Kathleen Moore, and I'm very excited on behalf of myself, my global co-chair, Dr. Toon Van Gorp, all of the co-investigators at Immunogen to give you sort of a recap of the late breaking abstract that I presented today at the ASCO 2023 meeting on the Mirosol trial. I think just to remind you, the Mirosol trial is a randomized phase three clinical trial comparing mirvotoximab sort of tanzine versus investigators choice chemotherapy for patients with platinum resistant ovarian cancer that is a folate receptor alpha high. What I'm gonna present to you today is practice changing. Never in our history as an organization have we demonstrated that a novel agent tested in a phase three trial has improved overall survival in the platinum resistant ovarian cancer setting until mirvotoximab, which is exciting. To remind you what mirvotoximab is, it is an antibody drug conjugate. It's targeting folate receptor alpha, and it's conjugated to a highly potent microtubule toxin known as DM4 on its tail. Folate receptor alpha is not a new target for ovarian cancer. It's almost ubiquitously overexpressed in high-grade serous ovarian cancer. And here's where we find it. It's highly overexpressed in about 35% of high-grade serous tumors. And so mirvotoximab sort of tanzine exploits this. The clinical benefit of mirvotoximab sort of tanzine was already demonstrated through the SORAYA study, which was a single arm phase three trial evaluating mirvotoximab sort of tanzine in platinum resistant ovarian cancer one to three prior therapies, and also fevicizumab pretreated. And in that study, which was reported in 2022, the overall response rate was 32%, and the duration of response on the average was 6.9 months. And that led to the accelerated approval in November of 2022 and made the medicine available in the United States. MIRASOL is the confirmatory phase three trial aimed at regulatory approval globally for mirvotoximab sort of tanzine. To remind you about the schema, again, this is a randomized phase three trial's open label. Eligible patients had platinum resistant ovarian cancer. They could have had up to three prior lines of chemotherapy. They could have had fevicizumab, but they didn't have to have fevicizumab. If they had had a BRCA mutation, they had to have had a prior PARP, otherwise they could or could not have had a prior PARP, didn't matter. And then their tumors had to have folate receptor alpha high expression as measured on a central test. And this is defined as greater than 75% of the tumors on the slide having two to three plus intensity on staining. And so that was our eligibility. If a patient was eligible, they were then randomized one-to-one to receive mirvotoximab sort of tanzine at six milligrams per kilogram IV every three weeks adjusted ideal body weight versus investigator's choice chemotherapy. And investigators could choose from weekly paclitaxel, pegylated liposomal doxorubicin, or tobotecan. The stratification factors were the number of lines of prior therapy and the selection of a physician's choice chemotherapy. The primary endpoint was progression-free survival as measured by investigator. And key analytic secondary endpoints were overall response rate and overall survival as well as patient reported outcomes. And you can see the other secondary endpoints reported on the slide. At ASCO this year, I was able to present the data for the primary endpoint progression-free survival as well as overall response rate, overall survival and safety. Other secondary and exploratory endpoints will be presented some this year and some next year at upcoming congresses. The demographics for the patients who participated on the Mirasol trial were well balanced because of randomization. I do wanna call out the fact that about 60% of the participants and it was evenly distributed on the study had prior Bevacizumab. And 55%, again, evenly distributed had prior PARP inhibitor consistent with current regulatory availability of medicines in the countries where Mirasol was open. Now the stratification factors were again, patients could have one, two or three prior lines of chemotherapy. And so those patients who participated in Mirasol had one prior line in about 14% of patients, two prior lines in 40%. And the most patients actually entered Mirasol with three prior lines of chemotherapy. This was 46%. So just under half entered Mirasol already having received three lines of cytotoxic chemotherapy. So relatively heavily pre-treated population on this clinical trial. And then the other stratification factor was the selection of investigator's choice chemotherapy. And for weekly Paclitaxel, this was the most commonly selected regimen at 41% followed by pegylated liposomal doxorubicin at 36%. And then finally, Tuboticam at 23%. So the primary endpoint is progression-free survival. And so I'm showing you here the Kaplan-Meier curve for the investigator's choice chemotherapy. And what you can see here is a median progression-free survival of 3.98 months. And this is very consistent with historical benchmarks and also importantly, consistent with the statistical assumptions that we made when the Mirasol study was designed. Here I'm showing you the progression-free survival Kaplan-Meier curve for those patients randomized to mirvoteximab. And you can see a median progression-free survival of 5.62 months. We met the primary endpoint for progression-free survival. Here, the hazard ratio is 0.65 with a P value less than 0.0001. This is a 35% reduction in the hazard of progression with use of mirvoteximab as compared to investigator's choice chemotherapy. The other thing I want you to note on this particular set of curves is the morphology of the curves. And I'm indicating this here with an arrow. I think we all know, if you reference any of the many well-designed trials, randomized phase three trials in platinum-resistant ovarian cancer, which haven't worked, unfortunately, we see