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

Good afternoon. We will begin the MacroGenics 2020 ASCO Conference Call in just a moment. [Operator Instructions] At this point, I will turn the call over to Anna Krassowska, Vice President, Investor Relations and Corporate Communications of MacroGenics.

Thank you, Victor. Good afternoon. And welcome to the MacroGenics conference call to review the preliminary clinical results from the ongoing Phase I studies of MGD013 and MGC018 that are part of the American Society of Clinical Oncology, ASCO20 Virtual Scientific Program. The presentation that accompanies this conference call is available under the Investors tab on the website of macrogenics.com. You can also listen to this conference call live via webcast on our website where it will be archived for 30 days beginning approximately 2 hours after the call is completed. For those of you listening by webcast, note that the slides for the accompanying presentation are advanced by the viewer. Before we begin, 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. And now I'd like to turn the call over to Dr. Scott Koenig, President and Chief Executive Officer of MacroGenics. Scott?

Thank you, Anna, and thank you all for joining us this afternoon to review the data that is part of the ASCO20 Virtual Scientific Program. On our agenda today, Dr. Jason Luke from the UPMC Hillman Cancer Center in Pittsburgh, will review preliminary data from the Phase I dose escalation expansion study of MGD013, a bispecific PD-1 by LAG-3 DART molecule in patients with unresectable or metastatic neoplasms. Next, Dr. John Powderly from Carolina BioOncology will review preliminary data from the Phase I/II dose escalation study of MGC018, our antibody drug conjugate targeting B7-H3 in patients with advanced solid tumors. Finally, Dr. Emmanuel Antonarakis from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore will provide an overview of the current treatment paradigm for prostate cancer. We will then open to Q&A where we will be joined by additional members of the MacroGenics team. First, as shown on Slide 4, our company is developing innovative anticancer therapies by engineering antibodies that engage the immune system using proprietary platform technologies, namely our Fc-engineering and bispecific DART molecules. We currently have 7 immuno-oncology product candidates in clinical development, including 3 in studies designed to support registration. We are pursuing mechanisms of action that are complementary and potentially synergistic, providing opportunities for combination. We will discuss 3 of these molecules this afternoon. I would now like to introduce our first speaker, Dr. Jason Luke. Dr. Luke is an associate professor of medicine at the University of Pittsburgh Medical Center in Hillman Cancer Center where he's the Director of the Cancer Immunotherapeutics Center. He specializes in the management of patients with melanoma and early-stage drug development, particularly novel immunotherapeutics and biomarkers of immunotherapy activity. Dr. Luke has been a lead investigator on many clinical trials of novel immunotherapy agents. We're very pleased to have him join us today to present preliminary results from the Phase I trial of MGD013 in patients with advanced tumors. Jason?

