MacroGenics, Inc. (MGNX) Earnings Call Transcript & Summary

Good afternoon, we will begin MacroGenics' conference call in just a moment. [Operator Instructions] At this point, I will now turn the call over to Jim Karrels, Senior Vice President and Chief Financial Officer of MacroGenics.

Thank you, operator. Good afternoon, and welcome to MacroGenics' conference call to discuss our MGC018 data presented to ASCO. We encourage you to download a copy of the slides that MacroGenics management and our invited KOL guests will walk through today. The PDF can be found under the Investors section on our website on the Events and Presentations page, where you'll see a link to the downloadable PDF. You can listen to this conference call via webcast on our website where it will be archived for 30 days beginning approximately 2 hours after the call is completed. I would like to alert listeners that today's discussion will include statements about the company's future expectations, plans and prospects that constitute forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our annual, quarterly and current reports filed with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change, except to the extent required by applicable law. Joining me on the call from MacroGenics are Dr. Scott Koenig, President and CEO; and Dr. Chet Bohac, our Executive Director of Clinical Research, who will introduce our guest speakers in just a few minutes. And now I'll turn the call over to Scott.

Thanks, Jim. On Slide 3 is the outline for today's agenda. Dr. Chet Bohac from our clinical group, and internal lead on this program, will start off and provide the background on B7-H3 as a target, an overview of the MGC018 molecule, followed by the dose escalation data. Dr. Jang will set the landscape for treating late-stage melanoma patients and the experience of his 3 patients in the Phase I trial. Chet will then comment on the dose expansion cohort of castration-resistant prostate patients. Dr. Antonarakis and Shenderov will follow with the current landscape of treating prostate cancer patients, I will wrap up with a few final points, and we will end with a Q&A session. With that, here is Chet.

Thank you, Scott. Looking forward to covering the slides with you today. If you can turn to Slide 5, you will see a representation of the B7 family of immune checkpoint proteins, one of which is B7-H3. B7-H3 has 2 roles, one is immunosuppressive, and the other is a role in tumor metabolism and metastasis. The role of B7-H3 in immunosuppression is when B7-H3 is overexpressed at high levels. First, it correlates with nonresponsiveness to anti-PD-1 therapy; second, a reduced CD8 infiltrate and exhaustion; and then third, the ability of cancer stem cells to abate immune surveillance. The role of B7-H3 in metabolism and metastasis is its ability to mediate chemotherapy resistance, promote progression and metastasis, as well as regulate cancer cell metabolism. The key takeaway here on the slide is that B7-H3 overexpression correlates with poor prognosis. Next slide, Slide 6. B7-H3 is an attractive target for cancer therapy because it is expressed in all 3 components of the tumor microenvironment. The tumor cells, the tumor vasculature, and the regulatory T-cells. Next slide, Slide 7. On this slide, you can see B7-H3 is overexpressed in many common and rare solid tumors. From our own internal database of over 1,500 tissue samples, we've seen that many tumors are expressing B7-H3, and not only expressing it, but at very high levels, 2 plus or above. And in bold font on the left column under potential indications, are the 5 tumor types that are in our current cohort expansion: head and neck cancer, triple negative breast cancer, melanoma, prostate cancer and non-small cell lung cancer. Now we can turn to our MGC018 Phase I data from dose escalation, which is being presented in a poster at ASCO this year. I'll have you go to Slide 9. On Slide 9 is a figure depicting the structure of MGC018. It is an antibody drug conjugate, and it has 3 components: first, the monoclonal antibody, which is directed against the B7-H3; second is that cleavable peptide linker in between the monoclonal antibody and the payload. The payload is a synthetic duocarmycin which is derived from a parent compound made by streptomycin bacteria. And duocarmycin is an alkylating agent. It is cell cycle independent and it's potent in multi-drug-resistant cell lines. So it makes it a very attractive payload as well as the B7-H3 target as being attractive. You can see the drug antibody ratio here depicted on the right under MGC018 is 2.7. On the next slide, Slide 10, is our study scheme-up. On the top is dose escalation, and in the bottom dose, there's cohort expansion or dose expansion. Dose escalation was a 3+3+3 design, and we enrolled patients from 0.5 mg per kg to 4 mg per kg dosing every 3 weeks. The tumor assessments were every 6 weeks and PSA valuation every 6 weeks. In cohort expansion, those tumor types I mentioned earlier, all enrolling -- are currently enrolling prostate cancer, lung cancer, breast, melanoma and head and neck cancer, tumors assessments here in this part of the study are every 9 weeks, and PSA evaluations, every 3 weeks. If you go ahead a couple of slides to Slide 12, we'll actually look at some of the data. On Slide 12, this is a waterfall plot of target lesions and the response to MGC018 from dose escalation. And pointing out during dose escalation, patients are very heavily pretreated, having up to 8 prior lines of therapy in this study in some of them. And you can see in the green bars on the right, these 2 patients were in our waterfall plot last year, the lung cancer and prostate cancer at 2 mg per kg. That hasn't changed. What has changed is that you're going to see participants that were dosed at 4 mg per kg that weren't in our poster last year. They are in the blue bars over on the right. This is where, on the far right, we have an ongoing confirmed partial response in melanoma, as well as 2 other melanoma participants with reduction in target lesions, and the pancreatic cancer patient and another prostate cancer patient. As you can see in the boxes, all of these patients had several prior treatments and fairly extensive tumor burden at baseline. Across the bottom of the slide, you can see the B7-H3 H-score as well as the vasculature score and you can see that most of the patients have fairly moderate to high scores, except that pancreatic cancer patient, which has a H-score of 17 and a vasculature score of 2 plus and still was able to generate a target lesion reduction despite having 2 prior lines of therapy, and was on treatment for 5 months. And then you can see the melanoma patient on the far right, had an H-score of 66, a vasculature score of 3 plus, and actually now has a confirmed partial response, and remains on treatment over 7 months. So at this point in time, it does not appear that B7-H3 level will be needed to predict responses in patients. But again, it's very early data. Now we go to the next slide. Slide 13, this is [indiscernible], so a lot of these patients were in the poster last year, not too much has changed here. We are showing target lesion reductions and disease stabilization. And on the bottom side, you can see the melanoma patient with the confirmed partial response with the green arrow at the end of the design. Jonas has been on -- this patient has been on study for over 6 months, currently, 7 months and ongoing treatment. And what still remains that I would like to point out is that round curve in the middle of the slide, where a patient was on this study for 35 weeks, this patient maintained stabilization of the disease for 3 months after their last dose. If I can have you go to the next slide, Slide 14, turning away from response data to looking at the safety profile. On this slide, Slide 14, are the related adverse events occurring in greater than or equal to 20% of participants. The main adverse events are hematologic, skin, fatigue and infusion-related reactions. And under hematologic toxicity, the primary adverse event is neutropenia, under skin is hyperpigmentation and palmar-plantar erythrodysesthesia, also called hand-foot syndrome, fatigue and infusion-related reactions. And what I would like to point out is that at 4 mg per kg, we did an amendment part starting to enroll, and incorporated premedication with corticosteroids. So we've actually seen a decrease in infusion-related reactions from around 50%, 60% to 30%. If we can go to the next slide, slide 15. Here are the related grade 3 or higher adverse events. Again, mainly hematologic and skin, these adverse events are manageable with growth factor support, dose reductions and delays. And at this point, it does not appear that these dose reductions or delays compromise efficacy. Next slide, Slide 16 is a slide of treatment-emergent adverse events. I'm going to go to the main row in the middle of this slide. If you can see at the top row, all patients had at least one adverse event. But in the middle of the slide, we go to the serious adverse events that there were 1 to 3 in each cohort, and these serious adverse events were mainly disease-related like a pneumonia and cancer -- a lung cancer patient at 0.5 mg per kg, this patient had multiple prior lines of therapy before coming on. At 1 mg per kg, there's a patient with non-infectious gastroenteritis. This was a colon cancer patient with peritoneal disease. On that 2 mg per kg metastasis dermatitis, small bowel obstruction, pleural effusion, these were related to conditions that were present prior to patients coming on study. And then on SAE, the thrombocytopenia and dyspnea, COVID, there was a patient that contracted COVID and ended up in the hospital, serious adverse event at 4 mg per kg. Then in the middle, you can see the dose-limiting toxicities. There were 2 of them. One at 2 mg per kg in a colon cancer patient with more than 5 lines of prior therapy, that was in the poster last year. And then at 4 mg per kg, there was 1 patient, a melanoma patient, that had a -- sorry, a prostate cancer patient that had grade 3 fatigue that lasted greater than 72 hours. And then in the middle of the slide, you can see the study discontinuations and withdrawals. And I'm going to point you to the column for 3 mg per kg. You can see that there were 4 each at 3 mg per kg. And then look at 4 mg per kg, there were 2 each of discontinuation and withdrawal. And I'd like to point out that there was a protocol amendment after 3 mg per kg to allow for dose modifications with reductions and delays, and guidance on toxicity management. So we went from about a 60% discontinuation withdrawal rate to 33%, even though the dose went up a whole milligram per kilogram. I'll have you now go to the next slide, Slide 17. On Slide 17, this is an update of the graph from last year's poster with the castrate-resistant prostate cancer patients. There is now added in the middle of the slide, a column for time to progression. And you can see that patients were able to maintain stability of disease for 6 to 7 months, 4 of them. One patient did come up at 4 months in the top row. This was an 80-year old gentleman, he had the pleural effusion, who was evident prior to study start. And about 4 months after therapy, he decided the visits were too much for him and came out of study. The next patient had a fall at 6 months, even though his PSA had reduced 99%. You can see on the right his curve, the orange curve, his PSA dropped to 0.5. He had a fall in that baseline. There were no bone lesions on the bone scan. There was no head CT baseline. But at the fall, they obtained a head CT and there were some new lesions. So by RECIST, those were redeemed new lesions and they persist through progressions. And then the middle column, patient came up on palmar-plantar erythrodysesthesia, underneath that a pericardial effusion. Patients -- actually, the effusion resolved on its own, did not require a third-party synthesis or other procedure, resolved on its own after several weeks after stopping therapy. And then the bottom patient came off. He had decided that the PSA started around 40, dropped to 30, was hovering around 40 to 50, and he decided to come off the treatment at that time. Next slide is Slide 18. And Slide 18 it's the same 5 patients that had PSA response. The thing to point out here is the H-score, the vasculature score -- and vasculature score in the far-left column. And you can see all of these patients had over a -- H-score over 100, and 3 of them were over 200. And there was one patient that had insufficient invasive tumor to be able to evaluate. And then you can see in the middle column of treatment, all of these treatment patients had multiple prior treatments, except the one who had abiraterone and the checkpoint inhibition on the patient #4. Okay. I'll have you go to the next slide, Slide 19, where I can introduce Dr. Sekwon Jang. He's one of our principal investigators at the Inova Schar Cancer Institute. He's a Director of Melanoma and Cutaneous Oncology Therapeutics and Research, and he will be presenting slides 20 through 22. Dr. Jang, I'll turn it over to you.

