Sutro Biopharma, Inc. (STRO) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Sutro Biopharma KOL discussion of STRO-002 data virtual event. [Operator Instructions] Please be advised this call is being recorded at the company's request and will be available on the company's website for at least 30 days. Now at this time, I would like to turn the call over to Ed Albini, Chief Financial Officer at Sutro Biopharma. Sir, please go ahead.

Thank you, operator. Good afternoon, everyone, and thank you for joining us. With me on the call are Bill Newell, Chief Executive Officer; Dr. Arturo Molina, Chief Medical Officer; Dr. Trevor Hallam, Chief Scientific Officer; Linda Fitzpatrick, Chief People and Communications Officer; and Annie Chang, Head of Investor Relations. We also welcome on the line Dr. Lainie P. Martin of the Hospital of the University of Pennsylvania and Dr. R. Wendel Naumann of the Levine Cancer Institute at Atrium Health. This afternoon, we issued a news release that you can find on our website at sutrobio.com, which includes updated data from our ongoing Phase I dose escalation study of STRO-002 in ovarian cancer, reflecting patient data as of October 30, 2020. Next slide. Before we start, I'd like to remind you that today's call will include forward-looking statements. These forward-looking statements are based on Suite's expectations and assumptions as of the date of this call. Each of these forward-looking statements involve risks and uncertainties that could cause Sutro's clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements. Please refer to Sutro's filings with the SEC, including our 2019 Form 10-K for information concerning factors that could cause Sutro's actual results to differ from those expressed or implied in the forward-looking statements discussed on this call. Except as required by law, Sutro assumes no obligation to update any forward-looking statements discussed on this call to reflect any change in expectations even as new information becomes available. Next slide. The agenda for today is as follows: Bill Newell will open up the discussion and introduce our KOL speakers. Dr. Lainie Martin will be discussing the STRO-002-GM1 clinical data. Dr. Arturo Molina will follow with a discussion of the STRO-002-GM1 program expansion. We will then close with a Q&A panel featuring Drs. Martin and Naumann, along with the Sutro team, including Bill, Arturo, Trevor and myself. With that, I would now like to turn over the call to Bill Newell for a welcome and introduction.

Thank you, Ed. Good afternoon, and welcome to our virtual discussion of STRO-002 data and our STRO-002 expansion phase. As you may have seen in our press release, we reported data from our Phase I dose escalation study as of October 30, 2020. We're excited to present this data and encouraged by the 10 patients in this study that met the criteria for RECIST in this heavily pretreated, unselected patient population. As a reminder, the data we will present today is part of the same dose escalation study for which we provided an interim data update earlier this year at AACR in both April and June and at IGCS in September. Next slide, please. Well, that's the right slide. To discuss this data, we are pleased to have with us Dr. Lainie Martin. She's a medical oncologist specializing in the treatment of gynecologic cancers and an investigator on our STRO-002-GM1 trial. She is the leader of the Gynecologic Medical Oncology Program at the University of Pennsylvania, Associate Professor in the Department of Hematology and Oncology and an Associate Director of the Gynecologic Oncology Clinical Research Unit. She served as the principal -- or site principal investigator on over 75 trials and has extensive experience in the design and management of Phase I, II and III clinical trials, including multiple ovarian cancer trials. Also with us and available for our Q&A panel is Dr. Wendel Naumann. He's also an investigator in our study and currently Professor and Director of Gynecologic Oncology Research and Associate Medical Director of Clinical Trials at the Levine Cancer Institute of Atrium Health. He has served as a Board member of the Executive Council of the Society of Gynecologic Oncology and the Chair of the Education Committee and a Co-Director of the SGO winter meeting. His clinical experience includes targeted therapies and immunotherapies, and he runs the Phase I trials in gynecologic oncology of the Levine Cancer Institute. We're grateful to have Drs. Martin and Naumann with us on this call today. As I mentioned, they are both part of Sutro's Clinical Advisory Board and are key investigators in our STRO-002 study. Between the 2 doctors, they treated 12 patients of the STRO-002-GM1 Phase I trial. Next slide. And with that, I'd like to turn this call over to Dr. Lainie Martin. Dr. Martin, please go ahead.