Thank you very much for the introduction. I appreciate everyone joining us here on Friday afternoon. And hopefully, people are able to get in into the ASCO system so they could view the presentation. But either way, I'm going to go through the data as was presented. So starting on Slide 5. Obviously, the introduction and the title of the talk. And I'll move quickly through Slide 6, which are my disclosures, probably less relevant right here. In the Slide 7, we'll talk about the rationale for dual targeting of PD-1 and LAG-3. So presumably, most of you are aware, the checkpoint molecules can be expressed by tumors and antigen-presenting cells to evade the immune response and in [ certain ] of the development of PD-L1 targeting that's clearly been kind of a big impact on the clinic. Now PD-1 and LAG-3 are both expressed on the punitive exhausted T-cell subsets where they can interact with corresponding ligands to negate antitumor responses. The synergy of PD-1 and LAG-3 monoclonal antibodies has been demonstrated in animal models, and combinations are ongoing, including registration intent clinical trials for PD-1 plus LAG-3 molecules. The right-hand side, you can see the figure, which beautifully outlines MGD013 as an investigational DART protein that targets both PD-1 and LAG-3 with a single molecule. And a preclinical model's greater synergy in terms of T-cell activation and interferon elaboration has been seen with this bispecific molecule relative to the individual component parts. MGD013 is a DART molecule, and the DART platform is a stable diabody that with multiple configurations and applications. Specifically, MGD013 is a tetravalent bispecific DART molecule that you can see in the middle of the slide. So I'll move on to the next slide where we describe our Phase I clinical trial with the primary objective of the study was safety and tolerability as well as dose funding, and secondary objectives around pharmacokinetics and the preliminary antitumor activity with exploratory biomarker analyses were also pursued as listed there. And we prefer to the dose escalation of MGD013 giving the drug every 2 weeks on a 3 by 3 dose escalation approach from 1 milligram up to 1,200 milligram, and you can see in the middle of the slide. This was in a population of advanced solid tumors. And separately, per FDA guidance, we performed a dose escalation of MGD013 in hepatocellular carcinoma for doses of 120 up to 600 milligrams. After determination of a recommended Phase II dose, which was 600 milligrams every 2 weeks, monotherapy expansion cohorts were pursued in several tumor types, including ovarian, triple-negative breast and nonsmall cell lung cancer as well as other tumor types that you can see highlighted -- listed in the bottom of the slide in the legend there. A combination cohort was also explored in HER2-positive solid tumors with the combination with the anti-HER2 molecule, margetuximab, and we'll come back to this later. This was given on a Q3 week schedule for the combination. So Slide 9 shows the baseline demographics of the treatment population. As you can see that this is a pretty large Phase I trial where in dose escalation, there were 53 patients who participated in the monotherapy cohort expansions across the different tumor types, there were 205 patients. And in the combination with margetuximab, 21 patients participated. You can see the median age ranges from 60 to 64. The gender is split predominantly by the tumor types. In the dose escalation, it was 60-40 male to female but less in the other tumor types. ECOG performance of 0 1, with the median lines of prior therapy being 2, but a quite a wide range as you can see across those different cohorts. In terms of prior exposure to checkpoint inhibitor, you can see that in dose escalation, we have 43% of patients who had prior checkpoint inhibitor much less than in the other cohorts. But again, that's predominantly because those are not cohorts, generally speaking, associated with treatment response to anti-PD-1. On Slide 10, we'll review the pharmacokinetics and receptor occupancy that were observed. You can see on the left-hand side, the kinetics, the PK profile of the drug, were above 400 milligrams in the pink line. You can see that there is a linear pharmacokinetics observed and that the kinetics are stable at concentrations above that predicted to be the c trough for pembrolizumab based on publicly available data. And that the dose -- the half-life of the drug was around 11 days in the study. Receptor occupancy was demonstrated that doses above 100 -- at and above 120 milligrams every 2 weeks, at 100% for both CD4 and CD8 T-cells. On Slide 11, we move on to the results from dose escalation for the monotherapy. And you can see a waterfall plot that nicely outlined the outcomes for patients across the various dose cohorts. Again, noting that at the 120-milligram dose cohort is where 100% receptor occupancy was observed, but the full cohort, including the hepatocellular cohorts are listed here, and some highlights to make note are the patients with previous checkpoint inhibitor therapy are denoted here by the black triangles, either above or below the waterfall plots, with each individual patient's tumor type are being noted. On the far right-hand side, you can see that 3 patients had partial responses by RECIST criteria during dose escalation, and these included a patient with triple-negative breast cancer who was on treatment for more than 5 months as well as 2 previously treated patients with PD-1, one with mesothelioma and one with gastric cancer again with treatment response at the 800 and 1,200 milligram doses. 18 patients had stable diseases. Overall best response here with a disease control rate around 49%. And the toxicity profile in monotherapy dose escalation is on the right-hand side for the immune-related adverse events of special interest. You'll note that overall, when you look at the numbers in the table, this is well tolerated. But the safety profile is generally consistent with that seen for PD-1 or L1 in the treatment-naive setting and that MTD was not exceeded or defined at up to 1,200 milligrams. But I think very importantly, on mechanism toxicities, we're observing this cohort of patients. So notably at 1,200 milligram, episode of immune-mediated hepatitis was observed. And at 600 milligrams, lipase increase with radiographic evidence of pancreatitis was seen. Both of these were easily managed with steroids. On Slide 12, we move on to discuss the monotherapy cohort expansion safety profile where, again, this is in 205 patients, so pretty good cohort of patients who observed the overall safety. And the various different outcomes are noted in this table, and I'll highlight the treatment-related severe adverse events, both of all grades and greater than Grade 3 in the fourth row down, noting that this is generally speaking well tolerated, did not lead to a lot of discontinuation. And that's noted even further down below that, the next line for AESIs leading discontinuation on the order of here about mid-single digits. Adverse events of special interest in more than 2 patients are noted at the bottom and, again, highlight that multiple immune-related adverse events were observed, but again at relatively low frequencies. And on the right-hand side, the tornado plot summarizes the total, the treatment-related adverse events and adverse events irrespective of attribution, noted in the color coding from Grade 1 to 4 at the bottom there across the various different toxicities. And you'll observe that common toxicities associated with immunotherapy, rash, fatigue, hypothyroidism were the most common as one would expect, and the incidence of other toxicities being [ less ]. Slide 13, we'll move on to the results -- efficacy results from monotherapy MGD013 in the expansion cohorts, highlighting the outcomes for patients with triple-negative breast cancer, epithelial ovarian cancer and nonsmall cell lung cancer. Note from the color coding, this includes both checkpoint inhibitor naive in green, as well as checkpoint inhibitor experience in the purple. You'll observe in the spider plot just above the waterfall plots, the incidence of the first new lesion on treatment as well as those patients who have treatment ongoing during therapy. I highlight these because you'll notice that in triple-negative breast cancer and the epithelial ovarian cancer cohorts, some of those patients are relatively early on, on treatment. The table at the bottom highlights the outcomes of these patients. The number of evaluable patients across the cohort is listed. And then the confirmed overall response rate and confirmed plus unconfirmed are noted below that. And again, you'll notice that some of the patients are early on in treatment, which is why this was the approach taken to summarize these data. The rates of stable disease and disease control rates also listed there at the bottom. And I'll highlight that activity obviously is being seen across multiple disease types here. And that includes the triple-negative breast cancer where certainly, there is activity to PD-1 monotherapy, but it is quite modest as well as epithelial ovarian cancer where activities, generally speaking, not seen particularly much with PD-1 monotherapy. And in lung cancer where we see responders in the PD-1 -- post PD-1 space, suggesting that MGD013 by LAG-3 blockade can actually engender response in that setting. Several -- expansion cohorts are still ongoing, however. And as we move to Slide 14, I'd like to highlight the case from the ongoing lymphoma cohort. This is a 27-year old man with diffuse large