Thanks, Chet. Hello, everyone. I'm medical oncologist specialized in melanoma over the past 11 years, and I've seen dramatic changes over the past 11 years, so please turn to Slide 20. So up until 2011, majority of patients with advanced metastatic melanoma, unfortunately, died within a year as previously available therapies such as old immunotherapy or chemotherapy didn't really work well for melanoma. Since 2011, new systemic therapies have been developed and approved, such as immunotherapy using checkpoint inhibitors. The program sell at inhibitors such as pembrolizumab or nivolumab and also the Cytotoxic T-lymphocyte-associated protein-4, called CTLA-4 inhibitors, such as ipilimumab. And on other class of medicines that's been developed called targeted therapy blocking the BRAF V600 new patient blocking agents with the dual inhibitors with the BRAF and MEK. So immune checkpoint inhibitors can achieve durable responses in 40% to 45% with a single agent pembrolizumab or nivolumab, and 50% to 55% with the combination of nivolumab and ipilimumab. Obviously, with the combination, there is an increased rate of toxicity. So for patients with the BRAF wild-type melanoma, immune checkpoint inhibitors, either single agent, pembrolizumab or nivolumab or a combination of ipilimumab, nivolumab are considered first-line therapy. And treatment choice between these 2 are usually determined by patients' age, comorbidities and then tumor burdens, and patient's and physician's preference. Patients who received single agent nivolumab or pembrolizumab as first-line therapy, then ipilimumab alone or ipilimumab added to nivolumab or pembrolizumab would be considered second-line therapy. Then for BRAF mutant melanomas which is from -- about half of the cutaneous melanomas, BRAF MEK inhibitors can achieve fairly rapid response in 60% to 70% of patients. And those responses are usually -- last about a year in most of patients, although there can be 20% of patients who continue to enjoy ongoing benefit, while they are taking these pills for a number of years. So for patients with the BRAF mutant melanomas, targeted therapies with the BRAF MEK inhibitors or immunotherapies can be considered first-line option. Although the optimal sequence for immunotherapy versus targeted therapies still needs to be determined in clinical trials. So there are about 40% to 50% of patients who eventually need subsequent therapies as their melanomas do not respond or stop responding to immunotherapies and/or targeted therapies for those with the BRAF mutant melanomas. So there is clearly still unmet need as a second line, third line or subsequent lines of immunotherapy for patients with advanced melanoma. Also, I would like to point out that there is a subtype of melanoma called mucosal melanoma, which is arising from mucosal surface of body such as in rectal areas, for example, and this mucosal melanoma typically has less likelihood of responding to immunotherapies. Please turn to Slide 21. So you can see the table summarizing 3 patients that are treated with MGC018 at 4 milligram per kilogram dose. Patient 1 and 2 had a mucosal melanoma originated in anorectal rectal, then spread to skin, soft tissue and also internal organs, such as lungs. And as you can see, in listed previous treatment, these patients did not respond to immunotherapy at all and participate in these trials. Patient 3 had a melanoma originated in toe, so it's called acral melanoma. And then spread through the skin. In fact, this patient, a few years ago, actually had a melanoma spread to the brain, single lesion, which was receptive. And then patient underwent multiple lines of immunotherapy and local regional therapy. And unfortunately, he still has active disease in his leg with the multiple cutaneous metastasis. So these 3 patients received MGC 4 milligram per kilogram dose. And when patients came back for the second infusion, I observed improvement in their skin lesions. Obviously, 3 patients had a skin lesions that I could monitor for treatment response. And this was very encouraging to patients because they had a multiple lines of previous therapy without any improvement. And I also noted most of these lesions responded to MGC018, continued to improve. So there's been some the preliminary signs of durability. And I would say most patients tolerated treatment well, although there were some side effects, which were mentioned by Chet on previous slides. For example, patient 1 had a pre-existing inflammation in the bladder from higher radiation therapy and then unfortunately, developed hematuria when his platelet count dropped as per 3 months of MGC018 treatment and had to discontinue treatment. Patient 2 unfortunately developed new brain metastases as well as COVID pneumonia and had to stop the treatment. Patient 3 remains on trial and continues treatment, and you can see more than 30% reduction in the size of the melanomas. And -- so this is fairly unusual to see all 3 patients showing improvement in target lesions. And also found MGC...