this 50% drop-off at the first disease assessment. Really often in both arms because very few things have worked in this space. So many patients progress at that first disease assessment. And you indeed see that here in the investigator's choice chemotherapy on in blue. 50% are off at that first disease assessment. You do not see this with mirvoteximab in the orange bar. There was an early separation of the curves that is maintained throughout, which is a very important signal in terms of estimating the benefit of mirvoteximab as compared to investigator's choice chemotherapy based on the morphology of these curves. So because the primary endpoint of progression-free survival was positive, we could move alpha to a key analytic secondary endpoint, which is overall response rate. And I'm showing you that here. And what you can see is a remarkable increase in the overall response rate when using mirvoteximab as compared to investigator's choice chemotherapy. We go from 16% response rate to 42% response rate. And notably in the mirvoteximab arm, we have complete responses in this platinum-resistant cohort, 5% versus none for investigator's choice chemotherapy. And so this is an overall response rate difference of 26.4% and an odds ratio of 3.81 against statistically significant. And because this was statistically significant, we can move alpha now to our third analytic endpoint, which is overall survival. But before I show you that, I want to show you the waterfall plots or the mirvoteximab arm versus investigator's choice chemotherapy, because this really shows you another sense of clinical benefit beyond the Kaplan-Meier curve and beyond just overall response rate percentages. This really shows you what happens radiographically when we use these two different types of medicines. For mirvoteximab, you can see that 80% of the patients who were randomized to mirvoteximab had some reduction in their tumor measurement. 42% were confirmed recessed responses, but almost an additional 40% had either an unconfirmed response or less than a 30%, but still a decrement in their tumor measurement, which is another estimate of clinical benefit. And this is as compared to investigator's choice chemotherapy, where the confirmed response rate is 16%, and only 55% had any amount of tumor shrinkage with the investigator's choice chemotherapy. So another way to look at benefit. But before I get to overall survival, I do want to show you the other thing we did. And remember when I showed you the schema of the trial, the primary endpoint is investigator-assessed progression-free survival, and this is an open-label trial. And so we really needed to do a sensitivity analysis of both progression-free survival and overall response rate by blinded independent central review, or BICR, to make sure that it was consistent. And this slide is really just showing you that it was. You can see the BICR read of progression-free survival on the left, and you can see the reread of the overall response rate on the right. And these are very concordant with what was assessed by the investigator. So our investigator-assessed endpoints can stand. And so moving on to overall survival, there was a pre-planned interim look at overall survival at the time of PFS analysis. And the boundary of statistical significance set for overall survival at this interim look was a p-value of 0.01313. So that's what we would have to beat or be less than to be statistically significant. At the time we looked at overall survival, there was 13.1 months of median follow-up, and we had had 68% of the final overall survival events occur at this time point. And so knowing that, here's the overall survival Kaplan-Meier curve for the investigator's choice chemotherapy. You can see this has a median overall survival of 12.75 months, which is, again, very consistent with historical benchmarks for a platinum-resistant population. And here is the Kaplan-Meier curve for mervituximab with a median overall survival of 16.46 months. Here, again, this is a statistically significant improvement overall survival with a hazard ratio of 0.67 and a p-value of 0.0046, which is less than that preset boundary. And so not only is clinically significant, but it's also statistically significant. Just like progression-free survival, the curves separate early and they maintain their separation throughout that median 13-month follow-up to date, and follow-up of this will be ongoing. We're going to be showing in upcoming months a lot of the exploratory subgroups and multivariate analyses as the data is further analyzed, but we did want to show this exploratory subgroup at this first meeting, because as I referenced in the introduction, the use of mervituximab, at least in the United States, is already, very recently, a standard of care based on the Soraya study. And this was similar to Mirosol in inclusion, except for the fact that it required bevacizumab. And Mirosol did not. Patients could come on with or without, and as I shared with you, 60% of patients had bevacizumab. And so we wanted to just look at the magnitude of benefit to see if there was any signal of differences between tumors that were bevacizumab-naive versus those that had had exposure to prior bevacizumab. And I'm showing you that here on the top row, you can see progression-free survival, and on the bottom row, you see median overall survival. And really the take-home from this slide is that both groups, bevacizumab-naive and bevacizumab-pretreated, benefit from mervituximab more than investigator's choice chemotherapy. And the magnitude of benefit is very similar in the two exploratory subsets, which I think is reassuring in terms of where you place mervituximab in the sequence of therapies for patients with platinum-resistant ovarian cancer. So before I move on to the safety data, I just wanna recap the efficacy data that you've seen to date. As compared to investigator's choice