B-cell lymphoma previously treated with CAR-T cell therapy, and prior to that, with DA-R-EPOCH. And so after the patient got JCAR017 CAR-T, he had progression of disease and got a single dose on protocol of MGD013 at 600 milligrams. Prior to going on studies, the patient did have a biopsy, which you can see on the right-hand side, and you can see that the patient had high levels of LAG-3 and PD-L1 in the tumor microenvironment. Now presume mechanism of CAR-T progression in this patient was actually loss of CD19. And other immunohistochemistries, the company has internally show beautifully that the B cells are present as stained by CD79. So as mentioned, this patient got a dose of MGD013 and went on to be admitted on day 11 with Grade 2 cytokine release syndrome-like symptoms. And by day 24, you can see these PET scan images on the right-hand side showing the patient had had a complete response. And at that time, the patient had assay in the [ purple ] circulation for CAR-T cells and none could be observed. The patient went on to have allogeneic stem cell transplant. It's currently in remission now at 11 months post MGD013 and 9 months post-transplant. So moving on to the deck. Considering those results, we move to Slide 15 where we want to integrate further these biomarker considerations around the treatment response we've seen in these various cohorts. And here, what we'll discuss are immunohistochemistries initially on the left-hand side from a retrospective archival tissues from the patients who were available in the triple-negative breast, epithelia ovarian and nonsmall cell lung cancer expansion cohorts. You'll see on the right -- left-hand side, excuse me, but sort of in the middle, the aggregated analysis of LAG-3 expression by immunohistochemistry related to clinical outcome. And on the right-hand side in the red box, you'll see that partial responders clearly had higher levels of LAG-3. Moving back to the left-hand side there for LAG-3 expression, you can see that individual patients' treatment outcome is color-coded there. So you'll observe that the patients with partial response are more likely to be on the far left side with high levels and less likely to be responders as you progress towards the right with fewer red dots. And that's somewhat in contrast actually with PD-L1 status, as you can see here. So PD-L1 levels are highest in this patient in the far left who had the best response, but other patients who responded had actually much lower levels of PD-1. And in fact, some of them were negative altogether for PD-L1. On the gene expression level, you can observe on the right-hand side, looking at transcriptional profiling for LAG-3 and PD-1 is a binary comparison that the patients most likely to respond were those who had high levels of PD-1 and LAG-3, presumably on lymphocyte antitumor microenvironment. And moreover, the interferon gamma associated gene expression as calculated on the NanoString profile clearly associates with treatment response in this population of patients receiving this PD-1 and LAG-3 approach with MGD013. And these data are quite exciting as potential punitive biomarkers to be explored further, but they also highlight the ongoing need in the field to identify therapies for patients with interferon low tumors or who have progressed on PD-1 monotherapy. And as we move to Slide 16, and we should consider that as a therapeutic approach, maybe you consider enhancing effector-cell activation via Fc-engineered monoclonal antibodies. And margetuximab, as all of you are probably aware, is an investigational Fc-engineered anti-HER2 monoclonal. They have similar properties to anti-HER2 as in trastuzumab, but enhance Fc-mediated effector function. You're also aware that margetuximab has had success with superior progression-free survival relative to trastuzumab in a head-to-head Phase III clinical trial in breast cancer, and margetuximab has also shown activity in advanced gastric cancer in combination with anti-PD-1. So to better understand the impact of margetuximab as an Fc-enhanced HER2 antibody on the expression of LAG-3, human PBMCs were co-cultured with N87 gastric cancer cells and then exposed to various -- to either control margetuximab or trastuzumab. On the right-hand side, you can see the induction of LAG-3 expression, most predominantly on the margetuximab-exposed cell, suggesting this augmentation of immune response. And as we move to Slide 17, we can observe this effective Fc-engineered margetuximab more broadly on multiple immune cell populations with upregulation of LAG-3 and PD-L1. And you can see of NK cells on the left-hand side, which show the induction of LAG-3, as I mentioned, but additionally, PD-L1. And this is the case across the multiple of immune subsets, NK cells, monocytes, CD4 and CD8 T-cells. This PD-1 LAG-3 MGD013 also enhances the activity of immune cells primed by Fc-engineered monoclonal, such as margetuximab. And to explore this antibody-dependent cell cytotoxicity as well as NK-cell killing assays were pursued where you can see that the number of live cells in both assays is essentially unchanged in the context of control antibody and with the addition of MGD013. That's in the orange. However, with the introduction of margetuximab as would be expected for an Fc-engineered monoclonal, you do get the induction of ADCC as well as NK-cell killing, and you can see that, that's further enhanced with the addition of MGD013. On Slide 18, we move to the initial clinical results for the combination of margetuximab plus MGD013. And you can see a waterfall plot that nicely summarized the patients who have participated to date with a substantial amount of treatment response and an overall response rate of 43%, 6 out of 14. We will note that this does include -- unconfirmed objective responders because as you'll see on the spider plot in the middle, you can see that several patients are early on treatment. Again, looking at the waterfall plot, again, however, you can see there are multiple tumor types listed here, all of which are HER2, predominantly refractory, and generally speaking, PD-L1 low. And it's worth noting that this response that we're seeing here is actually not associated with interferon [ single antitumor ] microenvironment. And on the right-hand side, you can see the PD-L1 CPS as well as the LAG-3 score, noting that most of these patients have low levels for both. And this suggests that the combination of an anti-HER2 with margetuximab can engender some level of T-cell inflammation, the tumor microenvironment, which can be enhanced for treatment response with MGD013. Two patients from the waterfall plot, I would highlight specifically, one is in the green sort of in the middle, and that's a patient who had gastroesophageal junction cancer. And you can see this patient is coded as progressive disease because of the -- on the spider plot, you'll see that initially, the patient has disease increase up to approaching 40%, but then it has a treatment response subsequently consistent with an immune-related response. The other patient I would specifically highlight would be the one the far right on the waterfall plot, a patient with confirmed partial response with breast cancer. And on Slide 19, you'll see that case -- for that patient, which is shown as a 67-year-old woman with HER2-positive breast cancer, previously treated with chemotherapy and anti-HER2 agents as well as hormonal agents who, at baseline, has this fungating mass on the chest wall. Other disease is in the right breast, liver and lymph nodes. The PD-L1 CPS in this patient is less than 1, and a low LAG-3 score was observed as well. So this isn't a patient that we would expect to be responding to immunotherapy. But you can see the baseline on the right-hand side out over 295 days this patient has been on treatment with substantial treatment effect. And note the day 15 and day 28, images are actually after a single dose of the combination, owing to a slight dose delay for the treatment due to a toxicity that's spontaneously resolved. And you can see that across the tumor assessments. From the first and fourth now, the patient now has stable reduction in disease burden in the mid 60%. So clearly, this is an impressive response. This is a HER2 refractory tumor where we would not expect treatment response to immunotherapy, and we have substantial treatment benefit for the patient. So we'll summarize on Slide 20, then of the deck that MGD013 is a first-in-class bispecific checkpoint inhibitor that's designed to independently and coordinately block PD-1 and LAG-3. It's well tolerated up to doses of 1,200 milligrams every 2 weeks and recommended Phase II dose at 600 milligrams every 2 or 3 weeks. Safety profile is consistent with PD-1 monotherapy. Encouraging monotherapy activities has been seen in multiple tumor types with baseline LAG-3 expression and interferon signature associated with objective response as we expected. Compelling preliminary combinatorial activity was seen with margetuximab in Fc-engineered monoclonal antibody with more than 40% observed overall response rate in this PD-L1 low and relapsed/refractory HER2 population and certainly, this compares favorably to historical roles. Evaluation of MGD013 as monotherapy and in combination with Fc-engineered monoclonals, such as margetuximab, is ongoing. And finally, in Slide 21, we'd like to thank the other investigators who participate, and of course, on Slide 22, thank the patients and their families who participate and continue to do so on the study. So thank you very much for hearing our presentation. I'll be happy to take questions later.