Dr. Jang, this is Chet. Would you like to make a comment? You talked a little about the toxicity. Just how you -- from your perspective, the toxicity balanced against the tumor response. How you're...

Right. So again -- right. When patients asked to continue treatment despite some side effects that typically means that the benefit outweighs the toxicity. And the side effects from this agent is -- it's not overlapping toxicity to immunotherapy-related side effects. So again, in melanoma patients, majority of them didn't have any chemotherapy in the past, although one of the subject, patient 1, did have a chemotherapy [ cabazitaxel ], which is probably why this subject developed pretty significant thrombocytopenia. The -- and then patient 2 and patient 3, they did have a pleural effusion requiring thoracentesis. But again, those were still manageable. And then, again, patients were asking to continue study treatment as long as it's permitted by the protocol. So...

Thank you.

Yes. And then from a patient perspective, obviously, the treatment schedule is important and it's once every 3 weeks treatment and very relatively short infusion, convenient for patients and also, we only had one subject create a minor infusion reaction, which is -- which didn't happen with the pretreatment. So I would say it's easy to administer and convenient for patients. And again, based on this promising data from dose escalation study, I asked MacroGenics to add melanoma cohort for dose expansion cohort. And also, I wanted to point out what's unique about this trial. If you can turn to Slide 22. As an investigator, I participated in many melanoma trials and actually, some of the trials listed here, I participated. And as you can see, most of the trials are adding investigational agents to anti-PD-1 immunotherapy, such as pembrolizumab or nivolumab or sometimes CTLA-4 antibody called ipilimumab, when the immune checkpoint inhibitor is no longer working. As you can see in this table, the responses, so ORR, the response rate ranges from 8.8% to 31.3%. And which is, I would say, modest. These combination trial designs make it difficult to conclude how much benefit is derived from investigational agents versus delayed response to anti-PD-1 antibodies, especially for those who only received very short course of PD-1 antibody prior to study enrollment. And then the last study listed here called lifileucel that's called tumor-infiltrating lymphocyte protocol. This is very highly selected patients with a very intensive treatment course, including tumor resection to harvest TILs and then chemotherapy for conditioning and then cell infusion for by interleukin-2. So this is fairly complicated and potentially at least transient or even a toxic treatment. And so from a patient perspective, obviously, something that can be done as outpatient is much preferred than inpatient treatment. So I'm actually -- it's actually difficult to find single-agent trials in this setting in melanoma patient population. So I find this MacroGenics study kind of been a very bold in a sense that they decided to first get the single-agent activity data. And I am very encouraged to see these responses in my 3 patients. And I really look forward to moving patients to those expansion cohorts and to confirm the responses that I've seen so far. So let me stop here and answer any questions that you may have or wait for the Q&A?

Yes. We'll wait for the Q&A. Thank you, Sekwon. This is Chet again. Thank you for the presentation. I will now move into the next section. We are going to go into this very early dose expansion data in the metastatic castrate-resistant prostate cancer patients. We've included a little bit of data in our poster. So we're going to have to go to Slide 24. And Slide 24 is the PSA waterfall front. It does have all patients from dose escalation and the cohort expansion, that dose escalation bars are green, red and lavender, the dose expansion or cohort expansion are the navy-blue bars. And you're going to see that in each part of the participants' time on study was included, most are on study from this data cut less than 12 weeks. You can see that 50% of participants have had PSA reductions in the cohort expansion. This is consistent with what we're seeing in dose escalation. Note that the patients that are still on study at 6 or less weeks, these patients are still responding to treatment and may have further decreases in PSA as they approach 12 or more weeks. So then I'm going to go to the next slide, Slide 25. This is again from dose expansion metastatic castrate-resistant prostate cancer patients where we're showing some antitumor activity in patients with measurable disease. There were 28 patients enrolled as of May 3, and of those 22 had at least one dose and at least one PSA level 3 of exposed first dose. And you can see on the left, there were 13 with measurable disease, 12 of these are still ongoing as of May 3. And then 7 of those had a first 9-week imaging as of May 3. And of those 4 had reductions in target lesion sums, 13%, 21%, 27%, and an unconfirmed partial response, 30% -- 35% reduction of metastasis in the adrenal gland. So it's a very brief overview of that data. And I'm going to ask Dr. Shenderov to make a comment since he's the PI from John Hopkins that has been managing patients at his side, just to give a comment about what you're seeing with your patients in terms of response and the adverse events.

Thank you, Chet. Yes, this is Dr. Shenderov from Johns Hopkins. The agent that -- with the patients we've treated at Johns Hopkins, definitely shows activity. And as noted by Chet earlier, definitely has a side effect profile that is notable for having toxicity as already summarized. And I think going forward, one of the things we're looking for in the dose expansion is really understanding the best balance between balancing the signal notable and the toxicity that is visualized.

Yes. Yes, in terms of managing the side effects, like your experience with managing the palmar-plantar erythrodysesthesia, the hematologic toxicity just to give a comment on the manageability of these toxicities.

Yes. We've noticed thus far that dose reduction from the 3 milligram per kilogram dose and/or dose interval changes from the sort of Q3 week, every 3-week dosing to maybe 4 weeks, 5 weeks or up to 6 weeks, has allowed the manageable toxicity profile of allowing the -- any toxicity so far that we have noted come up like, I mean, neutropenia, the low blood counts. Or any of the other toxicities really to be -- give enough time for it to die down in a sense. So again, dose reduction and/or interval changes have so far been, for most patients, the sufficient route towards increasing tolerability.

Thank you, Eugene. So now I'm going to turn over. On Slide 26, we're going to get some commentary from Dr. Antonarakis, who is the Professor of Oncology and Neurology at Johns Hopkins, and then Dr. Shenderov will be making comments as well as the Instructor of Oncology at john Hopkins. Dr. Shenderov is lead PI here on our MGC018 study. Dr. Antonarakis, I'll give it over to you to present Slides 27, 29.