Thank you so much for that kind introduction and for the opportunity to present the data from the dose escalation portion of this Phase I trial evaluating the safety and toxicity of STRO-002. This agent is an optimized antibody drug conjugate that uses precisely positioned nonnatural immuno acids, which allows for homogeneity and a very stable drug-to-antibody ratio of 4:1, with a proprietary cleavable hemiasterlin linker warhead that's stable in circulation, but upon internalization, after binding to the folate receptor alpha, releases the payload, resulting in immunogenic cell death of the cancer cells. This agent targets folate receptor alpha, which has been a validated target in a number of cancers and in particular, in ovarian cancer. Next slide, please. In this dose escalation portion of the study, 39 patients were enrolled and 31 patients were evaluable for response. Five patients were treated at 3 dose levels before reaching what was felt to be an antitumor-active dose, 2 were in single patient cohorts at very low dose levels and 3 at 1.8 milligrams per kilogram. The remaining 34 patients were treated dose levels of 2.9 milligrams per kilogram or greater. And all of these dose levels, as we'll show you, are associated with some antitumor activity. Enrollment completed in August of 2020 and the data that you're viewing comes up to October 30. 31 of the 34 patients treated at these higher dose levels are evaluable for RECIST. Three patients did come off study prior to their first on-treatment or post-baseline SAM. The maximum tolerated dose was not reached, but based on the data we'll show, we will be testing 2 dose levels in our Phase I dose expansion. And 10 of the 31 patients treated in this dose escalation portion of the study remain on treatment. Next slide, please. So this is -- this study has a 2-part design. And during the Phase I, we are limiting enrollment to ovarian -- patients with ovarian cancer. These patients are not being selected on the basis of folate receptor alpha expression. We're taking all comers. Treatment is given as IV infusion once every 21 days. And the first patient was dosed in March of 2019. The trial is activated at 10 sites. And I mentioned that 5 patients were treated prior to reaching the 2.9 milligram per kilogram dose level. The dose escalation have planned to treat at 2.9 dose escalating to 4.3 and then 6 and 6.4. During the course of the dose escalation, based on some of the toxicity we were seeing both at initial dosing and during ongoing treatment, a decision was made to look at 2 additional dose levels: 5.2 milligrams per kilogram and 5.6 milligrams per kilogram. And we've chosen one of those dose levels along with 4.3 for the expansion cohort, which we hope to start it very soon. Next slide, please. So the patients with ovarian cancer that were treated during this dose escalation portion of the study were very heavily pretreated. They had a median age of 61. Most patients were diagnosed with ovarian cancer, although we did also include patients with fallopian tube and primary peritoneal cancer. Patients had a very good performance status of 0 or 1, but the median time from diagnosis was 3.9 years with some patients -- the range from less than a year to 17 years. And patients, again, were heavily pretreated with a median number of prior regimens of 6, and a range of 2 to 11. All patients, as expected, to have platinum, but we actually have nearly half of patients 18 of these patients had more than -- 3 or more prior platinum regimens. So again, highlighting how heavily pretreated they were. The majority had received taxanes as well as bevacizumab. And in this modern era, the majority is 60% -- or 59% had received PARP inhibitors. We also had a number of patients on the study who had received prior checkpoint inhibitor therapy and other experimental therapies. And on the right, you see the patients that we had enrolled to each dose level. As I mentioned, there was 1 patient at the 0.5 milligram per kilogram dose, 1 at the 1 milligram per kilogram and 3 at the 1.8 milligram per kilogram dose. It was anticipated that these dose levels would not be clinically active, so we tried to move through those doses quickly. And then we went on to the -- what were expected to be clinically active dose levels. And we did prove that, and I'll show you that in some upcoming slides. But you can see that we did enroll some additional patients at the 4.3, the 5.2 and the 5.6 dose levels, which were not anticipated again to receive -- evaluate some additional safety and toxicity information. We saw 2 DLTs in the course of the study. One was a patient who experienced Grade 2 neuropathy and Grade 3 arthralgia at the 6-milligram per kilogram dose level, that just level was expanded with no additional dose-limiting toxicity. And since we did make criteria to escalate, we did move forward with the 6.4 milligram per kilogram dose level, the first patient and only patient to receive that dose did experience Grade 3 bone pain. And the decision was made to actually deescalate since we were seeing activity at some of the lower dose levels as I'll show you. Next slide, please. STRO-002 is generally very well tolerated. You see here the most common treatment-emergent adverse events As you can see, the majority of these were Grade 1 and 2 events. The most common grade 3 and 4 toxicity was neutropenia, which generally doesn't cause people symptoms, and these were mostly uncomplicated neutropenias that, for the most part, resolved relatively quickly. They didn't require a growth vector for resolution, but investigators were allowed to offer a growth vector for subsequent cycles to prevent dose delay in neutropenia. And then you see some of the other toxicities and treatment-emergent events that are seen common in this patient population as abdominal pain. We did see some arthralgia, some neuropathy. And remember that 97% of patients had had prior taxanes and could have had a bit of neuropathy preexisting. Next slide, please. So here we get into some of the efficacy data, and this is the waterfall plot. And as you can see, the vast majority of patients experienced clinical benefit. These lines or color coated to reflect the dose levels. And our STAR patient on the study actually was treated at the 2.9 milligram per kilogram dose level, this patient on the far right. What you see here on this dotted line, the 30% lines that reach below that are patients that achieved a partial response. But even to the left of that, you see this group of patients really -- so the right of the first 3 that have very minimal increases and some decrease. These are all labeled as stable disease outside of the shaded bar graph. We saw objective responses in 10 patients. And these errors or triangles denote patients who remain on treatment at the time of the data cut on October 30. Next slide, please. This is a spider plot. And what's interesting here, we see our patient with the complete response who remains on treatment more than a year out from treatment. And you see, this is the number of weeks on treatment. So we have a few patients already exceeding a year on therapy as well as a good number of patients exceeding 26 months on therapy, and the number's still ongoing and haven't reached that point yet. But what you can see, it's a little bit hard to see, but the majority of the lines really are below this 0. So again, emphasizing that the majority of patients are seeing some decrease in the size of their tumor. We also had a number of patients that had an initial increase, and then you can see their trend line is trending down. And so that is an interesting phenomenon on this drug that I'll point out a little bit later as well. Next slide, please. And for those that like to see a picture, I always love to see a scan like this, and it's something you can show the patient in clinic. This is a patient who actually remains on treatment was treated at 5.2 milligrams. She had platinum-resistant disease, 4 prior regimens and after 4 cycles has had a significant partial response. So those are always exciting to see next date. This is the swimmers plan. Actually, I really like these plots because it shows the duration of therapy. And what you can see again with the color coding, you see a number of patients on for more than a year, more than 6 months at all dose levels. One thing to note in this chart, you'll see that the color can change. These are patients that required dose modification as they were going along in treatment. And what's interesting is these orange circles denote partial response. And you see that some of these partial responses are happening early on, which we always hope to see. But we're also seeing partial responses occurring at a later point in treatment. And even this patient that achieved the CR, there was initial PR and over time, to continue to have response until meeting the criteria of a complete response. But you can see that even with dose reductions, including a patient here that had multiple reductions, these responses are coming on at lower doses. And again, just a number of patients that have achieved PR and remaining on study at this time. Next slide, please. This selects out the patients who actually met criteria of partial response. And again, just highlighting the starting dose and the dose reductions that we saw along the way, which having a dose reduction or starting at a lower dose didn't appear to impact the efficacy. So we're really seeing effectiveness and benefit across all dose levels of the regimen and a number of these patients still ongoing. Next slide, please. So we've started to look at the folate receptor alpha expression based on archival tissue that was collected for a number of these patients. And the graph on the right shows you that orange or patients who achieved a PR, yellow is an unconfirmed PR and then blue is stable disease. And when you look across, we're seeing activity and clinical benefit at all levels of folate receptor alpha expression. And so I think that is supportive of the strategy in an ovarian cancer population to continue to enroll all comers and not be overly concerned with the level of expression at this point. Next slide, please. So just to summarize, as I said, STRO-002 demonstrated clinical benefit in this heavily pretreated unselected patient population of women with ovarian cancer. And again, 6 prior regimens of therapy as a median is pretty significant. Remember, some of these patients that had other experimental treatments. So you're looking at patients who are not really expected to benefit from our standard treatments at this point. 86% of the treatment-emergent adverse events that we're seeing were grade 1 and 2. And one thing that we've noted with some of these antibody-drug conjugates are ocular toxicities, and we were prepared for that, but really have not seen that. The other side effects were very manageable. Neutropenia could -- will generally resolve quickly, and the peripheral neuropathy and neuralgias tended to diminish with dose modifications or delays. This point this wide therapeutic index and this prolonged dosing, I mean, again, going back to that swimmers plot, what we really want are we want agents that when they're effective, patients are able to stay on for a long time. Really doesn't do us any good to get an early response, but we can't continue on with the treatment. And so when you're thinking about what is meaningful benefit for these patients, these prolonged periods of disease control are very compelling. And again, we're seeing some of these responses and that complete response after a long period of time on treatment. So that's a very interesting aspect in this patient population. And again, we still, even with this early data, have 10 of the 31 patients remaining on the study. I think with that, I'll turn it back to Arturo, and thanks again.