Thank you, Jason. And as Jason said, there will be an opportunity for you to ask some questions later. Now turning to MGC018, I'd like to introduce our second speaker, Dr. John Powderly. Dr. Powderly is Founder of the Carolina BioOncology Institute in Huntersville, North Carolina. He's also currently Adjunct Clinical Assistant Professor of Medicine at both Duke and UNC. His research interest is in immunotherapy. Dr. Powderly [Center] serves as a regional referral hub for Phase I access in the community setting, and we are pleased to welcome him today to present the preliminary Phase I dose escalation results for MGC018 in patients with advanced tumors. John?

Thank you, Scott. So I'm happy to present on Slide #24, the preliminary dose escalation results from a Phase I first-in-human study of MGC018, a B7-H3 antibody drug conjugate in patients with advanced solid tumors. So next on Slide 25, B7-H3 is highly expressed in many solid tumors. This is a reference to an IHC summary of 1,400 tumor samples screened, which show very high expressions of positivity, including 2 plus or higher IHC scores on the right in many tumors. Also, interestingly, B7-H3 expression is associated with disease severity, risk of recurrence and reduced survival. And interestingly as well, B7-H3 is expressed not only on tumor cells but on the tumor microvasculature and the stromal cells within the tumor microenvironment. Next slide, #26. MGC018 is an antibody drug conjugate that is duocarmycin-based with a linker payload. So the DUBA, which is the actual toxin that is cleaved from antibody-drug conjugate, is internalized within the cell, and it is a fully synthetic DNA alkylating agent. DUBA is both cytotoxic to cells that are actively dividing and cells that are static at rest. And it retains potency in multidrug-resistant cell lines. It's a cleavable peptide linker that facilitates bystander effect, meaning that if one cell dies from DUBA, when that cell dies, it can be -- DUBA is released and may actually cause cell death in a neighboring tumor cell. Furthermore, because this is both an immune target B7-H3 with a cytotoxic payload, it induces an immunogenic cell death in preclinical models, meaning that inflammatory death is very different than a bland, apoptotic death. And that inflammatory death, we hope will induce further immune response. On the right of this Slide #26, you'll see that the drug-to-antibody ratio is 2.6 of the payload to the actual antibody. Next, Slide #27. There has been antitumor activity with MGC018 in human patient-derived xenograft mouse models. So you can see this is a prostate cancer, breast cancer and head and neck cancer xenograft model. And at the bottom, it shows the xenograft themselves in the amount of B7-H3 expression based on the H-score, the MHC expression. And most of these tumors had at least 2 plus or 3 plus B7-H3. And on the actual graphs themselves, on the left is the tumor volume after mouse inoculation and the study day along the bottom, showing that with the vehicle, there was tumor growth with a -- other antibody-drug conjugate, not the B7-H3 study drug, but another antibody-drug conjugate. There is a little bit of some tumor stability. But with the study drug itself, B7-H3 at a 3 mg per kg dose, there is very clear tumor decrease. And then many of the mice looks like the tumor is completely resolved. So next slide on #28. The rationale for targeting B7-H3 with MGC018 antibody-drug conjugate is that B7-H3 is highly expressed in multiple solid tumors with limited expression in normal tissue. B7-H3 also plays an immune suppressive and tumor-autonomous roles that favor cancer growth. In addition to B7 -- in addition to tumor cells, it is also expressed by the vascular endothelium and stroma in the tumor microenvironment. And it is a novel antibody-drug conjugate that delivers a potent duocarmycin payload. And because this drug has DNA targeting activity, it can be directed against both dividing and nondividing cells. Next slide, #29, is the objectives of the study designed for the Phase I study to evaluate the safety and dose-limiting toxicities and maximum tolerated dose in the dose escalation 3+3 (sic) [ 3+3+3 ] design. Dose was given every 21 days. Dose escalation cohorts, there were 6; 2, 1 ongoing, and the 6 1 is still planned at dose levels of 0.5 up to 5 milligrams per kg. Tumor response was by the investigator, RECIST 1.1, evaluated every 6 weeks for the first 4 cycles in every 12 weeks thereafter. Cohort expansion will enroll at the recommended Phase II dose to assess safety and tumor response. Primary objective was safety and maximum tolerated dose or maximal administered dose. Secondary objective was PK and immunogenicity and antitumor activity. Next slide, #30. Key inclusion eligibility criteria included patients with histologically proven solid tumors that did not respond or had failed to respond to other anticancer drugs, and tumor tissue had to be available either by archived biopsy or fresh baseline. But notably, B7-H3 expression was not required for eligibility. Key exclusion criteria included significant abnormality of lab parameters or any untreated brain metastasis. And there was a 3-week washout from chemo, and radiation was allowed 2-week washout. And also excluding were clinically significant cardiovascular or pulmonary disease. Next slide, #31, the enrollment status as of May 6, 2020. There have been 29 patients screened. 25 patients have enrolled, and you can see the breakdown of the different cohorts in blue and their tumor types. Cohort #5, which is the 4 mg per kg cohort is currently enrolling. Cohort 6 is still planned. There were 18 patients that have had measurable disease that can be evaluated thus far. One of those had prostate cancer. The other 6 patients with prostate cancer who you'll see their PSA trends, they had evaluable disease with bone-only metastasis but did not technically have RECIST measurable disease. Next slide, #32. This is the safety summary for all study drug-related adverse events of anything greater than 10%. So -- and being an immunotherapy doc giving a lot of these drugs over the years, noting that this drug both has a cytotoxic payload component and an immunotherapy component with the B7-H3. We saw side effects that I would attribute to some of the cytotoxic component and some of the immunotherapy component. For example, the neutropenia, as you can see, as we increase the dose, going from 0.5 to 1 to 2 to 3 milligrams per kg, we saw a little bit more of the neutropenia. Also being the cytotoxic side effects, we saw a little bit more of the GI nausea vomiting toxicities at the higher doses. However, the immunotherapy component of the drug, in my opinion, we saw those fevers, chills and fatigue, which is typical of immunotherapy, we saw that in all those levels, maybe a little bit more pronounced at the higher 3-milligram dose levels, but we certainly saw it at the lower dose levels. There also were infusion reactions, which I've experienced myself. Those tended to occur at the higher dose levels. These infusion reactions were managed safely with steroids and Benadryl and did resolve with good infusion room practices. We did also see significant cytopenias, and those tended to be related to the dose level. We did see one at the lowest dose cohort with neutropenia, but most of them were at the higher dose cohorts. I think kind of unique to this class of drug are probably unique to the duocarmycin component, there was some skin hyperpigmentation. And I had not seen that yet in our other ADC drugs. And this was mentioned in the earlier preclinical models. And we saw this in patients with some hyperpigmentation on the creases of their palms and soles. It looked like a melanin deposition. They also had a little bit of hyperpigmentation on the tongue or mucosa membranes that occurred after multiple doses. And you can see that also seem to be dose-related. The pruritus, I think that was lot of immunotherapy-related. And there was some palmar-plantar syndrome that occurred also at the higher dose levels. All those were manageable, with holding a dose or reducing the dose in with steroids or Benadryl and topical steroids as well. Interestingly, there was 2 patients, and I experienced this myself that they had some angioedema at the dose levels 1 and 3 mgs per kg. They were Grade 2, and they did resolve with a steroid taper and skipping a dose or 2. So those are the overall summary of the related adverse events. Next slide is Slide #33. Those that were Grade 3 or higher that were also related to study drug, most of these were cytopenias or skin issues as well. You can see neutropenias occurred at the higher doses on 2 and 3 milligrams. And other lymphopenia has occurred. There was one case of pneumonitis at the low dose level. That was also one of my patients that was with a bacterial infection that was concurrent, and there were cases of palmar-plantar syndrome that reached Grade 3 on a couple of patients. Overall, these were manageable, and in most cases, were reversible with good oncology practices. Next slides. Overall summary of treatment-emergent adverse events. There were 3 treatment-related SAEs that occurred. One was the pneumonitis, which was in my patient that was concurrent with the bacterial pneumonia. That was a Grade 5 that was a fatality but also was related to a significant bacterial infection and bacteremia. There was a noninfectious gastroenteritis in a stasis dermatitis event in a patient with chronic venous insufficiency. There was one DLT, which was also one of my patients with a Grade 4 neutropenia that resolved back to baseline with support of care. However, despite a couple of cases of neutropenia, there was no febrile neutropenia observed yet in any of the patients. So overall, this drug appears so far to be manageable with a treatment profile that so far is manageable at the current dose levels presented. So next slide, #35, is the best percent change of target lesions based on dose level, and each color is the dose level listed there and by tumor type. So although there were no RECIST technical PRs you can't do, there was objective tumor activity, including clinical benefit, with stability of multiple tumors and also objective tumor shrinkages in dimensions with prostate cancer and lung cancer being the patients having the most objective responses to date. We'll also be showing you the PSA trends, which I think is probably the most important data. Next is the spider plot of the percent change in the target lesions by tumor type. Broken down, you see that based on the patients presented here, many had a stable disease which was durable out to 20, 30 weeks. There were patients that progressed after their first scan, and some patients had a close but not quite full PR yet, but they were still -- many still ongoing on treatment. Next slide is #37. This is an example of one of the objective radiographic decreases in a nonsmall cell lung cancer patient who had been heavily pretreated with 5 prior lines of therapy, including doublet chemo with bevacizumab and 2 prior immunotherapies, nivo and pembro, and 2 other study drugs. And then when they came on to the MGC018, they had an objective response of 24%, which was stable disease duration of 2 months with the radiographic images shown there for right pleural-based lesion. Next slide is Slide #38. This, I think, is probably the most impressive slide with the data showing greater than 50% PSA decline in patients who were heavily pretreated with castrate-resistant prostate cancer. So I'll walk through each of these patients because I think each cases are relatively impressive for a heavily pretreated population. So the first patient #1, in red, at the 2-milligram per kg dose, had a RECIST measurable disease and had had 5 prior regimens, as you see listed there, including chemo, immunotherapy, hormonal therapy and PD-1 nivo. They had a 29% RECIST response, which was stable disease, and a 49 -- I'm sorry, 59% PSA decline, and that had been durable out to 4 months. The next patient #2 at the 3-milligram per kg dose had bone-only metastasis with 4 prior regimens, including chemo and a radioisotope and had stable disease with bone-only disease radiographically but had an impressive 99% decline in the PSA, which is durable and still ongoing at 3-plus months of therapy. Next, patient #3 at the 3-milligram per kg dose with bone-only metastasis who is also heavily pretreated with 4 prior regimens, had stable disease radiographically, but a 67% decline in the PSA, which -- with 1.5 months of therapy, which is also ongoing. Any of the plus signs indicating the patient is still ongoing and on treatment. Next patient #4 at the 3 mg per kg dose with bone-only disease who didn't receive prior chemo but had nivo with angiotensin -- I'm sorry, with rucaparib, also had stable disease radiographically but a 74% decrease in PSA and ongoing treatment of 1.5 months. And the last patient, patient #5, who had 5 prior regimens -- yes, 5 prior regimens and had a 78% decline in the PSA, still ongoing. His is probably the most remarkable decrease because he started with a PSA of 1,114, which had dropped to 249 at week 6 and further dropped down to 95 at week 12 with that latest data on May 18, 2020, just after the May 6 cutoff. So that is impressive from my standpoint in the trenches because we see a lot of heavily pretreated prostate cancer patients. So I would hope that this is -- both components of this drug, both in immunotherapy and a cytotoxic payload component that's contributing. Next, Slide #39. This is a nuclear medicine scan of the bone metastasis in patient #2 with prostate cancer who had baseline on the left. You can see the bone scan in November showing bone lesions with hypermetabolic uptake in the thoracolumbar spine, ribs, sternum and pelvis. Then in February, the uptake had decreased, and in May, had almost disappeared in the bones. So also a good imaging response. Although again technically, we can't measure the bone, so it's not RECIST. But still, it's an impressive resolution of bone lesions by nuclear medicine. Next slide, #40. Regarding the archive and pre-dosing biopsies. 18 of 23 patients had tissue samples that were evaluable for B7-H3 expression. The median H-score was 2 plus -- 200. And the vascular score in the cardiovascular tumor was 2 plus as well. Next slide, #40 (sic) [ #41 ]. So in conclusion, MGC018 has an acceptable safety profile to date with manageable hematologic and skin toxicity. One DLT occurred at the 2 mg per kg dose, which had resolved to baseline. And there is preliminary evidence of antitumor activity with objective radiographic improvement in heavily pretreated patients with lung cancer and prostate cancer, including, I think, would be described as a remarkable reduction in PSA on those patients on multiple patients. Current enrollment is at the 4-milligram per kg cohort, and there is a planned dose expansion dedicated to prostate cancer patients, which I'm hoping we can reserve plenty of those slots for our patients because, so far, I've been impressed with what I have seen in regards to prostate cancer patients. Next slide, I'll toss this back to Scott. Thank you very much.

Thank you, John. I'd now like to introduce our final speaker, Dr. Emmanuel Antonarakis, who will provide an overview of the current treatment landscape for prostate cancer and provide context for the early results observed in patients from the Phase I study of MGC018 with metastatic castration-resistant prostate cancer. Dr. Antonarakis is a professor of oncology and neurology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Dr. Antonarakis' clinical interest is the management of prostate cancer and other general urinary malignancies. He is currently the PI of several Phase II and Phase III prostate cancer trial and is an active member of the Prostate Cancer Clinical Trials Consortium and ECOG and as well as the NCI Prostate Cancer Task Force. Emmanuel?