Thank you. I'll start with Slide 27. And if Charles Dickens was alive arrived today and if Charles Dickens was an oncologist, you would say that prostate cancer clinical research is in the best of times and in the worst of times. We're in the best of times because we have so many therapies that are available for our patients, as depicted on this slide, but the worst of times because clinical development of new compounds has become so complicated and complex and requires really a lot of thought and discussion of all the considerations. And it's not a no-brainer anymore like it used to be 5 years ago. We think of prostate cancer in terms of clinical states rather than stage. And the clinical states are designed either by the presence or absence of metastatic disease, and by the presence or absence of castration-resistant disease as opposed to hormone-sensitive disease. So in this slide, the green boxes represent the hormone sensitive, which is sometimes called noncastrate states, and the red or orange boxes represent the castration-resistant states. And the main considerations for this talk are in the box to the far right, which says metastatic castration-resistant, first line, second line and beyond. And for those patients, we have a range of existing FDA-approved therapies, which ranges from androgen-receptor-targeting therapies like abiraterone and enzalutamide, to intravenous chemotherapies, docetaxel and cabazitaxel; one zone-targeting radiopharmaceutical drug, radium-223; one immunotherapy cellular immunotherapy product, sipuleucel-T. And then for some niche populations, we have the availability of pembrolizumab for the TMB high or microsatellite unstable patients as well as 2 PARP inhibitors for men with BRCA mutations or other related homologous repair deficiencies. So that's what we have to contend with when we bring in new therapies like MGC018. That's what we already have in the background, and we will need to consider that when designing the next study, especially the randomized Phase III study. I'm going to go off script, and I'm going to jump to Slide 29 next because I think that flows better. Slide 29 shows the same drugs that I listed before, right now, they are shown in order of use, first-line agents second line agents and third-line agents. And here, we are focusing again, specifically under the metastatic castration-resistant subset. And in general, just to simplify things, even though it's not simple, when a man presents with metastatic castration-resistant prostate cancer, you're either going to give him a novel hormone therapy, which is by mouth or an intravenous chemotherapy. After that, you're typically going to use a second-line therapy, which alternates between the AR targeting and the chemo. So if your first line was an AR-targeting agent, second line is usually going to be chemo such as docetaxel. And conversely, if the first-line systemic therapy was a chemo, your second one is going to be an AR-targeted therapy. Pembrolizumab and olaparib also fit in there for select molecular populations. And then the third line is typically viewed as those patients who have received at least one novel AR therapy as well as one taxane chemotherapy. And this is the population that the Lutetium PSMA-617 trial took place. And that's going to be the plenary abstract I presented on Sunday at this meeting. And that trial was positive for both progression-free survival and overall survival. And the abstract has been publicly released, although not the post or the slides themselves. And so the reason I mentioned that is, although it's a different mechanism of action of that drug, it's an example of a Phase III study that has -- that will likely lead to FDA approval in the third-line setting that is in the post AR therapy, post chemotherapy population of patients. So now let's go back to Slide 28. And here, we are showing summary data for the MacroGenics MGC018 prostate cancer expansion as well as 3 other large trials in the third-line setting, in other words, post 1 chemotherapy in post 1 AR targeting therapy. The CARD trial, which looked at a new chemotherapy called cabazitaxel, the VISION trial, which looks at this beta particle admitting PSMA targeting radioligand therapy, and then the KEYNOTE-199 was the -- was at least supposed to be the pivotal Phase II study of pembrolizumab, which did not make it because of lack of activity. If you focus on the third row from the bottom, the PSA response rate, you can see that pembrolizumab on the far right, has very few PSA responses in metastatic prostate cancer. In fact, prostate cancer is one of the few solid tumors where no PD-1 or PD-L1 inhibitor has been approved as a monotherapy. The only other common solid tumors that I can think of where PD-1 inhibitors don't work are pancreatic cancer and the microsatellite stable colorectal cancer. So this is really a cold -- immunologically cold tumor. In the VISION trial, they did not report PSA responses in their abstract, but they will likely report that on the ornery session presentation on Sunday. The previous studies of Lutetium PSMA have shown PSA response rates in the 40% range, 4-0. And then cabazitaxel, which is the second chemotherapy agent, that has a PSA response rate of 35%. So in the context of that background, a PSA response rate of 50% with MGC018 is quite remarkable and is admittedly probably an overestimate. But even if the true PSA response rate is 40% or even 30%, I think that this agent is on par with our 2 other best agents in the third-line setting, i.e., post AR therapy, post chemotherapy. And with that, I'd like to close, but I have a lot of optimism that with the right design, thinking into the future about a Phase III in metastatic prostate cancer, this drug would be a great contender against other comparable therapies, such as chemo or even competing against the Lutetium PSMA, which will clearly be a bold yield, but this drug may at least mimic, if not exceed the activity of those 2. So I will stop there for now.

Thank you very much. This is Scott Koenig again. Now that you've heard the current status of the MGC018 program and the competitive landscape for both colorectal -- I'm sorry, prostate cancer and melanoma, as I have commented, we are aggressively moving forward with the single-agent MGC018 molecule to determine the best pathway forward for registering this molecule, assuming that we see the continued benefit of the molecule, not only in prostate and melanoma as we obtain new data on our 3 other expansion cohorts of patients with non-small cell lung cancer, triple negative breast cancer and squamous cell cancer of the head and neck. We also look to future possibilities of further advancing our other molecules in several clinical indications where we can take advantage of orthogonal immune-mediated mechanisms to enhance clinical benefit. We have been providing examples of the mechanistic rationale for such combinations at scientific venues from both our preclinical and clinical studies. For example, while the data presented by Dr. Shenderov in KEYNOTE-199 suggests marginal benefit for treating late-stage castration-resistant prostate patients with pembrolizumab, we have reported at AACR preclinical models that anti-PD-1s can provide added benefit to MGC018. On Slide 31, the CT26 colorectal model containing a transfected copy of the human gene of B7-H3, treatment of animals with both MGC018 with a single dose and multiple doses of anti-PD-1 led to greater anti-tumor responses and rechallenge of those animals with CRs with the parental CT26 tumor line led to improved survival. Similar observations on Slide 32 in the MC38 colorectal model where we see enhanced antitumor responses in the primary challenge and slightly enhanced survival would challenge with the human B7-H3 transfected cell line. Furthermore, if you treat the tumor-bearing animals with multiple doses of MGC019 (sic) [ MGC018 ] to induce complete responses, as shown on Slide 33, and then challenge animals either with the transfected tumor line with human B7-H3 or the parental cells, an even more profound survival benefit was observed in animals with the human B7-H3 bearing lines. What this means in the future for MacroGenics is that we have the luxury of 3 clinically active checkpoint molecules in our portfolio, shown on Slide 34, that we can potentially combine with MGC018 in future studies, in particular clinical indications. Retifanlimab, the anti-PD-1 in registration by Incyte, tebotelimab, our PD-1 x LAG-3 DART, and MGD019, our PD-1 x CTLA-4 DART. Of note is our ongoing study of tebotelimab with our Fc-enhanced anti-B7-H3 molecule, enoblituzumab, in front line squamous cell carcinoma of the head and neck patients who are PD-L1 negative, where we are attempting to take advantage of the enhanced activation and increased checkpoint molecule expression observed by treatment with monoclonals with our Fc modifications. With that, let's move over to the question-and-answer session. Operator, are you available?