Sorry, I was on mute. Thank you, Dr. Martin for an excellent presentation. We also want to thank Dr. Martin and Dr. Naumann and all the other investigators and study staff for their hard work and diligence in taking care of the patients in STRO-002-GM1 study. Before I continue, Dr. Naumann would you like to comment on your experience treating patients with STRO-002, since you've been an active enroller as well?

Yes, sure. I think this is -- for anybody who treats ovarian cancer to the point that Dr. Martin touched on. When you have somebody who's had 4 or more kind of therapies, it's unusual to see any kind of response. So when you see patients -- I have 2 of the patients that have been on for over a year or more, that's very gratifying to be able to offer patients treatment options. And unfortunately, when these patients do progress, there's really not anything else out there. So when you look at these responses, this is almost like we see with the immunotherapy and other disease sites, where we have these long, prolonged durable responses with relatively manageable toxicity. We don't see any pneumonitis. We don't see any ocular toxicity that is troublesome. The arthralgias were a little bit of a problem at the higher dose levels, but have really not been an issue when we have dose adjusted or decreased the dose to a tolerable dose. So I think this is a great addition to the drugs that we have to treat our patients with. We're very excited about it.

Great. Thank you, Dr. Naumann. So as Dr. Martin noted, the objective responses and duration of disease control continue to improve as the data matures with longer follow-up. And 1/3 of the patients have had RECIST responses out of this 31 RECIST-evaluable patients. This dose escalation data is quite remarkable in this very heavily pretreated patient population. Now previously, we reported 2 confirmed responses and 6 unconfirmed responses when we updated the data as of August 31. And 4 of the unconfirmed responses were ongoing. Now as of October 30, 1 of the PRs became a CR, 2 unconfirmed PRs confirmed, 1 unconfirmed PR is still ongoing and has not confirmed and 1 of the unconfirmed PRs did not confirm. But additionally, we saw 2 new PRs. They're still unconfirmed but these were at the 4.80 mg per kg dose level. I mean that is very important, we think, because it supports the path forward that I will discuss shortly. If you look at the waterfall plots, you'll see that both patients who had an unconfirmed PR at 4.3 have had a deep response. One of them has had a 69% reduction of tumor, and the other 1 has had a 47% reduction of tumor. So we're very encouraged by how long the patients are staying on study. The median time on treatment is 19 weeks, and we still have 1/3 of the patients on treatment. This data is indeed very compelling, and we expect the efficacy outcomes to continue to improve with longer follow-up. So now I will give you an update on where we are with the dose expansion cohort. The ovarian cancer dose expansion cohort is open and is screening patients. I will review the rationale for the changes, but the main goal is to generate data in the 72 treated patients to inform a registration study. As we showed you, 4 patients will remain on treatment for over a year at 2.9 to 4.3 mgs per kg are doing very well at those doses. And we've shown you that we do not need 6 mgs per kg. more than necessarily better. So doses we're selecting or 4.3 and 5.2 mgs per kg, and we're actually randomizing between these doses. The goal with this randomization is to define optimal efficacious dose that is well tolerated and maintains dose intensity. Another important change for the expansion cohort is that fresh archival tissue will be required prior to enrollment to increase our database on fully receptor alpha expression, and then make an important decision on a potential enrichment strategy. So the study will begin with all comers and we'll be collecting the data and analyzing the data as the patients are being treated, but the patients could not start treatment until we have either archival tissue or tissue from any repeat biopsy. Now we've revised the patient inclusion and exclusion criteria and will allow both platinum-resistant and platinum-sensitive patients, and I'll get into that in the next slide. Additionally, patients with greater than -- or grade tumor higher per neuropathy will be excluded from the study. As Dr. Martin mentioned, some of these patients have had several lines of taxanes, not just one, and many of these patients who came on study were already on medications or treatment that are peripheral neuropathy. So the exclusion criteria of grade 3 peripheral neuropathy is for all the other sponsors do when studying ADCs in registration studies in expansion cohorts. So this is not irregular exclusion. And our goal again with these changes in the inclusion/exclusion criteria is to characterize the efficacy and safety profile in this heavily pretreated population, again, with the goal of going to a registration-directed study. Next slide, please. So the dose expansion cohort is in a preliminary data as expected in the first half of 2021. The fourth call was submitted to the FDA earlier in the call and no comments were received after the 30-day period. So we're starting with the ovarian dose extension cohort. And so the platinum-resistant patients can have 1 to 3 prior regimens, and the platinum-sensitive patients can have 2 or 3 more prior regimens, but they need to have had at least 2 platinum regimens. And so that will ensure that we're getting patients who have not had a lot of subsequent treatment options. As we explore regulatory pathways, it's clear we have to revisit and redefine the concepts of platinum status. Historically, platinum-sensitive and risk in populations have been used for regulatory approvals, but the current treatment paradigm and landscape has changed with be an introduction of PARP inhibitors in various therapies. So that -- what do we mean by that? Well, if you look at a patient who has a 12-month platinum-free interval with PARP inhibitor or on PARP inhibitor and then progressives the 12 months, is that the same patient or will that patient have a different response to subsequent therapies that the patient had at 4 platinum 3 interval without any maintenance treatment? So we are -- we've been talking to the key opinion leaders of the study, and everybody's in full support that we need to start having this dialogue with FDA. As I've mentioned, we are randomizing between 4.3 mgs per kg and 5.2 mgs per kg, and we anticipate approximately 20 patients in each of these 2 doses. The endpoints of the study are pretty straightforward. The RECIST response -- sorry, the primary endpoint is subjective response per RECIST. The secondary endpoints are overall survival, duration of response and safety. Also, the trial is now open for enrollment. It has been [indiscernible]. We plan to open the study in 35 sites in the U.S. and Europe. And as I mentioned, we will be getting preliminary data in the second half of 2021 with the goal of going to the FDA later on in 2021 -- second half of 2021. Next slide.