Thank you for the introduction. And hopefully, my session will be shorter than your introduction because nobody wants to stay late on a Friday afternoon listening to a third lecture. My task was to review the landscape of prostate cancer. And all the patients that you've heard about from John in the previous talk were metastatic castration-resistant. And on Slide 43, I wanted to make a point that there are 2 ways that a patient can end up with metastatic castration-resistant prostate cancer, and it all depends on when their physician chooses to start that person on hormone therapy. So the first way is that this patient has metastatic disease, either de novo or after previous local therapy in the non-castrate state. In other words, patient presents to the emergency room with bone pain is found to have metastatic bone lesions. Obviously, this person has never received hormone therapy. And so they're non-castrate metastatic. Those patients will then be started on hormone therapy, and over the course of 2 to 3 years will develop castration-resistant disease. So that's one way it can happen. The other way you can get to metastatic castration-resistant disease is that you have a person that develops a rising PSA after a local therapy like prostatectomy or radiotherapy, and the patient's doctor gets twitchy or the patient himself gets anxious, and that person has started on hormone therapy before they ever develop a metastasis, in other words, in the non-metastatic rising PSA situation. And over time, those patients will also develop castration-resistant disease but this time, it will be non-metastatic, also called nmCRPC. And then the non-metastatic castration-resistant patients will go through a number of other systemic therapies, some of which will be novel hormone therapies, and they would eventually develop a radiographic metastasis. Slide 44, which is my last slide, I wanted to keep it short and sweet, is a simplistic current treatment paradigm by lines of therapy for metastatic castration-resistant prostate cancer. The first line is that top row in blue and the most common agents, although there are others that are using, the first line setting are either taxane chemotherapy, namely docetaxel, or 1 of 2 so-called novel hormone therapies, but they're not that novel anymore, enzalutamide also called Xtandi or abiraterone also called Zytiga . And then in the second line setting, it all depends on what they received in the first line. If they receive their chemotherapy in the first line, they would probably receive a hormone agent in the second line like abiraterone or enzalutamide. If they received one of those 2 hormone agents in the first line, they'll probably get chemotherapy as a second line. And in the second-line setting, there's another taxane called cabazitaxel, also called Jevtana, which has been FDA approved. And then across the bottom row in the green, there are 3 genomically targeted therapies that are available. One of them is pembrolizumab based on the May 2017 tumor type-agnostic approval for MSI-high or dMMR prostate cancers of any solid tumor. And then the other 2, which are the PARP inhibitors, were literally FDA-approved on May 15 and May 19 of this month, respectively. And olaparib has been FDA-approved for patients with 1 of 14 HRR gene mutations, including BRCA 1/2 AGM and 11 others. And then rucaparib was FDA-approved only specifically for patients with BRCA 1 and 2 mutations. And then in the third line setting, it's usually reserved for chemotherapy, except in some cases where the patient is either intolerance of chemotherapy or turns it down where a second or a third androgen receptor targeting hormone therapy can be used. But we know that the responses to a second and third hormone therapy, and people that have failed 2 or more are very, very short lived. So I would be delighted to take questions. I didn't want to take up too much time on that. And don't ask me anything except for prostate cancer stuff because I'm a prostate cancer guy, but I can do prostate cancer.

Thank you, Emmanuel, for those remarks. We'll be very pleased to answer your questions. For the question-and-answer session, we will also be joined additional MacroGenics colleagues, Dr. Brad Sumrow, and Chet Bohac are the medical directors for MGD013 and MGC018 programs, respectively; and Dr. Paul Moore is our Head of Immunology and Cell Biology at MacroGenics. Operator, please open the call to questions.

[Operator Instructions] And our first question will come from the line of Christopher Marai from Nomura.

I was wondering if, first, we could touch upon the B7-H3 experience that you've had. And first, I would like to understand if you've seen any liver toxicity to be associated with this molecule or if you might have expected that. And then secondarily, as we look at the spider plots on Slide 36, if there are some patients that responded and then -- or had stable disease and then sort of stop responding or progressed, and I was wondering if you might comment on the dose they were receiving and if higher doses might be warranted in patients like this? And then I have a follow-up.

Great. So thanks for the question with regarding the liver toxicity. As you know, MacroGenics has been developing 3 different agents targeting B7-H3. Our Fc-engineered molecule, our previously developing bispecific molecule with the CD3 component, and then, of course, our ADC molecule. What -- as has been reported in the literature, depending on the specific antibody specificity, one can see some binding to liver. I would say that by and large, with several hundred patients experience with our Fc-engineered antibody, we've seen very little in terms of liver issues. The only time that -- and as John has pointed out to you, liver was not a major component of treatment with MGC018. The only time we have noted some liver effect was without bispecific, which we are currently no longer pursuing. And through a very thorough analysis, we determined that the rises in ASCLC as well as bilirubin in these patients were largely associated with our target effects of tumor metastasis within the liver and, in some cases, due to cytokine release. We had no evidence to date that I know of direct toxicity related to B7-H3 expression solely on the liver cells per se, although, in theory, that could happen. This is in part because we've selected antibodies with very low reactivity to the liver. We had picked the antibodies that have been used in our molecules off of a group of over 50 antibodies, and these were selected for that specificity. With regard to the spider plot on 36, maybe John or -- maybe could you answer that with regard to the doses where these were observed.

Yes. So regarding spider plot and it's just an immunotherapy comment in general, and with immunotherapy, we often see just the tumor smolder and stabilize. So in other words, the tumor stays in check. And so seeing a stable disease for the first second scan is still, to us and the trenches, is still a sign that there's some activity there. We kind of -- we tell our patients, you actually have to mount an immune response to have the cell killing on the immune side, not the cytotoxic side, but on the immune side. So I think just because the spider plot had some of those many patients with stable disease, that doesn't negate the potential that the drug will continue to show other benefit over the long haul. So that's just my only comment. And that's just a general immunotherapy comment. When you look back at the drugs that have been approved by the FDA over the many years, sometimes their response rates were a little bit underwhelming. And I think of ipilimumab in the early days, my own, but it had a big impact on the overall survival and durability. And I think that's classic immunotherapy. So it's just too early to make any conclusions based on a waterfall plot on a Phase I this early when it's still in dose escalation.

Yes. And this is Chet. I can -- this is Chet, the medical [monitor]. I can add on that small cell lung cancer patients in the spider plot persisted to have stabilization of disease for 3 months after last dose and then progressed. That patient was at 1 milligram per kilogram. To your point, that could have possibly been a deeper response at a higher dose. The nonsmall cell lung cancer patient did progress after having the 24% reduction. That was at a 2-milligram per kilogram dose. Yes, that possibly could have had a deeper response with a higher dose. And then the prostate cancer patient came off study actually without progression but came off -- withdrew consent and just -- there were some clinical things happening in the patient's ability to get to the clinic, so he came off the study.

That's very helpful. And then if I may follow up with one last question, and I'll jump back in the queue. Just on 013, perhaps the physicians could comment on this. The 27-year-old male with DLBCL progressed on prior CAR-T seem to do pretty well. There's still a lot of unmet need in the area of DLBCL. So I was wondering, one, is this data just sort of a fluke? Or is it something that perhaps warrants further exploration and potential development of 013 and its indication?

Jason, would you like to comment? And I think maybe Paul would follow-up comment about some of the histology and the staining of this patient. So Jason, first.

Yes, I'm sorry. I was cutting out a little bit on me real quick. Could you guys just repeat the question?

So Christopher was interested in the observation in the DLBCL patients. Given that there's still a need for improved therapy. Do you see that there's prospects for 13 in the lymphoma setting?

Yes. Sure. So I think the -- and in fact, I think this is really beautifully outlines the subpopulation of patients where -- one subpopulation of patients where this could be particularly helpful. So curative exhaustion of the CAR-T product has been identified as a potential resistance mechanism. Now to the extent to which in patient samples and patients, I should say, that, that's the dominant mechanism, it's not really totally clear, but some have suggested that could be upwards of a fourth or more patients who have progressed. And then beyond that, there is activity in lymphomas to PD-1 blockade. It's relatively less, but the interferon signal is there. So there are multiple mechanisms whereby the drug can be active in the post CAR-T setting. And MacroGenics can see to it further. But because of the -- both of those potential mechanisms I mentioned, they're actually not only exploring a post CAR-T, but also in the pre CAR-T spaces. So I definitely think so. And I think that as we learn more about CAR-T resistance and lymphoma biology as it relates to interferon signaling the PD-1 responsiveness, I think you'll see that there are multiple potential shots on goal here for where this can be a valuable add junk in lymphoma treatment.

Thank you, Jason. Paul, would you like to comment further?

Yes. For sure, DLBCL is really high in our radar. We know the LAG-3 levels are genuinely high in DLBCL. And in this particular patient, it was really high expression that we observed of LAG-3 in the DLBCL patient. And we're also got other patients that we've been treated with DLBCL, and we're seeing this trend of response with level of LAG-3. Obviously still early there. We're not ready to discuss that in too much detail, but we're encouraged with what we see there.

Thank you, Paul.

And our next question will come from the line of Evan Seigerman from Crédit Suisse.

So one of the things that was very striking to me was on Slide 18, looking at large plus MGD013. Can you comment as to how this could potentially set up to a registration path or thoughts on what the combination of MGD013 and marge would look like in a subsequent trial? And would that also inform how you would partner that out, marge out or keep it in-house? Then I have a follow-up on 018.

