong, and you also mentioned that at the top of our call. I mean, what would the reason for that be?

Jose Alejandro Rauh-Hain: Yes. So the pembro regimen, and this is KEYNOTE-B96 is weekly Taxol, pembro, plus/minus bev. And if you think about it, it is compared directly with the ROSELLA regimen, right? Both of them are weekly Taxol regimens. It is hard to imagine that we can sequence one after the other at this point. We don't have that much data to do that. So I think we have to make a decision very often between one and the other. So if you look at the PFS estimates, overall survival estimates, they are very similar, essentially in my mind, in terms of efficacy, they are the same.

You know, some people might argue it's like, oh, but KEYNOTE-B96, the longest overall survival that has been reported in platinum-resistant disease. And I would say that's true. But again, numerically, it's only two months. And no one, you know, I don't think we can ever claim that with the cross-trial comparisons with a two-month difference, ok? So in my mind, I think efficacy is the same. So then the next question is the side effect profile. And I think that is where nab-paclitaxel, relacorilant is slightly better.

You know, it's on paper, if you look at the rates of the Grade 3 and above toxicities, probably a little bit worse with

10/12/2026 at 06:06 AM UTC

KEYNOTE-B96 than ROSELLA. So that's why I choose ROSELLA. And so that is the main reason, the side effects. And I think with the KEYNOTE-B96, you have the side effects from the weekly Taxol, so the neuropathy, the hematological toxicities. And then in addition to that, you have the side effect profile from the immunotherapy for the pembro. So that's the rationale.

The other part is that there's another regimen with pembrolizumab that you can — there's data from a Phase I study of using Cytoxan, so not Taxol, but Cytoxan, cyclophosphamide, pembro, and bevacizumab. So to me, and they had actually very good response rates in the early-phase study. I can save the pembro for later lines if a patient is still fairly active and their performance status is fine.

So those are the two main reasons, but most is related to side effects. I mean, if you — if there's a patient that comes and says, I want to do KEYNOTE-B96 because all of these reasons, or another oncologist tells me that they use KEYNOTE-B96, I think that's fine. I don't think there's anything wrong with that. I think it's just a preference.

MS: And you mentioned — I mean, what percent of your patients would be like greater than 75% folate alpha receptor expresser sort of patients, where you are using ELAHERE?

Jose Alejandro Rauh-Hain: It's around 30%.

MS: And so because Rina-S is for — like it is not restricted by expression level, it is — I think it is for 0%–100%. Or — so then how — I mean, yes, how would that be?

Jose Alejandro Rauh-Hain: Yes. I mean I would say that's huge, right? I think — and we've seen the data across different levels of Rina — of folate receptor alpha. So I think that is — it's huge because, first of all, you give a larger opportunity to a larger number of patients. And you know, we'll see whether it's truly agnostic, so we don't have to do the testing. But yes, I mean, I think that opens so much opportunity for a larger number of patients. So I think that is huge.

MS: So then for these patients, how would Rina-S be used? And right now, what is happening with these patients? Because — yes.

Jose Alejandro Rauh-Hain: So what — like in platinum-resistant disease?

MS: Yes, yes, for less than 75% folate receptor expressers where Rina-S can be potentially used in that subgroup?

Jose Alejandro Rauh-Hain: So I think that is the group of patients that as first-line, they're getting either nab-paclitaxel relacorilant or for other providers, weekly Taxol, pembro, bev. So that's what they're getting. If they are HER2 positive, 2-plus or 3-plus, they might be getting Enhertu as well. They might be enrolling in clinical trials or then, you know, or worst-case scenario, they are getting chemo plus/minus bev. But yes, I mean, I think the options are very limited for sure.

MS: So then with this — with the sort of like with 45% sort of ORR and nine, ten months or maybe like seven, eight months sort of PFS, would — can the Rina-S be preferred agent for this patient population? Do you think? Or would it be directly competing with ELAHERE for high folate receptor expressers?