Dr. Molina, your line is a little bit staticky. I don't know if you can adjust maybe your Internet connection or something.

I'm not sure if that can. So I apologize for that, but it'll do my best here. So we have selected as well as validated a receptor assay for -- as for competitive diagnostic. The assay is up running in our study and will further support the STRO-002 clinical development towards registration. As Dr. Martin mentioned, we have seen patient benefit across a broad spectrum of all receptor alpha expression levels. What we know about this assay is that the assay exhibits a dynamic range of staining. It has crisp membrane staining, low cytoplasmic staining and low background staining. Now the fact that we've seen activity in low, moderate and high expressers is not totally surprising given the preclinical cell line and PDX model data where we saw self-killing antitumor activity in low, medium and high-expressing models. So so far, the data we have generated today will suggest that if we were to exclude patients who are low expressers or medium expressers, we would be denying clinical benefit there. So we do need more data to make a decision on the enrichment strategy. But the observation that we've been able to help patients with different varying levels of folate receptor alpha expression is very encouraging. Next slide. So the maturing efficacy and safety profile appear to provide a clear path for accelerated clinical development and registration of STRO-002. The safety profile continues to be favorable with 86% of the treatment-emergent adverse events being grade 1 to 2. STRO-002 has been clinical efficacious on multiple doses starting at 2.9 mgs per kg. We showed a disease control rate 74% at 12 weeks and disease control rate of 58% at 16 weeks. 13 patients remain on study for over a year and 10% of patients remain on study for 64 weeks. Most of the patients who stay in treatment or our long-term responders have been treated at doses that range at 2.9 to 5.2 mgs per kg and, therefore, that is the basis for our expansion cohort randomization. We will further optimize this dose in the expansion cohort, and again, this information will be very valuable as we select those for registration studies. The observation of antitumor activity across a broad range of expression in the dose escalation study is very intriguing. A larger sample size will be used to to determine an enrichment strategy. Currently, patients with medium and low-quality receptor alpha expression are being excluded from ongoing registration [indiscernible] studies of other ADCs under development, so we're hoping to be able to help broader population with STRO-002. To that end, the expansion cohort will enroll heavily pretreated patients. The ovarian cancer cohort just opened this month and is actively screening. We also will open the endometrial cohort. I didn't get to talk a lot about it in the previous slide, but we plan to initiate the endometrial expansion cohort next year. And additionally, we're finding combination studies with the goal of initiating the combination studies next year as well. Ultimately, we anticipate the end of Phase II meeting with the FDA for the second half of 2021. We believe that the preliminary dose expansion data that we will generate in the first half of 2022 will inform this registration strategy, with the same amount in the registration trial first, and then a confirmatory randomized study as well as potential registration strategies with combinations. So this concludes my presentation, and then I will ask the operator to take us to the Q&A. Dr. Naumann and Dr. Martin will be joining us in the Q&A panel. Operator?

[Operator Instructions] Our first question comes from Konstantinos Aprilakis of Stifel.

Congrats on the impressive update here. So my first one for Dr. Martin and Dr. Naumann. So first of all, thank you both for taking the time and sharing the news with us. A comment was made about sort of the analogy to immunotherapies, seeing this response rate that's associated with durable responses. I'm wondering, if I interpreted the spider plot correctly, you sort of saw some of the tumor volumes go up and then come back down and move toward a response threshold, almost analogous to like a pseudo progression. So at least, my interpretation, it seems like there might be sort of early engagement of the immune system here. Any -- what are your thoughts there? Any other anecdotes? Is this sort of -- are you thinking about it just like that, that you are getting engagement with the immune system and maybe there's rational sort of combinations that jump to mind with something like an immune-mediated mechanism to get into earlier lines of therapy sort of in the future? Any thoughts there would be much appreciated.

Well, so this is a phenomenon we actually do see in patients with resistant ovarian cancer that when you start a cytotoxic therapy, sometimes, you'll see a little bit of progression before you actually see a dip. So that's not unusual. As to the mechanism of action, it's hard to know exactly how this engages. I've been impressed that it's -- that it has worked as well as it has, being a targeted therapy, because while targeted therapy is beneficial, it's also a double-edged sword if the tumor doesn't carry the target. So when you see these long, durable responses, you do have to wonder if something else is going on there. Is it immune mediated, I don't know, but this is a patient population you would not expect to see long durable responses, if you see any response. And generally, your response is less than on the median of a couple of months. So I think that's why it's so encouraging as a clinical investigator when you see things like this.

I would completely agree with what Dr. Naumann said. It's that duration of response, that duration of meaningful benefit for these patients who've struggled in ovarian cancer to find an effective immunotherapy. We haven't seen the kind of successes in ovarian cancer that have been seen in some of the other cancers, and it's really tough that you don't see much pseudoprogression in the solid tumors. That's more of a melanoma phenomenon. Although I think we're still -- we still have a lot to learn about the immunotherapy. But we still have a lot to learn about what neoantigens trigger immune response. There is old data that there are immune cells in the microenvironment, so I think we have a lot to learn about these agents. But most importantly, as Dr. Naumann said, this is a patient population. You rarely see this kind of duration of benefit. We -- usually, these people are seeking out Phase I trials because standard chemos might work for a month and then they're already developing resistance. So it's compelling. And we are going to do some -- need to do some work to figure out the mechanism.

The next question comes from Boris Peaker from Cowen.

I'd like to add my congratulations on the data. First, on a fully receptor alpha expression, you've shown results from 13 patients. I'm just curious how many patients in total were tied folate receptor alpha? And also on the that table, the CR patients was not included. I'm just curious if that patient was folate receptor alpha or not?