Thank you very much for the question, Evan. Obviously, number one, is we like to obviously follow the patients that we're currently treating and looking at the length of responsiveness. As noted, many of these patients have only been observed first scan. We are expanding this cohort again opens up to other HER2-positive tumors, but we're very encouraged given the broad histology that we're seeing is affected. And particularly, as you know, patients, for instance, with colorectal cancer that are unstable, and as they stable, are quite resistant to late-line therapies. We obviously also want to follow up regarding the signal that we believe is being induced in terms of LAG-3 and other checkpoint molecule ligand expression. And so in future studies beyond adding additional patients to the studies, we'd like to obtain additional biopsies post therapy to see the effects here. With regard to the clinical development plan, it will obviously be determined based on our follow-up results. We are thinking about 2 avenues for going towards registration, either a basket study defined by the conditions that we just described or looking at -- particularly in a chemo-free regimen, these late-line patients in combination for specific tumor types. As you know, we have a strong program in late-line breast cancer as well as in front-line gastric cancer. So this fits nicely into our strategy going forward.

Excellent. And then my follow-up on 018. I know you're doing the dose expansion in prostate cancer. Any thoughts on combinations and what could potentially be additive? I know the data we saw was really nice, but we probably want to see more. Do you think you could combine it with the PD-1 and get more efficacy or other potential immunomodulating assets or drugs that could enhance the efficacy of 018?

Yes. In fact, preclinical data actually shows that this is possible that you can have additive effect that using an ADC with a checkpoint blockade enhances antitumor responsiveness in preclinical studies. And in fact, our study -- currently, our Phase I study has an arm in which we can add at our anti-PD-1 retifanlimab that we have partnership with Incyte on to this protocol. So initially, what we plan to do is define the dose, expand initially into a late-line prostate cohort. We're thinking about a second tumor to pursue independently as monotherapy. And then we'll also hope to begin a combination study with retifanlimab.

Our next question will come from line of Debjit Chattopadhyay from H.C. Wainwright.

So firstly on prostate cancer. As -- if you look at through the biomarker landscape in the metastatic setting, how would you rate B7-H3? And could you contextualize B7-H3 expression versus PSMA post androgen deprivation therapy, especially in the bone?

Yes. So just from our experience, and I know Emmanuel, he's had experience as well working with us on an IST, and maybe you want to comment subsequently. But our experience has been very favorable in regard to overall appearance of B7-H3 in prostate tumors. We're seeing it both in newly diagnosed tumors as well as in metastatic tumors. We're seeing this in our experience at greater than 90% of the tumors of B7-H3 positive. With regard to the various expression levels, we see it sort of in the midrange. As was noted by John earlier, we were seeing H-scores below 100 to over 200. And so this is moderate to high. It's not the highest of all tumors. But so far, given the patients that were treated so far with that variable expression pattern and responsiveness, we don't see this to be a deterrent for the treatment regimen. Emmanuel, maybe you would like to comment on your experience using our other molecule or Fc-engineered molecule in the setting.

Yes. I mean my initial comment is that we should not be thinking of this as a molecularly-targeted therapy. We should be thinking of this as something that would be going into the [ outcome ] population. And the experience that we've had both in primary and [mets] is that more than 90% of the prostate cancers are going to express this, and they're going to express it at high levels. One thing that is very important to state is that at every disease stage, whether it's localized disease, whether it's metastatic hormone-sensitive or whether it's metastatic castration-resistant, the prevalence of B7-H3 expansion is way, way, way higher than the prevalence of PD-L1 expression or PD-L2. Of course, the other name for B7-H3 is PD-L3. It's not really called that anymore, but -- so the point that I wanted to make is, yes, it seems to be highly expressed in prostate cancer relative to other cancers. But more importantly, if you consider the other notorious immune checkpoints, prostate cancer does not really express those other ones. So PD-1 or PD-L1, you can pretty much forget about it, very, very low expression. LAG-3, probably on the lower side, although still probably higher than PD-1. And then B7-H3, very, very high. The other very fascinating thing about B7-H3 is that there's no better population to examine immune escape or [ support ] surveillance than if you look at the mismatch repair-deficient prostate cancers, and these rare. These are like 3% or 4% of all prostate cancers. But the problem with mismatch repair-deficient prostate cancers unlike mismatch repair-deficient colorectal or endometrial is that only like 30% to 40% of them respond to pembro or nivo, which is much, much lower. And so we asked the question, why are these tumors so immunosuppressed? And there's many theories about this. But when we did transcriptomic studies and RNA sequencing studies from bone metastases in MMR deficient prostate cancer patients, the highest expression of RNA and the highest quantified RNA-seq data is for B7-H3. So B7-H3 is the single highest transcript and RNA molecule and the bone mass of these patients who are MMR deficient microsatellite unstable and TMB high. So that tells me and convinces me that at least in prostate cancer, there's been a lot of debate about whether this is immunosuppressive or stimulatory molecule. The early work of the MD Anderson Group has suggested that it might actually be stimulating rather than suppressing, Jim Allison's work. I am much more convinced that in metastatic CRPC, it is immunosuppressive. And it's an acquired secondary immune escape mechanism, which, of course, can happen in all prostate cancers, but is exemplified very dramatically in the mismatch repair-deficient.

Great. That's very helpful. Can you also help us kind of put the greater than 50% PSA reductions in the context of bone-only disease? I believe there has been a lot of confusion on this, not so much from the medical community, obviously, but from our side. And what does that mean in terms of the durability of disease control and implications for patients with visceral disease as you expand to the 4 mg per kg cohort? And I have one more follow-up.

Well, I think in short, the PSA response is as they continue to be this prevalent are unprecedented. I mean if you -- 5 out of 7, I can't do the math in my head, but it's a high number. And all the -- other antibody-drug conjugates that we have used in prostate cancer have a 15% to 20% PSA response rate, PSA response being defined as a 50% reduction. Now you do have a good point, which is that whether or not you get a PSA reduction does not necessarily equate with the durability of the response. So there isn't really a one-to-one correlation between PSA response and progression-free survival, let's say, or overall survival, except in the context of hormone therapies where, in that case, there is a direct correlation, but those drugs directly decreased the transcription of the PSA gene itself. So that's not just the antitumor effect. But in the context of non-AR therapy, such as this one, a lack of a PSA response cannot be taken as lack of activity. But when you see a PSA response, it's always a good thing. There's never a bad outcome for a patient that you see a PSA response. So they always means that tumor cells are dying if you're using a non-AR targeting therapy. And so what I would say is it's early days. But if the trend continues to be 5 out of 7, and 10 out of 14 and 15 out of 21, I guess if we're continuing on that percentage rate, whether it's bone only or whether it's bone plus visceral, by the way, the majority are going to be bone only, that is a very intriguing signal of activity that I think any investors would probably be drilling over, I would if I was investing in it.

Very helpful. And just one last question. This one is on the LAG-3 program. So any thoughts on the LAG-3 expression in patients who are inherently resistant to anti-PD-1 or in patients who experience disease progression after a preliminary response? What I'm trying to get at is where do you see the PD-1 LAG-3 program fitting in as a monotherapy?

So Debjit, I think that we're going to be exploring this more looking at both naive anti-PD-1 as well as experienced anti-PD-1 population. There is some degree of association. Obviously, it will vary from tumor-to-tumor type and the microenvironment in terms of what that relationship is. As you saw, though, in the case when they are -- either one is low, we think that we have now tools to increase expression certainly of LAG-3 and probably PD-L1 as well so that a molecule such as MGD013 would be ideally suited for the setting. Paul, do you have any other comments on this?

Well, I'll say is that we are -- you noticed we're doing NanoString analysis, and we're looking -- we're trying to understand what the profile is of our patient responses and whether we're seeing responders that you wouldn't expect to respond to PD-1. And there's data out there to suggest that LAG-3 is a good handle on that, but we'll learn that as we go over the studies. So it's a little bit early to see it in our patients, but that's definitely something we're looking at.

And our next question will come from the line of Jonathan Miller from Evercore ISI.

Great. I guess I'd love to start with the 013. The monotherapy data doesn't seem to show a really strong dose response. So I was wondering how you were making your justification for a go forward...