[Operator Instructions] Your first question comes from the line of Jonathan Chang with SVB Leerink.

A couple. First question, for the study investigators on the call, I'd love to hear about your experiences with the drugs, specifically as it relates to the [indiscernible] profile and the management of adverse events.

So I'll leave -- Chet, would you like to lead that and select...

Let's start with Dr. Jang with the melanoma patients. And then once Dr. Jang is finished, we'll turn it over to Dr. Antonarakis and Dr. Shenderov. So Dr. Jang, if you'd like to reply?

Sure. I think the hematologic side effects like neutropenia, I have one subject who is getting prophylactic growth factors on day 2, when patients had neutropenia after -- I believe, that was after second dose. And then we reduced the dose and then with the GCS, that support hasn't recurred. And then the subject who were developing a thrombocytopenia, obviously, transfusion support is recommended. The patient who developed pleural effusion, again, I had 2 subjects who had a pleural effusion requiring therapeutic thoracentesis. And then one of them required more than one thoracentesis, but the other subject, after thoracentesis, pleural effusion remains very mild and asymptomatic. So I've been just watching. And then I would say, yes, I noticed some skin hyperpigmentation, which doesn't require any interventions that I didn't see any hand-foot syndrome, but I noticed one subject having almost like lymphangitis, inflammation along the lymphatic chain that I just treated with antibiotics and anti-inflammatory agents. I think those are the key points that I wanted to make. I haven't seen any, like, again, nausea, vomiting, diarrhea type of side effects. And I haven't seen any flare in immune-related side effect because these patients that I treated, they had prior immune checkpoint inhibitors, but they didn't have any new or any worsening immune-related side effects.

Dr. Antonarakis and Dr. Shenderov, if you'd like to comment on your experience with drug and tolerability?

Sure. I can go first. This is Eugene Shenderov. So we have noticed that really 3 main drug side effects have been noted within our patients here at Johns Hopkins. One is this palmar-plantar erythrodysesthesia or hand-foot syndrome. Another is the pleural effusions that Dr. Jang has mentioned. And then the third is the hematologic toxicities like low blood counts. In terms of all 3, starting with the hematologic, we have noted that so far dose spacing -- dose reduction has really allowed us to manage that toxicity pretty successfully so far in terms of the patients who have come on the study. In terms of pleural effusions, it is unclear, first of all, if it's a direct side effect, "on/off treatment" side effect or if it's related to disease potentially within the lung for [ incumbent ] causing off-target treatment effects. Either way, we've had patients who have had symptoms managed, utilizing Lasix or water pills as one would find for, for example, congestive heart failure. And that has been pretty manageable so far for most of the patients, though it can be a dose or treatment limiting toxicity if sort of it becomes something the patient does not wish to tolerate, of course, for quality of life considerations. And then lastly, in terms of the palmar-plantar erythrodysesthesia, we've noted that, again, a combination set of mostly symptomatic supportive therapy/dose reduction and dose interval changes have been pretty successful in managing most of the patient's symptoms thus far, again, utilizing sort of all 3 approaches I just mentioned. And I'll turn it over to Dr. Antonarakis to give his point of view as well.

Well, not much to add. I'm going to take the longer-term view, and I'm going to say, what would this drug look like in the Phase III trial? And what would the comparator be? If you're going to do a Phase III trial compared against chemotherapy, then you would want to make sure that the toxicity is not greater or more annoying or has special aspects that patients don't like. The part that concerns me, I have to admit, but some of the fusions, we never see that with docetaxel. We don't see that with any of the other side effects. So even if it occurs in 10% of people, a man with prostate cancer is not going to want to have his pleural effusions drained, that's just something that we don't see in this disease. In lung cancer, we see it all the time, and those patients may be willing to tolerate that. So that's one that could be a red flag if the prevalence of that is more than about 10% to 15%. The second is in our disease, we use taxanes, docetaxel specifically, and cabazitaxel, both of which have peripheral neuropathy as their major side effect. And so if this drug is going to be developed in the post-taxane prostate cancer setting, then the incidence of hand-foot syndrome is likely to be greater or exaggerated in those patients, especially the ones that have any degree of peri neuropathy. In this trial, the restriction on neuropathy for eligibility was so tight that if the patient had even grade 1 neuropathy, that was an exclusion at baseline. So these were all patients who had grade 0 neuropathy in order to enroll, and yet a number of them got the hand-foot syndrome. So I would worry that if this became a post-taxane registrational study, would that hand-foot syndrome be even greater? It's something that I wonder, and I don't know the answer to that.

Understood. And the second question, can you discuss differences in the patient profiles, if any, between the expansion versus -- and the dose escalation? For example, would you expect the average prostate cancer patient in the expansion to be similar or different than a prostate cancer patient in the escalation portion of the study?

Chet, did you want to take that?

I can take that, sure. So in the dose escalation, we had no restrictions on the number of prior therapies. So as we noted that there were patients with up to 5 prior lines of therapy, end-stage the survival had to be at least 3 months. In expansion, we did restrict the number of prior therapies in prostate cancer, no more than 1 prior chemotherapy, no more than 2 prior next-gen hormonal therapies. However, in lung cancer, we allowed at least 2 prior lines of therapy. And in triple negative breast, there was no restrictions. But in the eligibility criteria, we did ensure that patients had a little more robust organ function with the albumin level, platelet level a little bit higher than an escalation. So there were some -- also some finer points about organ function that were introduced in the cohort expansion, as Dr. Antonarakis pointed out. We did include a restriction of prior neuropathy greater than or equal to grade 1 to help manage the hand-foot syndrome coming on trial. So there is a bit of difference between the escalation and the expansion. And we are seeing a bit less I would say, toxicity and the expansion. Again, we're still enrolling, still dosing. It's hard to give a precise response to, is there going to be much difference other than that infusion-related reaction where we incorporated the premedication of corticosteroids, which helped very, very much. So there is a difference between expansion and escalation, but it's going to take a little while to see how that plays out in terms of the toxicity profile.

Your next question comes from the line of Stephen Willey with Stifel.

I just have a couple of, I guess, specific questions related to the prostate cancer cohort. So I was wondering if you can speak to I guess, firstly, just the kinetics of PSA response that you're seeing in the 4 patients who are sub-50% PSA reduction? And I guess, specifically, whether or not you can say if the patients, I think there's 2 who are at 9 to 13 weeks, are kind of still trending downwards? And then I have a follow-up.

Chet, could you get that on the expansion on those?