Can I answer the question?

Yes.

We are still collecting specimens, and we've included only the samples for patients treated at 2.9 mgs per kg. We don't have a specimen yet from the CR patients. But having said that, recently, we've been getting more samples come in. I know I've been nudging Dr. Naumann and other of our investigators. But we wanted to start out with patients treated at 2.9 mgs per kg or higher because we think those are the clinically relevant active doses, and those would be the ones that we'll be pooling with the samples that we get from the expansion cohort. I hope that answers your question.

No, that's helpful. And my second question is on the expansion study. It sounds like there's an echo on line. You're testing similar doses in a 2-arm expansion study of 20 patients, 4.3 and 5.2. Just curious, what happens if the efficacy is relatively similar between the 2 arms? What are you going to advance forward?

I think the tolerability may be something that got existed in one direction versus the other. The key long term is which dose [indiscernible] such that we can treat consistently every 3, 4 weeks for a year or 1.5 years. We know 2.9, at least in those 2 patients have been well tolerated for over a year, and 2 of the 4.3 mgs per kg patients have been on treatment also for more than a year. I believe one had a little dose production at the very end at 2.5. But with 5.2, we have seen some of dose reduction. However, we are going into a patient population that is less heavily pretreated, so -- and we're also not allowing tumor neuropathy. So the tolerability of 5.2 mgs per kg could be very good in the less-heavily pretreated patient population. And we'll be -- some of it will be more of a judgment call on which way we go, but we will look at the -- when they get their first post-treatment scan and there seems to be equal rates of tumor control or it's one of those a little higher. So it will be looking at the [indiscernible] of the data as the data emerges. But we want to feel comfortable, even if we started 5.2, and we end up dose reducing down the line of 4.3 that the data from the 5.2 mgs per kg patients show that we still achieve and maintain and preserve good responses [indiscernible].

I think Konstantin had a follow-up. I might have disabled his microphone too early. Konstantin, go ahead, you should be able to talk now.

I appreciate that. I just had a follow-up on the mechanism. I wanted to get at sort of -- you're seeing this very impressive efficacy, patients who are taxane refractory, your hemiasterlin payload is likewise tubulin acting. So this is impressive for another reason. What do you think explains that activity in late-line setting in patients that have received taxanes. And on a related note, just for the life of me can't recall if you disclosed this, is the payload a substrate for drug efflux pumps? Is that maybe one of the mechanisms why it's kind of concentrating in cells and that would be the mechanistic explanation for why you can see activity when you wouldn't expect otherwise? Now I'm done.

Okay. Thanks, Konstantin. I'm going to ask Trevor Hallam, our Chief Scientific Officer, to weigh in first.

A couple of things around the design of this particular agent that I think gives it unique advantages. So you know that it's a single molecule in the drug which is actually quite unusual in antibody drug conjugates, and we've also been able to design into some advantageous properties, so the hemiasterlin, although it's a tubular inhibitor. It sort of stands out on a couple of attributes we think are quite important. The first is that it has a very short terminal half-life such that when it's generated in the tumor, it does its business, kills the primary tumor cell that it's produced in. It has the potential to give some limited business before it's clear, very rapidly systemically. And that's important because you don't want an active warhead that could cause collateral damage hanging around at all. You mentioned Pgp efflux pump or efflux pumps, tumors, particularly and in ovarian tumors, it has been reported the patients that have been treated with platinum exhibit ovarian tumors which have induced Pgp efflux pump. So these are secondary devices, which are physiologically relevant to healthy cells, but of course, are there to get rid of toxic agents. In tumors, they induce that and actually escape death. So many tubular inhibitors are actually substrates of Pgp efflux. We've designed this hemiasterlin to be a very core substrate of those efflux pumps. So it creates an opportunity for us in that we need minimum of the hemiasterlin to be internalized to force death. One other point about mechanistically, which I'll just raise, and this is just a point we've shown preclinically. This hemiasterlin warhead also induces immunogenic cell death. So not all cytotoxic payloads are equal, some are very potent at killing and some are very potent at also inducing release of certain agents that stimulate the innate immune system. And hemiasterlin is one of those agents that can actually drive production of molecules like HMGB1, which in turn, are released into the microenvironment and can signal to innate immune cells and mimic that there may be an infection there. So they stimulate the innate immune system. Now we've shown preclinically we can get that, and we show the STRO-002, and we've shown that those things actually synergize with checkpoint inhibitors very well. So it's further indicative that there's something else going on other than just a directed death of the cell with the warhead, but the immune system is potentially playing a part. Because we don't know any of those things yet in humans and in patients, but that will be a sort of source of a great deal of interest now based on these data.

The next question comes from Roger Song with Jefferies. [Operator Instructions]

Great. First of all, I offer my congratulations again as well. So I have 2 questions. So one maybe for Dr. Martin and Dr. Norman. I think the company, they provided some kind of interesting design for the expansion cohort, particularly for the patient population, redefine this platinum sensitivity. And just Chris, your kind of comments around this kind of maintenance therapy just define this platinum-sensitive will have for similar activity expected with the platinum-resistant patient population. And what will be your expectation for the objective response rate and durability of the response for this expansion cohort patient population?

So the trend, when you study agents, when we have had trials that have included both platinum-sensitive and platinum-resistant patients, you usually see a more pronounced benefit both in terms of response and duration of benefit in the patients with platinum-sensitive disease. Given that this is a base of cytotoxic payload, I would expect to see as good as or better results in that platinum-sensitive population But these are patients that are not purely platinum-sensitive, so we're still sort of defining what platinum-sensitive means in the PARP era as more and more patients are having platinum followed by maintenance therapies, as Arturo pointed out earlier. But I still would expect to see as good as or better as results.

I certainly agree with Dr. Martin. The -- and what she said was very, very important in that platinum sensitive today is not like platinum-sensitive was before the PARPs or before BEV because these patients have a prolonged response even if they're "platinum resistant" or have limited response to platinum. So these are tougher to treat, but again, you're going from an extremely heavily pretreated patient population to one that's less-heavily pretreated. So we would expect a higher response rate with that expansion cohort.