Jose Alejandro Rauh-Hain: So I think there are two separate questions. The first question is if a patient develops platinum-resistant disease and they have a 75% expression level, right? So they are positive for folate receptor alpha. So the first question is, are physicians going to use mirvetuximab or Rina-S first? I would say most likely, most people are going to still use ELAHERE first, unless they blow it out of the park and we say the results of the practice-changing results that we talked about.

10/12/2026 at 06:06 AM UTC

Other than that, if someone is high expresser, I think at this point, most people will say that ELAHERE is standard of care for those patients, ok? So that's the first kind of step. The second step — or the second question is, let's say that the patient is folate receptor alpha negative or they progress on ELAHERE, right, either second or — first or second- line in platinum-resistant disease. Then at that point is the question is, are we going to use Rina-S first? Or are we going to use ROSELLA/KEYNOTE-B96.

In my mind, even with the best case scenario that we discussed, right, the PFS that you said of around eight to nine months and response rates of 45% and OS, let's assume 17 months. In my mind, I will probably use Rina-S first before ROSELLA or KEYNOTE-B96 for two reasons. The first one is that Rina-S is given every three weeks. And the other two regimens are weekly regimens. So that means patients have to come almost every week to get their chemotherapy infusion.

And that's very hard for patients. So an every three-week regimen in this setting makes a big difference in my mind. So that's the first aspect. And the other aspect is the fact that, again, at least on paper, the side effect profile seems to be perhaps a little bit better with Rina-S than the other two regimens, although the neutropenia is still, you know, an issue. But the other two regimens, also there's very high rates of neutropenia.

So that's what I think Rina-S would be — you know, at least in my practice, if you ask me now based on those results, I would use it before, nab-paclitaxel relacorilant and KEYNOTE-B96. And the third reason is that like the data behind those two regimens, meaning ROSELLA and KEYNOTE-B96, even though they have positive Phase III randomized trials, like they're — both of them, and we can go into details like there are issues in the data, in their prior data that make me a little bit hesitant about the use.

MS: So just to confirm my understanding. So for 30% patients that are high folate receptor expressers, 75% or more, those would be ELAHERE and — but 70% patients who are non-expressers or like less than 75% if Rina-S shows efficacy — similar efficacy in that subgroup. For those 70% patients, Rina-S can be a first-line agent in resistant setting.

Jose Alejandro Rauh-Hain: I think that's how I think about it. Yes.

MS: And so for ELAHERE as well, the ocular toxicity and neutropenia, I mean, what sort of burden is that right now? Is it manageable? Or have you discontinued due to those?

Jose Alejandro Rauh-Hain: Yes. I mean the — it's very well — I mean, I think overall, it's a drug that's well tolerated. I mean, having the ocular toxicities and having to have the eye examination, certainly, it's an extra hassle for patients. But I would say that overall, it's very well tolerated. And the discontinuation rate because of ocular toxicities is not very high.

MS: And because of neutropenia?

Jose Alejandro Rauh-Hain: We almost — we don't see that much neutropenia or neuropathy with ELAHERE.

MS: And so the safety data that came out with Cohort C, yes, I mean, just your thoughts on that as well.

Jose Alejandro Rauh-Hain: Yes. So I think the big thing to consider with Rina-S is neutropenia. So there's definitely high rates of neutropenia. I think on the other side, if you look at there's no ocular toxicities, no cases of pneumonitis that I'm aware that they've been reported. So, you know, and no neuropathy. So I think the biggest issue is the neutropenia. I would say that of all — and also no mucositis, right? So of the side effects seen on neutropenia, I'm not saying — I'm not trying to minimize it by no means, and it's important to account for it.

But neutropenia is something that we can manage, right? We can — we extensively — oncologists have a lot of

10/12/2026 at 06:06 AM UTC

experience managing neutropenia with growth factors and so forth. So it is, I think, as a side effect, easier to manage neutropenia than ocular toxicities and certainly pneumonitis, right? I mean we've — just to give you an example, in patients taking Enhertu, if they develop Grade 2 pneumonitis, that means that we cannot give Enhertu anymore technically, right?