Yes, I'll probably turn it over to Eugene. But with that question, I know the patients in particular. Eugene knows this patient at Sidney that started the trial 1,000, I think, and was going up on treatment. And then we maintained treatment and we got through and the patient actually at this point is, I think, a near 50% reduction. So in time, there are patients that start going up a little bit, but they're trending down as they get to the 12-week and greater mark. And Eugene, I'll let you comment as you've been following the patients through expansion on our PI calls to see if you'd like to comment on that.

Sure. Thank you, Chet. Yes. So we've noted PSA dynamics that have really been a range. But for the most part, I think that even within the first dose or 2 doses, pretty potentially deep PSA responses of up to 50%, even within the first dose or 2, we have noted on some patients. As Chet mentioned, there has been a patient who, after the first dose really didn't appear to have much of a response with a PSA that really continued to escalate. But with additional dosing, did eventually have a PSA that did trend down again. So it's pretty clear that there is PSA dynamics that may take a dose or 2 to sort of kick in. And then in terms of PSA range over time, it's very early to say, but one of the notable things that we've noted is we've highlighted how managing toxicity requires either dose de-escalation or interval changes to how the trial was initially set up, and this is a Phase I. So it's very early days. And the 3-milligram per kilogram dose selected and the dose interval were all based on the few patients in the dose escalation. So there's significant room for improvement based on what's found in the dose expansion. And there, we see that PSA changes may be influenced by not yet understanding what the optimal sort of interval that we are trying to modulate for each individual patient to manage the toxicity, or potentially dropping the dose from 3 milligrams to 1 milligram to manage toxicity, but that may be subtherapeutic. So we are, as a group, sort of in the process of trying to understand the PSA dynamics as asked by the question in terms of all the on-trial dynamics. But right now, this is all anecdotal. So there definitely is PSA response. There definitely can be pretty significant clinical PSA responses or reductions within a dose or 2, and then the question is how to sustain those. Those seem to be a question related really to tolerability of the agent, which as highlighted so far, is a work in progress.

Okay. That's helpful. And then I'm not sure if you have this information or not, but I was curious if you knew off-hand, I guess of the 7 response evaluable patients for whom you completed the 9 week assessment thus far, do you know how many of those are PSA50 responders? And are you seeing a correlation between reductions in tumor burden via assessments and PSA reductions? And then also just wondering, of the 6 patients who are not yet response evaluable or who have not yet had a week 9 assessment, do you happen to know what proportion of those patients are PSA50 responders?

Chet?

I have to be honest because the EDC, the data cutoff on May 3, but I do not know the exact PSA response in those 4 participants. And the 6 that did not yet have 9-week imaging, if they've had it recently, might not still be an EDC. I honestly don't even know the responses to those patients, nor their PSA. So I don't have that information in front of me, I apologize.

Sorry, can I take [indiscernible]?

Go ahead.

Sorry, as Dr. Shenderov said, in slide number 28, to the question, just so that this is already slide talk, in the dose escalation, 5 out of 9 of the patients so far have had a PSA reduction of greater than or equal to 50%. I believe that was part of the question. So we have highlighted that on Slide 28.

Your next question comes from the line of David Lebowitz with Morgan Stanley.

This is Avatar Jones on for Dave today. A few questions from us regarding safety. Firstly, looking more closely at the data, how many patients in the 3 mg per kg dose experienced grade 4 AEs, and secondly, as we digest the data, can you [indiscernible] characterize the safety profile of MGC018 relative to other later line therapies that are used both in melanoma or prostate cancer?

Chet, could you take the grade 4? I don't have that data in hand.

No. Yes. Can you repeat that question? I'm sorry, I think I missed the first part, but I did hear the 4 mg per kg. But what was the -- go ahead.

3 mg per...

Yes, at this 3 mg per kg dose, how many patients experienced grade 4 AEs? So the data disclosed, I believe 3 plus?

Yes. I do not know that granularity of the data off the top of my head either. There were very few grade 4 events, but I do not know the specifics of that off the top of my head.

Okay. No worries. And the second was just regarding -- as we look at the safety profile of the drug, can you help us characterize it relative to other later line therapies [indiscernible] melanoma?

Yes. No, thank you. Yes, I actually did do a review of that for about a month or so ago where I compared it to kind of a benchmark melanoma product and also to benchmark products in the prostate cancer like cabazitaxel, which is kind of a similar line of therapy with what we're doing in cohort expansion. And I will note and Scott Koenig, who's on the call, right, he can -- I showed that table to you, and it's not that disparate. Actually there's more neutropenia with cabazitaxel in that setting. But in melanoma, when comparing it to checkpoint inhibition, very different class of therapy, it's more -- the immune-related events and our product doesn't have that. So it's hard to characterize exactly how it would compare. But the percent incidence of Grade 3 events, it's pretty comparable, if not a little lower than with MGC018. However, we're still early in our cohort expansion. And so getting -- as you know, data entry isn't -- it takes site 10 business days to get a data point into the EDC. So it's a little -- it's just a snapshot of the data from May 3. But when I look at comparability to other benchmark trials that we're looking at, it's not that disparate from my perspective. And Scott, you saw that table about a month ago, I shared, if you'd like to comment on that?

No, I agree with you. We were very encouraged by that. And again, as I've commented on previous calls, what we're seeing is sort of consistent manageable toxicities going forward and certainly not different from those of other late-stage therapeutics.

Your next question comes from the line of Etzer Darout with Guggenheim.

Great. First one, still early days here in terms of the number of patients have gone but just in light of the sort of the vision data set, any thoughts or changes to the development path and metastatic prostate cancer? Then secondly, again, early days, but wondered if you could put the target lesion reduction in the unconfirmed partial response into context with MGC018 in this particular metastatic castration-resistant prostate cancer setting.

Well, so with regard to the VISION study, obviously, we need to see the specific data coming out. There were a lot of holes from the press release and particularly given that this was a treatment on top of standard of care to understand what the previous treatment regimens were for these patients as well as the concurrent stance of care. I mean, as was shown earlier, you were seeing responses in similar -- not so dissimilar from the cabazitaxel. I will let the experts on the call comment on this further. But at this point, we don't see this changing our plans going forward for future pathways towards registration. Obviously, we need to get -- complete this expansion cohort and make some decisions about dosing intervals and the ultimate dose that we would take forward. But we would -- one of the -- DR Shenderov the -- Dr. [ Antonarakis ].

Yes, I'll try to address the other question. And just to verbalize, the question was about the response in that unconfirmed partial response in context of the treatment of MGC018 compared to other therapies. And what I can share with you is that it was a lesion in the adrenal gland. So it's a soft tissue organ lesion that's responding, not a lymph node, not a bone lesion. So I think that adds some context to what kind of response when you're seeing treatments in prostate cancer. And then Dr. Antonarakis or Eugene, if you want to make a comment about that kind of unconfirmed partial response in an adrenal lesion? Can you kind of provide any type of thoughts on that?