Jonathan, you cut off. So I heard you with regard to how to select the dose. As was observed in the analysis for PK and receptor occupancy at the doses of 400 mg flat dose or higher, we're seeing full saturation. And we selected 600 Q2 as just as a [starting point]. As you know, in the combination study with the marge, we were giving it Q3. So going forward, we will look at alternative dosing strategies where we can give this drug even less frequently and appropriate with other combinations going forward. So we feel we have a very nice range based on occupancy and PK to use this in different settings.

Okay. That makes sense. Then I guess building off of that, in the margetuximab combo arm, I noticed that you were enrolling both 300 and 600 milligrams. The only 2 patients at 300, but of course, they're both responders. So I guess why not continue there if you still have activity at the lower dose? And what's the justification moving forward there?

Well, again, as -- whenever you start a combination study, just from a toxicity standpoint, you usually have to work your way in to get to the upper dose. Given that we haven't seen any increased toxicity, and as I noted before, the saturation level at -- was 100% at 400 and greater. I think the 600 is fine. But again, there are opportunities to explore other dosing regimens going forward.

Makes sense. Again, on the monotherapy stuff, looking at the ORRs and the expansion cohort, there's clearly some activity there. But a very important question I have is what's the PD-L1 status, especially in TNBC and nonsmall cell lung cancer where we know that has a huge impact on expected response rates from PD-1 monotherapy.

Well, Paul can address that because he's the one who helped to do the analysis. Those subsequent data that you saw on the slide were the results of analysis for PD-L1 and LAG-3 in those varying population. Paul, maybe you want to comment on that.

Yes. So that's what's shown on Slide 11. That is the PD-L1 levels that are in those patients. So as Jason pointed out, the levels are not very high in those patients. I mean we've actually got some negative patients, PD-L1 negative patients that we had response in. So we're continuing to monitor that through. And so we're doing the DAKO analysis. We describe how we do it in the footnote. And we're, of course, scoring the PD-L1 levels. But when some of those patients are quite low and we're seeing responses, particularly where we saw the low levels were in the HER2 patient cohorts, they were really -- the CPS were below 1 for most of those patients. But again, that is their motivation and with the activation with the Fc optimized to enhance the immune [ score ] there.

I should also point out with regard to B7-H3, there are lots of ways of improving PD-L1 negative expressing lung cancer patients where, as you recall, getting back to the Fc-engineering story, we -- enoblituzumab, which is our B7-H3, when combined with pembro in a study we pointed out about almost 2 years ago, we saw a phenomenal response rate in combination in this PD-L1 negative population between 35% to 40%. So again, there is a significant number of these lung patients that have low expresses, and I think we can address these in varying ways.

Yes. So then the follow-up then. The final question I've got there is on that marge combo. I mean you're just talking about those responders in PD-L1 minus patients. How many of those 4 responses in the PD-L1 negative patients that you saw were confirmed versus unconfirmed?

I don't know the answer. Maybe, Brad, could you remember what -- how does the breakout between confirmed and unconfirmed in that population?

Yes. So as you can see on the slide, of the 6 responders, there are 2 unconfirmed responses, one an unconfirmed complete response in cholangiocarcinoma and also an unconfirmed complete response in the microsatellite stable colorectal cancer. I believe off the top of my head, I think the cholangiocarcinoma responder is one that the analysis is to be determined at this point.

Okay. And both of those were PD-L1 negative?

So I think he was saying we haven't done the PD-L1 with cholangio.

That's correct. That's correct.

The cholangio is the one we didn't do yet. That's to be determined, TBD.

Our next question will come from the line of Peter Lawson from Barclays.

Just for the prostate patients or, I guess, for Dr. Powderly and Dr. Antonarakis, what kind of response rates would you expect from these heavily treated patients using standard of care? And then how does 018 rank in the sense of other clinical trials that could potentially put those prostate cancer patients on?

Emmanuel, do you want to start? And then, John, follow up if you have additional comments?

Sure. I'm happy to let John go first, too, because I didn't hear anybody on this.

So if you get -- yes, so this is John Powderly here. So I think the question was in typical prostate cancer care, patients who were hormone refractory and have gotten one line of the taxanes and maybe some of them had a second line of another cytotoxic. This is just -- there is no proven standard of the next line after that. So as the response rates, there really is nothing to -- off the top of my head that can quote. I would just say that response is very low. Usually those patients going to hospital or they go into a clinical trial. But in my experience, a heavily pretreated bone metastatic patients with PSAs in the hundreds or a thousand that have failed prior chemo and/or radioisotope generally don't have a very good prognosis, much less something that decreases a PSA greater than 50%. So that's just a general comment. So I hope that helps you. In this particular study, I actually treated more the visceral patients with solid tumors. I'm a solid tumor guy, not a prostate doc. But I can tell the B7-H3 parent compound, the enoblituzumab, I remember we presented data on this before we did have some patients that have a very prolonged stable disease with just the B7-H3 antibody, and they were prostate patients. So...

So John, when I look at the list of the 5 responding patients, one of them was receiving second line therapy, but 3 were receiving fourth line and 1 was receiving fifth line therapy. So by the time you get to third, fourth or fifth line, you've got very few options. You can take a second or a third taxane chemotherapy. We often use a drug called mitoxantrone in those patients, which was never FDA-approved because of a survival advantage, but it has some pain benefits. A third chemotherapy or fourth agent in that setting that without a PSA response rate of like 5% to 8%. So in drug development for prostate cancer in general, our bar for getting excited is seeing a 15% to 20% PSA response rate. If we see a PSA response rate of above [ 5% to 8% ], our eyes are basically like gauging out of our heads. And so again, it's very few patients because it's only 7 guys. But 5 out of 7, it wasn't like these were all 51% reductions. I mean it was a 99%. There was a 70-something percent. There was people's PSAs going from 1,000 to 90. These are not like cherry-picked PSA responses that just barely made it. These are all very convincing ones. Now the question that comes up, of course, or should come up is, how do you move this forward into Phase III? And what would your comparison arm be in the Phase III? And just to answer that shortly, you would have to go head-to-head against cabazitaxel is my personal opinion. cabazitaxel in a third-line setting, in other words, a person has received both docetaxel and one or more of the novel hormone therapies, will have a PSA response rate of about 20% to 25% and an objective response rate of about 12% to 15%. So that is sort of the [indiscernible] that you would have to beat if you're looking for a signal. You will not be able to use PSA response or objective response in the Phase III trial, but you could use that as a benchmark. And if you're way beating that, then you're probably going to win in a randomized Phase III that looks at PFS as an end point or PFS plus OS as co-primary end points.

Emmanuel, can I ask you a question head on? Could you actually cite the statistics in terms of overall survival in that late-line population as well that you're going to treat through cabazitaxel?

Yes. Overall survival would be like 8 to 12 months. The median would be like 10.5 to 11 months.

Thank you.

And progression-free survival will be like 3 to 4 months. So it's a very doable population to study, unfortunately, because their outcomes are so poor.

Thank you very much.

And then just kind of the second part, how does this rank in sense of other clinical trials that you could potentially put these patients on?

Yes. I mean, unfortunately, the PD-1 and PD-L1 inhibitors, at least as monotherapies, have been robust in prostate cancer. We're never going to have a PD-1 monotherapy FDA approval. So that has gone out the window. For patients that have a homologous recombination deficiency, PARP inhibitors are very attractive and would be expected to have activity even in the third, fourth, fifth line. So a BRCA 2 patient would clearly probably not get this before they had a PARP inhibitor first. But other than those 2 sort of hot drugs across all of oncology, there isn't really much else. Now there's one thing that's specific to prostate cancer, which are these PSMA-targeting radioligand therapies like lutetium PSMA. So these are either beta particle or alpha particle emitters that are liganded to the PSMA molecule, which is a prostate-specific membrane antigen expressed on the surface of 85%, I would say, to 90% of metastatic CRPC. So there's an ongoing Phase III trial that some people expect to be positive. I have no inside information. I have not personally been that impressed with lutetium PSMA. You do see PSA responses somewhere in the 30% to 40% range and objective response is somewhere in the 15% to 20% range. So the drug clearly has activity, not breathtaking. The activity is not long-lasting. In other words, you don't get immunogenic cell death. You just get radiotherapeutic apoptotic cell death. I'm not sure about abscopal effects. So the competition is not that vast. Lutetium PSMA might be sort of the best kind of comparator if you had to choose one.