So pneumonitis, patients with pneumonitis can get very sick very quickly. And you know, again, we don't see that apparently with Rina-S. So I think overall, you know, aside from the neutropenia that is something important to consider and the fact that many of the patients end up going to take growth factors other than that seems to be a well- managed therapy.

MS: And the discontinuation rate of 5.5% with the Cohort C, I mean, how — is that concerning? Or is that something — yes?

Jose Alejandro Rauh-Hain: I think — I mean, I think for a heavily pretreated population with platinum-resistant disease, 5% discontinuation rate is, again, also very favorable. I used to say less than 20% is very good, less than 10% is excellent. So 5% is really — it's excellent.

MS: And — so you gave those scenarios, like best case, base case, and like not the — we have, I mean, 45% ORR sort of scenario. So I mean, I know it's a bit speculative, but with whatever data we have right now, what is the probability of that best-case scenario, or practice-changing scenario, in your view?

Jose Alejandro Rauh-Hain: That I don't know. I mean I think it's less than 10 — I mean, if you ask — and this is a wild guess. I think it's less than 10%.

MS: And then how important would any like subgroup analysis be in Phase III? Because when they say that it is for like less than 75% folate receptor expressers and all those things. I mean, how important would that data be? Or what else would you want to see in Phase III to be convinced to use it in all in the — like in the current ROSELLA and KEYNOTE, I mean, the pembro regimen patients?

Jose Alejandro Rauh-Hain: Yes. I think there are two analysis that I would be very interested in looking at. The first one is looking at the efficacy across different levels of folate receptor alpha, right? So what happens in patients that have low expression of folate receptor alpha? So that's one of the analysis that I will be interested in seeing. The other analysis that I think is important is what is the efficacy on post ELAHERE patients, right? I mean, at least in Part C, around a third of the patients had received ELAHERE before. And it seems to be that there was activity in those patients.

So I think that is very, very, very important to have an understanding. The reason why this is important is because, obviously, there's activity and efficacy in post-ELAHERE patients, and everyone, even if patients have high expression of folate receptor alpha, is going to open the opportunity that if you have a patient that progresses on ELAHERE, then you're going to be able to use Rina-S afterwards.

MS: And what— Jose Alejandro Rauh-Hain: Go ahead.

MS: No, sorry, I did not mean to interrupt. Please go ahead.

Jose Alejandro Rauh-Hain: And why we feel encouraged that it's going to work is because ELAHERE and Rina-S are just very different antibody conjugates in terms of their technology, but more importantly, in terms of the payload. So the payload for ELAHERE, it's a DM4. So it's a tubulin stabilizer. And the payload on Rina-S is a topo 1 isomerase inhibitor ADC. And what we know from breast cancer data, and this is the first time truly in a Phase III randomized trial

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that we're going to have some data about sequencing ADCs. But — so again, all of this is new to us.

But at least if you look at the breast cancer data, it seems that the largest driver of resistance in antibody conjugates, it's the payload more than the receptor. So both of them are important, but the largest driver of the resistance is the payload. So what that means is that if that is true, you should be able to sequence ELAHERE and Rina-S one after the other.

But we'll see. I mean, again, this is the first time in a Phase III randomized trial that we're going to be able to look into this. I believe the CDH6 from Daiichi is also allowing patients to receive ELAHERE before. So you know, we'll have also that data.

MS: And what — how many — like how often do you — would you be seeing ELAHERE resistance or patients progressing over ELAHERE?

Jose Alejandro Rauh-Hain: So all the patients progress on ELAHERE, right? I mean once the patient has platinum- resistant disease, all of them are progressing eventually. We are not curing them. As long as they are alive, they're going to progress.

MS: And like what percent — can it be quantified? I mean I'm just trying to understand that what — how much — like what percent can be the patients then who can be candidates for Rina-S after patients progressing on ELAHERE?