Yes. I wouldn't focus too much on those. I would focus on the objective responses confirmed. And we would love to see a confirmed objective response rate that is at least 20% to 25%. If you think about VISION, yes, there are many holes, but we do know from their press release that there was a 29% objective response rate, which is impressive. In CARD trial, it was 36% objective response rate. So if we figure out the dose and the safety and we treat 50 mCRPC patients, and we don't see at least 10 to 15 out of 50 with objective responses, and I would not be that encouraged, but I think that it could happen. And then with respect to comparator arms down the line for Phase III registration, I think it would be hard to use [indiscernible] estimate as a comparator because that is a PSMA-directed therapeutic. And this is not a PSMA-directed therapeutic. So it would be impossible, I think, to design a trial like that. I think a more likely comparator would be cabazitaxel. And the way that I would view it is that the trial would allow but would not mandate a pleural effusion therapy for patients that have received it before. That will be okay, but it will not be required. No way to get exclusion. And in that setting, you would want to see objective response rates that are comparable to PSA response rates that are comparable to cabazitaxel. In the Phase III charge, you will need to show PFS benefit in addition to just response metrics. And again, the toxicities of note, the hematological toxicities, I think are better than cabazitaxel. So we've been using that drug now for about 10 years at Johns Hopkins and the great Grade 3, Grade 4 hema toxicities with cabazitaxel are quite severe. And it is clearly that drug's dose-limiting toxicity. I don't think that [indiscernible] is a dose-limiting toxicity for MGC018. I do, once again, worry about the hand-foot syndrome and the pleural effusions because the rate of -- those 2 side effects with cabazitaxel was about 1% or less. So we don't see hand-foot syndrome with cabazitaxel. We don't see pleural effusion. So I think those will be the things to look out for.

Your next question comes from the line of Peter Lawson with Barclays.

Just a couple of questions around the side effect profile, just maybe a little bit granular. What proportion of toxicities were Grade 4 versus Grade 3?

I do not know the answer to that off the top of my head. I do not know the answer. Sorry.

Yes. Chet, I -- very few.

Yes. I don't know the exact percent, though. There was the grade for neutropenia that was DLT. There was the Grade 3 fatigue DLT, but there was a couple of other grade for neutropenias, but it wasn't -- I just don't know the exact percent.

Peter, did you have another question?

Yes, yes. As you kind of move further in clinical development in prostate cancer, how manageable are those toxicities? And do you think you get them reduced with [Technical Difficulty] chemotherapy?

Yes, you broke up here. When you asked about manageable toxicity and then you broke up. Can you just ask that again? Are you there?

Is that any better? So just a question whether that you can reduce the toxicities as you move into further development?

As you've heard from a number of the speakers today, is exactly the data that we're deriving from the expansion cohort is looking at increasing the dosing interval between treatment and still maintaining the therapeutic effect and then potentials for adjusting the dose and reducing the dose, again, to maximize the effectiveness and limited toxicity so that the patients get a much more prolonged exposure over time of the drug. So we are optimistic that, that can be done. But obviously, we need to have additional data from the expansion cohort before we make decisions what the next right step for next phase studies.

Yes. I'd like to add to that. I do think it's going to be possible to reduce toxicity through all the things you just said with dose modifications, delays, reductions but also incorporating now that we're learning more about the hand-foot syndrome in these patients, learning more about effusions, how to incorporate diuretics, how to incorporate steroids, so that we are employing that earlier. Right now, again, we're still understanding safety profile, but as oncologists learning how to incorporate supported care prophylactically, preemptively rather than reactively, I think, will help us as well as we continue to develop the product.

Got it. And then what does PSA durability look like in that expansion cohort? Do you think it's got better versus the escalation?

No, I think it's too early right now, like most of the patients have been on less than 12 weeks at that data cut. And I honestly, I don't have the durability -- like how durable they are yet. Eugene, I know you had the 1 patient that was on -- from -- there's 1 patient from November that's still on that has a durable response at 7 months. So -- but very few patients over 3, 4 months right now to know the durability.

Yes, we'll have to wait. We'll have to wait with time.

Your next question comes from the line of Tom Shrader with BTIG.

I had a question on Slide 16. The DLT level [Technical Difficulty] and the role are so different. Is that -- does that jump out to your eye the way it does to mine? Why are so many patients dropping off but not hitting a true DLT?

Yes. Good question. I think it's because of -- in the early part, it was -- the patients like that was a patient that had the noninfectious gastroenteritis related to [indiscernible] disease colorectal cancer. There was a patient that had stasis dermatitis with prior history of stasis dermitis, large extremities, never had a DLT. There are just some patients that were at end-stage that -- coming on to study with some medical history that led to them having challenges with the study rather than a dose-limiting toxicity. Dose-limiting toxicity is a predefined criteria that has to be met to call a DLT. And so there are patients that have adverse events that don't meet those criteria, yet the patient finds them to be a challenge for themselves, like the patient that had a near partial response with PSA reduction at 2 mg per kg, he was a final study. He did have the [indiscernible] synthesis pleural effusion, but he was doing well ECOG performance status wise. He chose -- he was 80 years old, decided he didn't want to do visits anymore. So some of these things that are happening that aren't DLTs because they're not classified as DLTs, however they come offset anyway. I don't know if that helps.

It does. Okay. And then I had a question for Dr. Jang in the -- in late-stage melanoma, you'll be competing against a lot of PD-1 add-on immunotherapies, which are going to have response rates around 25%, but you're going to get some real long responders. Do you think that's going to be the key for getting excited about an ADC in this line? Or would responses of 6 months in these kinds of patients compel patients to take the drug? Just your thoughts about the landscape?

Well, I think you have to see what's going to be the like threshold for new investigational agent approval from FDA, what is the, like, incremental response rate when the investigational agent is added to the PD-1 antibody. And the -- well, there are various agents added to the PD-1 antibodies, some are more like trying to induce immune activation such as like there was no intratumoral toll-like receptor agonist. And you may probably already saw the most advanced agents. Unfortunately, the Phase III trial didn't show improvement when it's combined to the EP compared to EP [ alone ]. The -- I think I have a -- I'm sure that there will be a lot of trials trying to add a -- add investigational agents to the PD-1. And then in -- as a clinician, I would like to see at least like 30%, 40% incremental benefit, if possible. And probably that's something that the FDA is going to use, 10%, 15%, 20%. Is it going to be enough? And it's a very competitive landscape with the multiple investigational agent. So I have to see. And the -- and then other targeted agents that's combined to PD-1, I know in renal cancers, there's lenvatinib with PD-1 antibody. In melanoma, again, there's Phase III ongoing trial with the lenvatinib with the pembro, so we have to see the data. And what's going to be the incremental benefit. So the -- having said that, again, MacroGenics, I know the plan is to eventually combine with the PD-1 antibody with this MGC018. And again, you have to see whether there's any synergistic benefit or at least added benefit with those in a combination, what's going to be the response rate with the combination. And again, I -- it's very -- only data and only limited experience with these agents, I only treated 3 patients. But it's kind of been very unusual to see all 3 patients at least having a response in the index lesion. So that's why I'm so encouraged and I really look forward to enrolling more patients to dose expansion cohort.

Your next question comes from the line of Jonathan Miller with Evercore.