Got it. Okay. Maybe another question for company, maybe Arturo, particularly. So we understand you see response across the dose level. And you also see those responses happen even after the dose reduction from the higher dose, 6 mg per kg. But just curious, do you want -- do you plan to do any kind of PK analysis to determine what kind of real dose exposure will really drive this kind of response?

That's a good question, Roger. And again, I apologize for the static. [indiscernible]. We are doing the PK, and we are doing some modeling. And it's quite possible that there will be heterogeneity in the PK response relationships because some patients respond rapidly, and some patients takes a little bit longer. And so we'll look at rate of response and correlate it with PK. But having been a practicing medical oncologist for a long time, one of the things that always try to remember is that no patient is alike. And we tend to lump them in categories, but in the real world, some just respond better, and some things you can identify them with biomarkers. I don't know that PK will list all the answers that we need, but it will provide information on what's the minimum exposure that we needed to get a response. But we are interrogating dose response, dose toxicity to relationships, exposure response as well as we continue to add to the database and we will be analyzing PK and expansion as well.

The next question comes from Edward Tenthoff from Piper Sandler.

Great and thank you, and thanks for the update. Congrats on the data, especially in such heavily pretreated women. And I wanted to pick back up on the earlier question and comments made about combination therapy. It really seems like the opportunity there is pretty compelling. So appreciating that there's the opportunity to be rapidly in late-line therapy and get approval. Obviously, current standard of care, PARP. So what would be next steps for combination? And I appreciate it if you -- I apologize if you already answered that question.

No worries, Ed. Arturo, would you like to comment on that?

Yes. Well, another combination would be with bevacizumab. And that I think there's a lot of rationale where we can go with that, that's one. And that's the one that we're planning to start with next year. As Trevor and others have mentioned, the preclinical data is interesting, in as much as the immunogenic cell death. In the fact that we see -- it's not clear to have seen that same effect reported with other warheads from other ADCs. And this could be very advantageous for us because the data with checkpoint inhibitors as a monotherapy, or even in combination in ovarian cancer, has not been very compelling. But we also take that based on the preclinical data, we can explore combinations with a checkpoint inhibitor and trying to use a biomarker-driven approach to identify patients who are more likely to respond. And then as far as combining with cytotoxin, because as we've shown, we don't need 5.2, or we don't even need 6 to combine. We can combine at 2.9 or a lower dose and still have antitumor activity in combination with other cytotoxins. So I don't think we're limited in our ability to combine with any of the agents that are currently being used in standard of care treatment or maybe future agents that get approved because we see quite a bit of activity across a very broad range of doses. So I think we'll have quite a bit of flexibility on combinations. But those 2 combinations that I've mentioned make a lot of sense for us, and the combo with the checkpoint inhibitor makes a lot of sense for ovarian cancer and particularly for endometrial cancer. And for the part of what we'll be doing next year is convening our current clinical advisory board and bringing in additional key opinion leaders to have those kind of discussions so that we can map out an aggressive and accelerated registration strategy.

Okay. The next question comes from Jim Birchenough.

Great. Well, congratulations on the data, and thanks for the great presentation. I guess a few questions. First, just based on the time course of some of these responses developing later, would you expect some of these patients that are currently in stable disease to convert to a PR or some of the PRs to convert to CRs?

Arturo, I know your line is a little scratchy, but do you want to talk about some of our experience to date?

Sorry I hear it. The minute I come on, I hear it come. So I'm sorry, I didn't hear it before because I was talking. But anyway, yes, I think that already has happened as we've updated data over time. And I believe that's what happened with 1 of the 4.3 mg per kg patients who, at the previous presentations, had stable disease, and now, is an unconfirmed PR. So I think even with having more of some of the unconfirmed PRs confirming and there may be other patients that are regressing slowly. But I want to get back to a point that Dr. Martin made that really what is clinically beneficial to these patients is the disease control so that they don't have to go to another treatment because many of them don't have other treatment options. And I think what we're getting the sense of, and we'll report this in the future when the study is final, is that other types of variables like progression-free survival will compare favorably to other therapeutics in the space because, ultimately, that's going to be one of the endpoints for a randomized study in the future. So I don't know if I answered your question. I think I can comment a little bit more than what you actually ask me.

That's helpful. And maybe just a follow-up on the dose expansion, the cohort expansion going into next year. In the 20 patients that are receiving each of the 2 doses, is there a crisp criteria for approaching FDA regarding the regulatory path? Is there a point in time, some interim point where you can convert either of those cohorts to a registration-enabling study?

We are not just doing any specific statistical hypothesis, and we'll be providing descriptive statistics. But I think that the FDA probably wants to see that we've tested a couple of doses. I anticipate that they will be encouraged that we have done this rather than testing to different doses during the registration study. I'd rather not do that then. And so we think that when we get a little bit more input on the impact of folate receptor alpha expression that could also be very important. There may be some relationship on dose and folate receptor alpha. We've just started to enter the folate receptor alpha expression into our PK modeling also, so we'll be looking at a lot of that data. We have a robust PK program with very experienced clinical pharmacologists involved, but I think maybe if we go with a dose and we have a plan, the escalation we need it or a planned escalation if we need it. So we're still -- we want to get some of the data to crystallize our thoughts before going to the FDA, but we anticipate that the trial will accrue risk-free that we'll start getting patients enrolled and we'll get at least first post-treatment line scan data at least 2 of the patients before we go to the FDA.

And maybe just a final question for Dr. Martin and Dr. Naumann. I just wanted to understand the unmet need, now that we have PARPs available as maintenance therapy, and I wanted to understand the comments earlier. A patient who's platinum-sensitive and subsequently gets a PARP inhibitor to maintain that response and then fails, how do you view that unmet need relative to the patient who's resistant to the platinum out of the gate? Just trying to understand those 2 segments or if there's other patient segments that you think define the unmet need today.

Well, unfortunately, all patients become platinum-resistant at some point. So this is always going to be a high unmet need in ovarian cancer. As people progress through therapy, depending on what they've been treated with before, there are not a lot of good options. And we know even if you retreat patients with platinum that their platinum response is going to go down over time with lines of therapy substantially. And so we are desperate even in that patient population for well-tolerated treatments that patients can stay on because if you fail in 6 months of retreatment, your response rates are going to be pretty poor in the third line.