Jose Alejandro Rauh-Hain: What percentage of patients that were on ELAHERE can be on Rina-S afterwards?

MS: Yes, yes.

Jose Alejandro Rauh-Hain: Yes. I mean, again, it depends on the data, right? But if the hypothesis is correct that you can sequence them, right, that there's no this resistance to the receptor. It may mean that every patient on ELAHERE can receive Rina-S afterwards after they progress as long as they are alive and their performance status is fine.

MS: And do you think — I mean, this other group of less than 75% folate receptor expresser. So I mean, what can — I mean, what can go wrong there for Rina-S to not be a treatment option in that group?

Jose Alejandro Rauh-Hain: Yes, it's a good question. So let's just, you know, right now, if you have a patient that has less than 75% and let's say that in your practice, you don't use ELAHERE plus bev, right? But I think that's — majority of the people don't use ELAHERE and bev in low expressers or medium expressers. So for low and medium expressers, the only options that we have are ROSELLA or KEYNOTE-B96 and then after that, chemo plus bev. That's it or chemotherapy eventually, right? But chemotherapy doesn't work very well.

So I think, you know, this is, you know, for this low, medium expression, this is where Rina-S can be, you know, a game changer because even if the estimates for low and medium expression are within the ballpark of a PFS of six, seven months, response rates of like 40% and overall survival of, you know, 18 months or 16 months, I still think that a lot of people — I mean, for sure, as long as the patients are alive, they will see this therapy.

And I think for a lot of people, they might prefer to use this instead of nab-paclitaxel, relacorilant and KEYNOTE-B96 just for the fact that I mentioned that it's every three weeks and that the side effect profile seems to be at least a little bit better than the other two regimens.

MS: So in terms of — so just to clarify, the benchmark for efficacy would be lower for this subgroup for Rina-S is what I'm understanding like compared to the ELAHERE patients? Is that— Jose Alejandro Rauh-Hain: I mean we don't know, right? I mean I think we — what we've seen from the data in the low

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and medium — and if your question is about low and medium expressers, you know, we've seen definitely activity with Rina-S in low and medium expressers, right? Rina-S's, it's a — the technology is just better than ELAHERE in terms of the antibody in terms of the linker, in terms of the payload. And we do think that there's a bystander effect with Rina-S.

What that means is that the bystander effect means that even that patients have low expression of the, you know, receptor, you can see some activity, right? So similar to what happens with Enhertu with the ultra-low HER2 patients. So whether that's going to happen or not in the Phase III randomized trial, I don't know for certain. But I mean, so far, what we've seen of the data is that there is activity in the low and medium expressers.

The question is, is it similar because of this new technology in Rina-S, whether that activity is going to be similar to the high expressers or at least very close to that. And that answer, I just don't know what would happen. We'll have to see — wait for the Phase III randomized trial.

MS: And so I mean, do you think that the first data that would come out would be the PFS HR ratio for Phase III? Or would that — would it be ORR and PFS like they have given out this like for this? Because I'm just trying to understand like when the first data comes out topline or topline data maybe, what should we expect if they give the hazard ratio?

Jose Alejandro Rauh-Hain: I mean, probably the response rates and PFS is going to be what they present with immature overall survival data.

MS: And the competition from Eli Lilly's and AstraZeneca's Phase III ADCs as well. And then also at the top of our — and I mean, just a last question before we conclude. At the top of our call also, you mentioned that what we are discussing right now might change after six months. So yes, I mean, was it due to the competition? Or was it due to — I mean, what would the reason for that be? And then also competition from these two agents as well?

Jose Alejandro Rauh-Hain: Yes. So I mean, again, I think it's a very exciting time for all of us that treat patients with platinum-resistant disease. There's a lot of options coming out, right? So you mentioned another ADC against folate receptor alpha, but there are at least two others that have shown, one from AstraZeneca and one from Lilly, that have shown similar activities in platinum-resistant disease with response rates between 50%–55% in much smaller cohorts. So I think that data is going to come out. There is a whole FONTANA program from AstraZeneca that is ongoing.