Great. And just one follow-up. Did you say some of these patients had homologous or combinations?

I don't believe in this study that was checked. But 25% of all metastatic prostate cancer will have homologous recombination deficiency. Those patients would probably be prioritized for a PARP inhibitor before they got this.

Our next question will come from the line of Jonathan Chang from SVB Leerink.

This is David Ruch on for Jonathan. Given the time, I'll just ask one. For MGD013, I was wondering if you could comment on the activity of 013 in head and neck cancer. It looks like today, there have been some promising data of a soluble LAG-3 in combination with KEYTRUDA in head and neck. And I was wondering if you could just speak to the [ end of therapy here]. Any plans to pursue that patient population further?

Yes. So David, we have seen activity as monotherapy. As you know, we are initiating a study later this year of enoblituzumab in combination with the 013 as 1 arm, comparing it to the retifanlimab, the anti-PD-1 because we like to take the best combination going forward in front-line metastatic head and neck cancer. So stay tuned for that.

Our next question will come from the line of Stephen Willey from Stifel.

Yes. I guess maybe for Dr. Luke with respect to the 013 trial. Can you maybe just comment on the prior treatment history of those patients that are extracting meaningful clinical benefit in the margetuximab expansion cohort? And I guess specifically for the nongastric, nonbreast patients, was this their first line of HER2-targeted therapy?

Brad, do you want to comment on that? Yes.

It might be better if Brad can comment on that if he hasn't. The numbers are terribly small, so it's going to be exploratory anyway.

Sure. So yes, thank you for the question. So amongst the 14 responsive valuable patients that are presented on Slide 18, 8 of the patients have received prior anti-HER2 therapy, including all the breast cancer patients, the GEJ carcinoma patient and one of the cholangiocarcinoma patients. The other 6, they're essentially HER2 therapy naive prior to enrollment on the trial.

Okay. That's helpful. And then do you know offhand if the responding cholangio patient had seen prior HER2 or if it was the patient who progressed?

Brad?

Yes. So the patient who responded has seen prior HER2.

Okay. And then just with respect to 018, is there any interest in trying to maybe enroll more patients that have RECIST evaluable lesions so that you can, I guess, maybe just get a better understanding beyond PSA reductions with respect to clinical benefit?

You talking about patients with prostate cancer?

Yes. Correct, [indiscernible].

Yes. Yes, yes, of course. I mean these were -- if John Powderly can accommodate us with the proper patients, we're all for it.

Okay. And then maybe just lastly for Dr. Powderly. Is there any reason to believe why a DNA alkylating payload would be a better cytotoxic to deliver via B7-H3 targeting versus something, say, like a topoisomerase inhibitor?

John, do you want to...

Yes. Just a quick follow-up comment to your last question. We've done over 100 Phase I studies, and I can -- and they're all immunotherapy over 15 years. And I can tell you maybe only a handful of studies have dedicated prostate slots for bone-only. It's like a whole different genre of the prostate cancer working group, non-RECIST but evaluable. So in the solid tumor Phase I immunotherapy world that I live in, it's a delight to see something respond for prostate and even though it's bone only and non-RECIST evaluable. So I'm hoping this is the beginning of some other momentum where we can enroll, finally start enrolling more prostate patients into immunotherapy or drug conjugate studies. So it's a pleasure. So we advocate for more studies that will allow bone-only. And we don't see them very often, so this is great that there may be momentum in that direction. The other comment about the drug -- the toxin, I just don't know the answer to that. I just don't know. I know that the antibody side and the targets with the checkpoints, but no, I can't comment on the toxin.

So let me comment on it and maybe, Paul, you can follow up if you have additional comments. There was a study done at NCI up in Frederick in an animal model study, and what they had observed with a cytotoxic agent, it was better effects using an ADC, conjugate, the B7-H3 antibody as opposed to an antibody alone. And the reason we believe that this is working more effectively and probably more effectively than a topoisomerase inhibitor is that you're hitting also the vasculature, the endothelial cells, which have high expression of B7-H3, which are not actively dividing. So we do believe that, that as a component here that probably the topos won't be able to address. Paul, do you have any additional comment?

I think that's a good response.

And our next question will come from the line of Etzer Darout from Guggenheim Securities.

Just wanted to talk a little bit about lymphoma data and if you had the opportunity to profile additional patients for LAG-3 PD-L1 and also next steps maybe for DLBCL given that you previously mentioned prioritizing the combination of PD-1 LAG-3 with margetuximab and maybe where DLBCL could potentially fit in the sort of the bispecific next steps.

So we'll let Paul Moore respond with regard to expression of LAG-3. And then, Brad, do you want to follow up where we are on that?

Yes. I mean I think in the earlier response, that one patient, we saw the dramatic response, and we had very high LAG-3 levels. And we've also been analyzing other patients that we've been studying and looking at. And we also see a high level in a patient that had -- it looks like it's having a response. So we'll continue to monitor that. And what we do know is that DLBCL is, if you just scan patients outside the clinical trial, DLBCL is one that has a very high level of LAG-3 and we've confirmed that with some collaborators, and there's been publications on that.

Brad, maybe comment on the trial.

Yes. Yes. So let me add on to Paul's statement. We're very excited about the prospects for DLBCL with MGD013. The data to date is somewhat immature, but we're continuing to enroll more patients in both slots dedicated to the post CAR-T setting and also the CAR-T naive to better be able to dissect the underlying biology there.

And our next question will be from the line Yigal Nochomovitz from Citigroup.

This is Samantha on for Yigal. Just on the MGD013 and margetuximab cohort, it's interesting you have responders in the PD-L1 and LAG-3 negative. I noticed you gave the data for the responders. But was the baseline for the nonresponders similar to what you saw? And is there [indiscernible] could maybe select the patients that are most likely to respond?

Yes. Regarding the PD-L1, most of the patients that we see -- that we saw with the HER2-positive were PD-L1 low in this cohort of patients that we observed. So that was the observation. We did see a little bit more variation in the LAG-3 expression amongst the patients. So a little bit higher LAG-3. But for the most part, the patients we've analyzed and had a chance to analyze so far were PD-L1 negative.

Got it. That's helpful. And then on the B7-H3 program, maybe one for Dr. Powderly. Is there anything specific about prostate cancer biology that would make it particularly amenable to B7-H3 targeted therapy versus other cancer types, especially given B7-H3 being so widely expressive in cancers? Or is there potential something about the duocarmycin payload that is active in prostate cancer? Just curious on your thoughts there.

My first comment is we typically tell patients that the hormone positive tumors like prostate and breast are relatively stubborn with all immunotherapies, at least the singlets. So I'm pleasantly surprised, we're seeing some data with this ADC. But I don't know if what I would -- how much I would weigh, what percent is from the toxin versus the B7-H3. I just don't know. I think that the former comment by one of the biomarker specialists or the biologists at MacroGenics was that it may be that there's just no other checkpoints in a lot of the prostate cancers. I mean you typically don't see the PD-1s or the PD-L1s or maybe a little bit of lag, but it's just maybe that the B7-H3 is the one that might be important. So that's just my only crunch. I do think the toxin matters significantly because we do have the enoblituzumab, the B7-H3 naked antibody by itself. There is data about that. I don't know how much prostate data there is, but there is data out there that this drug, to me, I think, looks a little more active, but it's not a direct comparison.

So John, this is Emmanuel. I agree that the toxin matters. There was a recent buzz around another ADC, which targets a different protein called STEAP1, S-T-E-A-P-1 which is published in JCO by Dr. Danila from Memorial. And in that one, which is also expressed in about 85% to 90% of prostate cancers, they use MMAE. And they saw an 18% PSA response rate, 8% objective response rate. The people got pretty excited about that, which I wouldn't have. But there's definitely something about the payload that I think is increasing the cytotoxicity, but it can't be just that. I mean if you're getting PSA responses above 50%, even docetaxel would not do that in the docetaxel-naive patient. So there's got to be immunogenic cell death component as well that's linked to the B7-H3 itself.

Yes. Good point. Maybe we should chase it with some PD-1. At least it will get the immune cells that are in the environment that are tolerant. So I'm sure MacroGenics is listening. So...

Yes. [ It's a protocol. ]

And I'm not showing any further questions at this time.

Thank you all for joining us this afternoon. We look forward to discussing future progress. Have a nice evening.

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