I would agree. All patients or virtually all patients ultimately become platinum-resistant. It's more a matter of when than if. That being said, I think this upfront initial platinum-refractory, platinum-resistant patient population, they don't benefit from PARP inhibitors. They have very limited benefit from any of the available chemotherapeutics that are already available to them. And so the results we're seeing right now are very exciting for that patient population. I think, though, in the long run, the high recurrence rate after frontline therapy, we haven't really seen much improvement in that. The question of what PARP maintenance will do in the HRD and BRCA population may change that. But if we see a regimen that's demonstrating this degree of efficacy in a very heavily pretreated patient population in the long run, the question always is, and we have a few steps to go, but can we move this to frontline if we can identify the patient population that needs it and improve the long-term outcomes from initial treatment.

The next question comes from Asthika at Truist.

To the Sutro team, I just want to offer my congratulations as well for some pretty good looking data here. I have a couple of questions for Dr. Martin and Dr. Naumann. Dr. Martin, the -- on the Phase I mirvetuximab data that I think -- I believe, you're on the poster at SGO, when you looked at medium and low folate receptor alpha expression, I'm wondering, do you see differences, be it in tolerability, duration response, et cetera, between those patients on mirvetuximab versus those low and medium folate receptor alpha expressers that you presented for 002 today?

I mean that's a tough question to answer because in both trials, it was a pretty heavily pretreated patient population. If I recall that initial Phase I, it did include the platinum-sensitive patients as well. I think one of the issues is that was very early on in the development of the assay and there is some degree of heterogeneity. So I think it's going to be very hard to compare the patient populations in the 2 different trials. You also do have a patient population at the time we were not using the same degree of maintenance therapy. So while they were heavily pretreated, we didn't have a high preponderance of PARP maintenance and bevacizumab maintenance that we're seeing today as much.

Got it. Okay. And then also to Dr. Martin, Dr. Naumann, I mean the relevance of a complete responder in this heavily pretreated patient population. I was wondering if you could give us clinicians' view on that? And give us some context here, please?

Exciting and unexpected because, again, any response in this patient population is exceptional. But again, I want to emphasize, too, as long as patients are taking the drug and their C0125 is not increasing and their CT scan is not getting worse, they're pretty happy about that as long as they're tolerating the drug because they know that their response rate to other agents in this setting is very poor.

Dr. Martin, do you have anything to add to that before my last question?

No. I absolutely concur with Dr. Naumann.

Okay. Great. So then again, to keep it with the track of tough questions, apologies here. Dr. Martin now when you both worked on other ADCs in ovarian cancer, so in a theoretical scenario where you were forced to pick your favorite child based on comparable Phase I data, what is the main criteria you would look at?

From my perspective, I think efficacy is always going to be the number one thing, but again, the goal is for meaningful benefit and control. And so you want to have a regimen that's tolerable for the patient that the patient can live as normal a life as possible, and so toxicity is very important. And we have very good tolerability here given this heavily retreated patient population. And there is a history of FDA declining to approve or consider agents that are extremely toxic. So I think this is well poised for serving the needs of our patients from those perspectives.

I agree. Duration of response and toxicity are the 2 most important things for the patient. I mean -- it's really about halting symptoms. And if you have a toxic drug, you're really not doing somebody any favor by treating them with it, particularly if they have a very short response time.

The next question comes from Reni Benjamin from JMP.

So let me add my congrats as well. Maybe just starting off to Dr. Martin and Dr. Naumann. Just going off of Jim's question about where this fits within the kind of current standard of care that your current therapeutic paradigm? Is it kind of fair to say that if this gets approved, let's just say, next year, it's kind of relegated to last line as you see it right now? And then ultimately, through head-to-head studies, you would move it up? Or do you kind of feel that based on what you've seen? And I think Dr. Martin, you mentioned that, hey, you wouldn't expect PARP inhibitors to work in this patient population, you might move it ahead of a potential PARP exposure.

Yes. I mean I think that I have been impressed in general with the tolerability. And the dosing schedule is a big deal for patients. So many of the treatments that we already use for recurrent disease are dosed once a week. They caused hair loss, weekly topotecan, weekly paclitaxel. I think patients would want to have this drug before they have either of those. It certainly has efficacy that looks to me to be greater than what we've seen in the Phase II data that we use to support use of those drugs for recurrent platinum-resistant disease. So I think if this were approved based on what I've seen so far, I might move it ahead of some of the other things we already have on the menu.

I think there are some other questions, too. So I suspect this is not only going to combine with bevacizumab but there is a possibility of some synergy there, particularly if you have some immune killing and -- with bevacizumab's alteration of tumor microenvironment. In theory, you could combine us with platinum because of the nonoverlapping toxicities and the relatively mild bone marrow toxicity. So I think it's hard to know. As Trevor and Arturo mentioned, there is some preclinical data with checkpoint inhibitors, so we've -- we know checkpoint inhibitors work in some circumstances in ovarian cancer, but we haven't made them work very well. So I think there's a lot of questions on the table in terms of what the combinations are going to actually look like and where this will ultimately land. But certainly, when you see activity in very heavily pretreated patient populations, it's a good sign that this is going to be an active drug when you move it closer to frontline therapy. I think it's going to be hard to beat right now, platinum and taxane. A lot of people have tried and have it in frontline, but you could imagine that you could use either a maintenance strategy or as a second-line agent.

Got it. And then just as a follow-up, maybe to, Arturo. I missed during your prepared remarks, kind of the patients who became a CR. It seems like a couple of people have dropped off. So I'm trying to follow the numbers here. There were 33 evaluable patients, I think, on the September call. There's 31 now. And it seems like there's still 6 unconfirmed PRs even though 3 months have passed. I'm kind of curious about when they might ultimately become confirmed. And just as a totally separate question regarding folate level -- folate expression, it doesn't seem like it correlates with response. It seems like maybe there's other things that might be impacting response. I don't know if it's platinum sensitivity versus resistance. Anything else that you might be able to talk about, especially when we're thinking about archival versus rebiopsy tissues.