chemotherapy, mervituximab improves progression-free survival by 35%, it more than doubles overall response rate from 16 to 42%, including 12% complete responses, or I'm sorry, 5% complete responses as compared to none in the investigator choice chemotherapy arm, and then a 33% improvement in overall survival. The blinded independent central review showed that it was consistent with that assessed by the investigator, so that sensitivity analysis was done. And really the two bevacizumab subgroups appear to show, really, I think we can say equivalent benefit of mervituximab irrespective of prior exposure to bevacizumab. So now moving on to safety, this is a high-level safety summary. Really what I wanna point out to you is the fact that we had less grade three or higher treatment emergent adverse events with mervituximab as compared to investigator's choice chemotherapy, 42 versus 54%. We had fewer serious adverse events, 33 versus 24%. And then really notably, we had almost half as many discontinuations from mervituximab as compared to investigator's choice chemotherapy at nine versus 16%, which really kind of tells us that our patients were tolerating this therapy well. But how well? So let's look at the adverse events in a more granular way. First, hematologic. And so what I'm showing you in the salmon color are the adverse events related to mervituximab. And in the blue bars are the adverse events related to each investigator's choice chemotherapy, Paclitaxel, Pagli-Libosomal doxorubicin, and topotecan from left to right. So this is hematologic toxicity. And what the take-home here is that there's almost negligible hematologic toxicity with mervituximab as compared to investigator's choice chemotherapy. If we look at peripheral neuropathy, we see that it's a little bit less than it's probably most appropriate comparator, which is weekly Paclitaxel, and we have no alopecia as compared to other investigator's choice chemotherapy. We have about the same rate of common but low-grade GI toxicity with diarrhea and nausea being common in a little less than a third of patients and their mitigation strategies for each of these with over-the-counter and prescription medications, which work well. The known toxicity of mervituximab that is treatment emergent and treatment related is ocular toxicity, which again is common and low-grade, and about 42% of patients who receive mervituximab, you can see dry eyes, keratopathy, or blurred vision, and often these can be in the same patient. Again, these are predominantly low-grade and there are very well-described prevention and mitigation strategies in place and have been present through all mervituximab trials that really lead to a very low rate of discontinuation from mervituximab due to ocular toxicities, and in fact, in Mirasol, only four patients discontinued treatment with mervituximab because of an ocular toxicity. It's also worth noting that with the mitigation strategies, these ocular toxicities are reversible, and they don't tend to repeat for the vast majority of patients. So once they happen and we mitigate them, they don't tend to be an issue for the remainder of that patient's experience on mervituximab. So really in conclusion, our big take-home is that mervituximab is the first novel treatment tested in a phase three trial to demonstrate an improvement in overall survival, which is an exciting day for our patients. It, of course, also demonstrated a statistically and clinically significant improvement in progression-free survival, as well as overall response rate as compared to investigator choice chemotherapy, and is characterized by a very differentiated safety profile comprised mainly of low-grade gastrointestinal and ocular side effects with well-established mitigation strategies. So mervituximab is the first antibody drug conjugate approved for ovarian cancer. It is the first biomarker-directed therapy approved for platinum-resistant ovarian cancer, and is only the second biomarker-directed therapy ever approved in ovarian cancer at all following PARP inhibitors. So this is a big accomplishment in a number of fronts for our patients in terms of developing agents that help them live longer, live better, and get us closer to individualized therapy based on biomarker status. We believe these data are practice-changing and really do position mervituximab as the new standard of care for platinum-resistant folate receptor alpha-high expressing ovarian cancer, and ongoing studies that incorporate mervituximab into earlier lines of therapy, most notably platinum-sensitive, and small studies in the frontline will further inform how we best utilize this exciting new agent. And we look forward to launching this globally in the upcoming months. I would be remiss, again, if I didn't acknowledge that this was a global trial, and you can see all of the countries that participated, and many of you watching this will have participated, and from the bottom of my heart, I thank you for your commitment to developing mervituximab and getting this drug across the finish line, the first finish line. There are others now for our patients, and I would be utterly remiss if I didn't dedicate this great achievement to the over 1,000 patients who have volunteered to participate on mervituximab-containing clinical trials over the past decade. Unfortunately, we have lost many of them, but I hope their families, and I hope those of them that are still with us are able to see this presentation, and see the press releases, and know that their volunteerism supported a novel new agent that will help the women that come after them hopefully live longer and live better. We are indebted to their participation in clinical trials, and I thank you for your attention, and I hope you enjoyed this presentation. Thank you.

Mirosol trial

mirvotoximab sort of tanzine

MST

platinum-resistant ovarian cancer

overall survival

progression-free survival