But on top of that, there's a large number of other ADCs that are being tested, right? So I mentioned briefly CDH6. So Daiichi has their ongoing REJOICE Phase III randomized trial. That antibody-drug conjugate is also a topo 1 isomerase I inhibitor ADC against CDH6. And it seems to be, again, agnostic in terms of activities across different levels of CDH6. So I think that's going to be the next big Phase III randomized trial that we're going to see in platinum-resistant ovarian cancer.

But in addition to that, there's claudin-6, B7-H4 that I'm happy to discuss at length, but, you know, the NaPi2b from Tubulis is super exciting. So a lot of different ADCs that have shown response rates between 50% and now close to 60% response rate, again, with small — much smaller cohorts than Rina-S. The thing with all of this landscape is that most of these antibody conjugates are in some way topo 1 inhibitor antibody conjugates.

Meaning that if we — based on what we discussed about the breast cancer data, it's hard to imagine that we're going to be able to sequence one after the other after the other, right? So like you have Rina-S and then after that, you're going to be able to sequence the one from the Daiichi and then after that, NaPi2b, I don't think it seems unlikely that, that to happen if truly the biggest driver of resistance is a payload.

So what I think is going to happen in the next five years is that of all of these, you know, 12, 14 ADCs that are being developed, maybe only three, four are actually going to be used consistently in clinical practice. And which one is the

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winner is going to be so hard to know, right, because we're not going to have to do cross-trial comparisons. And unless there's a clear winning in which shows like very large estimates compared to other ones, all of these are going to be in the mix.

And physicians are going to have to make those decisions based on their experience, the side effect profile, what they're used to doing. So you know, I think that's going to be very interesting how it evolves. But again, I think the big issue is that most of these use a very similar mechanism of action for the payload.

And that's why therapies that are not antibody conjugates, right, WEE1 inhibitors and PARP inhibitors and all the other therapies that are being developed in the DNA damage response mechanism are exciting because they are using a very different mechanism of action, right? So I think that is, to me, the biggest — I mean, the most exciting part because there's going to be more therapies for sure, but also, you know, the biggest question mark in terms of what therapies are truly going to become available and how we're going to use them.

MS: And just one last question. Like what would be the worst-case scenario for Rina-S in terms of data? I mean, like anything less than 40% or I don't know, yes. Or for— Jose Alejandro Rauh-Hain: I think I would not only focus on the response rates at this — I mean, once you have the Phase III randomized trial, it is — I mean, it's powered for progression-free survival. So I think that is — you know, I would say that is the number one metric. Then after that is overall survival and then after that response rate, right? So I mean, worst-case scenario is the PFS is similar to chemotherapy, right? It's a negative trial. It's only three or four months.

I think that is extremely unlikely to happen based on what we've seen in the Phase II study, what we've seen with other, you know, with mirv. So I think that's unlikely to happen. But if you ask me the worst case scenario, that's the worst-case scenario, I guess. But I think that's very — that would be extremely unlikely to happen.

MS: So basically, what we are seeing right now in Cohort C that like that seems more realistic Phase III data?

Jose Alejandro Rauh-Hain: Yes. I mean — and again, the bar for platinum-resistant disease is so low, right? I mean the bar for these trials being single-agent chemotherapy, response rates are 8%–10%. PFS is like around four months. So the bar is so low that, you know, it's hard to imagine that it's going to be a negative trial.

MS: All right. Dr. Alejandro, I think with that, we are at the end of our designated time. Thank you very much for taking out time today for this call and for the insightful discussion.

Jose Alejandro Rauh-Hain: My pleasure. Thank you so much. Have a very good day.

MS: Thank you. Have a nice day. Bye-bye.

Jose Alejandro Rauh-Hain: Bye.

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