I guess I have 2, mostly for the [indiscernible] for Professor Antonarakis and Dr. Shenderov. From prior mCRPC trial, it seems like radiologic responses generally are pretty quick and correlate well with PSA responses. Granted we've only got 1 scan here, but what's the expectation to see those patients that have already gotten the scan, but haven't yet responded, to see a continued positive impact on tumor burden, i.e., can these patients who are not yet in response, should we be expecting them to continue to have their tumors decrease? And then secondly, just the VISION trial, obviously, got mentioned a couple of times both in presentation and Q&A. Radioligand antibodies commercially, historically, have been pretty challenging because they're limited in where and how they can be given. Assuming that the presentation on Sunday looks good and VISION does get approved, does that push unmet need even further down to the fourth line? Or is that more of a niche agent?

Dr. Antonarakis or Shenderov, could you comment on both questions? Hello? Am I cut off?

This is Dr. Shenderov. Yes. Happy to address the 2 questions and with Dr. Antonarakis. I can take sort of the first question about the radiographic responses and the PSA responses. I think that one of the things we're still trying to fully understand in this trial is the relationship within -- for this specific agent between the 2, given the just low numbers of patients that have been enrolled to the expansion cohort thus far. Both sort of -- and timing for those. So a lot of the patients have been enrolled recently. It does appear that, one, radiographic responses are being noted in terms of -- by response, I mean there is radiographic changes. We have some patients who have been included in the presentation and others who have not. So it's a bit early to sort of speak to it, but we do see patients who have them. And then we also see -- we kind of summarize the PSA responses thus far or reductions. And in some cases, the reductions on PSA have been noted to be sort of congruent or in the same direction as that in -- compared to the radiographic. In other case, we had 1 patient who had a partial response by radiographic response and their PSA had responded greater than 50%. And then subsequently, the PSA started to trend up, whereas their radiographic response hadn't yet necessarily changed in the target lesion. And so again, that's an end of one. It's very early because many of the patients, as Chet as pointed out, have not had really a significant follow-up beyond really a handful, to 12 weeks or so. And so to that question, we'll have more data, I think, over time for our patients. But it is notable in terms of just signal finding at the moment that we are seeing both deep PSA reductions, as I highlighted earlier, within a dose or 2, and we're seeing radiographic reductions that seem to match the PSA reductions, but again, the question will be both the durability and sort of how one informs the other. The data is just not there. I can comment on the PSMA, but I'll also just turn it over to Dr. Antonarakis. He can talk about that and then I can chime in. Or he may not be available at the moment. So I can continue. So with the PSMA radioligands and of course, the VISION trial results, one, I will caution right now, we're discussing the results of a trial where we are handicapped by the fact that none of us have seen the data that will be in full presented on Sunday. So a little bit more to come, I think, for the scientific community and for us, as oncologists, to truly dissect what it means. For example, we don't have the PSA response as noted just yet in the abstract. So we'll have to wait on the full data in the presentation and publication eventually. That being said, in the current setting of what we've seen so far as summarized, which table was that? That was Page 28 on our slide -- sorry, Slide 28. We do note, obviously, the overall response, the median overall survival that's presented and, of course, the radiographic progression free survival. And so in that setting, sort of going back very briefly to the initial question. Yes, radioligands, of course, have been limited by the fact of preparation of that ligand, administration, scanning infrastructure and that has been an issue. I think, partly that -- I mean, looking out a few years, if the therapy is approved as anticipated, if the results really are completely as shown here and published and eventually, everyone can analyze, I mean, they look pretty much as good without any serious caveats being seen. The introduction and adoption will potentially change the ability to give it as well. So as -- kind of like electric cars in a sense. As they become more ubiquitous, charging stations to become more plentiful. It leads to a virtuous cycle possibly. And I think the same idea could be seen there early days. That being said, I think, yes, I think in -- definitely for some patients in low-resource settings in more rural areas -- and again, this is partly speculation, it will still be much more difficult to gain access to a radioligand than would potentially be to gain access to a drug that can be stored in the fridge, freezer, and administered as needed. So there will potentially be a need in terms of lines of therapy. And then, of course, as discussed by Dr. Antonarakis, the question still is up in the air because of how early this agent's development is, where it would fit in, and it can always fit in potentially even after the PSMA ligand if the therapeutic side effect profiles are not additive. So we don't know what the true durability is of the response, et cetera, et cetera, sort of beyond the Phase III results. We'll have to see in clinical practice. So well, a lot of things to be determined. It's the early days of an agent that, again, with what we've summarized on this call, has clinical activity, it looks like. It has clinical toxicity profile, it looks like. And we still need to figure out how to manage one and optimize the other. And if that can be done successfully, to then go into further line trials to -- with or without additional, say, PD-1 agents, et cetera. Develop the agent for true clinical benefit. However, as Dr. Jang has highlighted in addition to myself and Dr. Antonarakis and Chet Bohac, so far, it does appear that there is clinical signal of activity, which is promising.

Your next question comes from the line of Yigal Nochomovitz with Citi.

This is Carly on for Yigal. On the prostate cancer expansion cohort, first, can you confirm that the patient who achieved an unconfirmed PR is still on the study with the potential to be confirmed ? And then second, on safety. Are you able to comment on what proportion of patients in the dose expansion are receiving either a reduced dose or receiving doses at a widened dosing interval?

Chet, can you comment on the unconfirmed PR...

I'm just looking right from my PI minutes from Thursday. I believe that patient is still on study. I didn't hear that they've come off study.

Right. And what about the safety profile in terms of reduction? Do you have any sort of general sense on the expansion cohorts?

Could you repeat the question again?

They want to know -- kind of want to know on the patients and expansion. What percentage has some reduction in their doses. Do you have any general sense?

Yes. No, I mean, there's a fair number, but I will share with everybody that was built into the protocol. There is a specific section. Patients are able to dose reduce from 3 to 2 mg per kg. And that shouldn't be as time -- as lack of efficacy or otherwise, it really was built in to make sure that we got a good response with the first dose. So there are a number of patients that are dropping from 3 to 2 mg per kg. And as you can see from dose escalation, the patient on 2 mg per kg almost have that partial response. So there is a fair number that have dose reductions after a couple of doses to maintain efficacy, but improve tolerability. I don't have the exact percent but there are...

Okay. That's helpful. And then we could have 1 broader question on the development strategy. Are there any tumor types that appear that are suited for combination strategy with a checkpoint inhibitor versus tumor types where monotherapy is 018 may be sufficient?

We haven't -- from our preclinical data, we have no evidence that particular combinations would work better in one tumor than another. Obviously, mechanistically, one could envision based on the tumor microenvironment. For instance, if you're combining with a checkpoint molecule, certain tumors might respond better. But at this point, we haven't segregated these out with regard to particular tumor type.

Your next question comes from the line of Boris Peaker with Cowen.

Boris, are you there? Are you on mute?

I'm hearing no response from their end.

Let's go to the next one.

And as of the moment, sir, we have no further question at this time.

Okay. Well, thank you very much, everyone, for staying on this long conference. I hope we will provide you updates on this program. As you know, we are very active on recruitment now and look forward to providing additional commentary at future conferences. So thank you.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation. You may now disconnect.