A lot of questions there, but I'll try to take them one by one. I think we -- what we have seen is that the responses are deepening over time. And even if a patient did not convert, some of these patients are out over 24 weeks. There are studies in other agencies in dose escalation where, yes, they have all these PRs, but none of them are ongoing by week 24. And it goes back to what Dr. Martin and Dr. Naumann mentioned about it's the duration of disease control that is clinically meaningful. And we're still exploring ways to exploit that observation because it really is what keeps the patients from progressing. And so if you get a lot of early PRs that are confirmed, and then the patients drop treatment at 24 weeks. I'd rather have a patient with stable disease at 64 weeks than a confirmed PR that drizzles out by week 24. So I think we're going to be going away from singling out individual patients and trying to just look at the whole population and see how many patients are there after 16 weeks. So we have disease control rate at 16 weeks or 58%. For this patient population this is very, very remarkable. So then your question about the folate receptor alpha expression, I think Trevor has shown the data that presents that our therapeutic is very efficient at killing, and we've shown that in the clinical models. And we've shown activity in medium and low-expressing models when it comes to PDX models, for example. So it may be that we will get activity and be able to help patients with lower levels of expression. Here, you see that one of the PDs had like no expression, and we have the age score of that other data. But it may be that we end up with a cutoff that is not high, medium, low, but we take a cutoff that is age score lower than 100 or age score lower than 80. I think as Dr. Naumann mentioned, this data is kind of very tantalizing because it raises a lot of important questions. It can give us leads on additional experiments and questions that we want to address with combinations, be that component of immunogenic cell, there could be something that impacts different ovarian cancers in a different way. So there is that [indiscernible] I was talking about before. So I hope I answered some of your questions, and if not, I'd be happy -- if you just repeat it, I'll answer.

I'll just ask one final one regarding archival versus fresh biopsied.

I'm going to ask Dr. Martin to comment on that since she's the first one on paper that I always quote. Maybe Dr. Martin can share her experience because she's been involved in looking at archival and then comparing fresh, and then comparing post-treatment samples. So Dr. Martin, if you can kindly answer the question.

Thank you. So we did that. We did a biopsy cohort in the margetuximab Phase I study where we collected archival tissue and performed pretreatment biopsies. And for the most part, there was no significant change in a few cases. It seems that on the biopsy -- the fresh biopsy that we saw slightly higher levels of folate receptor alpha expression. But I think the consensus in the end was the differences were generally minimal and could be explained to some extent by tumor heterogeneity. Occasionally, you get an archival specimen that's very, very old, and I think with the -- I mean, this folate receptor alpha has really become a true important target. And we think 80% plus of ovarian cancers have this present, so we're going to learn a lot more about this as we go on. And I think for now, I think doing archival tissue is sufficient based on the available data.

The next question comes from David Nierengarten from Wedbush.

Just a couple. First off, maybe for Dr. Martin. I mean, were you surprised at the lack of correlation or just general efficacy across levels of folate receptor expression? And then my second question is on the -- looking at both patients -- or both groups of patients, sorry, in the next study of platinum-sensitive platinum-resistant, is there -- do you think there are going to be enough patients to see if there's a difference in outcomes between those groups of patients? Or is it more of an exploratory look to see if there's any hints of differences in efficacy there?

Yes. I mean, I was gratified to see the activity. And I think it speaks to the mechanism of these agents -- this agent, rather. Having a little bit, but not too much by standard effect is very valuable because you are going to have cells in the mix that are supporting tumor growth that may not necessarily have fully receptor alpha expression. So as Arturo said, I think there probably is a point below which you're not going to see benefit, and we just have to figure that out. And we haven't seen it yet, but it's very small numbers. In terms of the platinum-sensitive and platinum-resistant population, it is going to be small numbers and I was thinking after we answered the prior question, somebody asked about platinum sensitive, the efficacy is already so good in this population, how can you improve upon that? And even you have to remember that the platinum "sensitive" patients that enroll in this trial are not true, true platinum-sensitive in a sense because we've changed our definitions of platinum sensitivity over the years. It used to be 1 year post-completion of platinum therapy. Now we use 6 months. And patients who are still doing well with chemotherapy are not always the ones that are seeking out of Phase I trial. So I'm not going to be too, too disappointed if we don't see dramatic differences in a small patient cohort. I think I would anticipate over a long period of time, you would see better results in a platinum-sensitive population, but I think the numbers are going to be a little small. So we'll see what we'll see. But you're going to start parsing when it's this small number, how platinum-sensitive are these patients because it's really a continuum. It's not black or white.

I probably would add too, it's the number of lines of therapy. So we actually looked at that in our data here. Platinum-resistant patients have about a 20% response rate, maybe 15% response rate. Second line platinum-resistant therapy, we had a 3% response rate. We had no responses in third or more lines of therapy after the development of platinum resistance. So these patients get very, very resistant to chemotherapy. So unless you have something that's either extremely potent or acts through a different mechanism of action, you're not expected to see any response in those patient populations. And so when you move to a less heavily treated patient population, yes, I think you're going to see a lot more responses, whether it's platinum sensitive or platinum resistant.

Thanks, David. Arturo, did you have anything to add?

No.

Boris Peaker, did you have a follow-up question? Okay. Well, if that's the case, then we are actually running a little bit over. With that, that this does conclude the question-and-answer session of today's program. I'd like to hand the program back to management for any further remarks.

Thank you all for attending today. We're excited to be able to present this data and to really see such good responses in so many women. As we indicated earlier, we have 10 women who have net response -- resist response criteria, and there are more patients still on study. In fact, 10 more patients still on study. So this is still really an interim look at this data set. Having said that, we know that we really want to press forward aggressively with the dose expansion phase and then proceed with a dialogue with FDA about how we might move quickly to a registration trial strategy for this program. We have some questions to answer during the dose expansion phase that we've alluded to today. We believe we will get those answers and be in a good position to have a regulatory dialogue. Overall, the fact that the median time of women dosed at 2.9 mgs per kg are higher of 19 weeks is -- on study, that's a remarkable period of time for these women. And we're certainly gratified to see that they are able to stay on treatment for that long period of time. I'd like to thank all of our investigators, but especially Dr. Martin and Dr. Naumann, for sharing their clinical views on STRO-002 and for their diligence in caring for the women who've been on our study. I'd like to thank those women and their families for their participation in this study. It's an important study for us, and I think they're doing a great thing for other ovarian cancer patients. I hope you all are staying healthy and have an opportunity to enjoy the upcoming holidays. And we look forward to speaking with you in the near future. Thank you for attending our presentation.

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