Lecture Presentation:

Phillip Koo: Hi, this is Phillip Koo from Banner MD Anderson Cancer Center in Phoenix, Arizona. Very fortunate to have with us today Dr. Michael Hofman, who's the Director of the Prostate Theranostics and Imaging Centre of Excellence at the Peter MacCallum Cancer Center. And he's going to be speaking to us today, as another part of our series on precision medicine, PSMA targeted therapies and progressive metastatic prostate cancer educational forum. And we've already referred to several Dr. Hofman's studies in some of our other modules, so it's very fortunate to have him live and in-person to speak to us about this very exciting topic.

So thank you, Dr. Hofman, for joining us.

Michael Hofman: Thank you, Phil. It's a pleasure to be with you and to present my perspective on PSMA targeted therapies in metastatic prostate cancer, an area that we've been actively engaged in research for probably the last five years. This has been the focus of our research and it's a really exciting area. So I'm pleased to present some of our data with you and where this field is going. So prostate-specific membrane antigen or PSMA is a cell surface glycoprotein that is overexpressed in prostate cancer, in the order of 1000 to 10,000 fold times compared to normal prostate tissue.

And this is not a glycoprotein that's really expressed on other tumors. Its exact function in prostate cancer is not really well elucidated. It is a [inaudible 00:01:43] hydrolyzed receptor. It's not a new target. We've been trying in nuclear medicine to target this at receptor for some time, some of the older people listening to this will be aware of ProstaScint®, a radiolabeled antibody, bound to indium-111 which was used for imaging, and it wasn't particularly good. And there has been a game-changer that has occurred around five years ago with the use of small molecules, rather than antibodies that bind with really high affinity to the extracellular domain of the PSMA.

And the lead compound here was gallium PSMA-11 used for imaging, and this produced really striking images. There's now a library of PSMA PIP at radio traces available. And it's fair to say that all these small molecules perform really extremely well. And there's been an exponential growth in research in this domain. This is a graph of any PubMed abstracts containing PSMA in the title or the body of the abstracts and it's not a cumulative graph, and it's really rising very sharply, and I'm going to focus on therapy for the rest of the talk, but I thought I'd just touch on its use as a diagnostic imaging agent because our group had led a 10 site Australian multicenter randomized trial in men with newly diagnosed prostate cancer.

And we compared gallium-68 PET/CT compared to the combined findings of a CT bone scan. And the results were published earlier in 2020 in The Lancet. And we demonstrated an accuracy of 92% for PSMA PET/CT compared to 65% for CT bone scans, so we're really picking up a lot more small tumors, particularly subcentimeter tumors. And that consequently had a greater treatment impact. There were fewer uncertain or equivocal findings with PSMA PET. Interestingly, it also has lower radiation exposure than a CT in a bone scan, had high reporter agreement. And these small molecules, when used as a diagnostic tracer, have no adverse effects.

We're going to switch checks and talk about theranostics. So theranostics is a field of nuclear medicine where we're using a targeted therapeutic combined with a diagnostic companion. So in this image on the right, we can see a man with widespread bone metastases imaged with gallium PSMA-11, and he also has adrenal and pulmonary metastases, and there's very high uptake of the radiotracer at all sites of disease. And then that's very good for [inaudible 00:04:24] concept is we can take the same molecule, or at least a very similar molecule, here we're using PSMA-617, which is a slight variant on PSMA-11 optimized for therapy. And we just change the type of radioactivity. So we're changing from a positron emitter, a radioactive substance that passes out of the body, that produces the scans on our PET scanner, to lutetium-177, which is a beta emitter, which delivers really high doses of radiation to sites of tumors.

So in nuclear medicine, we've got three types of radioactive substances we can use for therapy, beta emitters, Auger electrons, and alpha emitters and it's fair to say that the most commonly used are beta emitters. For example, I-131 for thyroid cancer or I-131 for other purposes. And this is also not a new concept in prostate cancer because we have been using theranostics for a long time, primarily for targeting bone for osteoblastic lesions, because bone tends to be the site of osseous metastases and strontium-89, or samarium-153-EDTMP, or more recently radium-223.

And I think the world is changing towards tumor-targeting theranostics rather than bone-seeking theranostics. And here we're using lutetium bound to PSMA-617, and here are the characteristics of lutetium. It has a 6.7 day half-life. And it travels around at one millimeter with an average penetration of actually only 0.3 millimeters. That means we get very high doses to tumors, with really very low doses to surrounding at normal tissues. And this was the article that really got me very interested in this area, data from the University of Heidelberg, a compassionate access use of lutetium PSMA-617 in a man who had progressed after standard therapies. And after two cycles of therapy, there was a complete response on PSMA-PET.

We commenced in 2015 a Phase II single-arm study in our center at Peter MacCallum in Melbourne. And we took men who had progressed after conventional therapies. So in this 30 patient study that was subsequently expanded to 50 patients, 84% of men had progressed after docetaxel. 92% had had abiraterone and/or enzalutamide and half the population had progressed after cabazitaxel. So really a patient population without many treatment options available. And what we showed was a PSA decline over 50%, in 64% of these men, which is really quite remarkable when you compare it to the treatment activity of other treatment options available, in this setting. And we produced this striking image of the eight best responders in this series. And these are the PSMA- PET/CT before and after therapy. And it also just highlights how beautiful these PSMA-PETs are, to both visualize the extent of tumor and also to be able to visualize a response to treatments. But it's fair to say that in this 50 patient cohort of men who had progressed after standard therapies, despite these exceptional responses in some men, all these men eventually progressed and indeed 44 out of the 50 men in this trial have died. And this was the overall survival in this cohort, 13.3 months. And you can see if you did achieve a PSA response over 50% your survival was 18 months compared to around nine months in those men who didn't achieve that PSA response.

One of the nice things about theranostics is that we can see what we treat. So we can put men on a nuclear medicine gamma camera after our treatment, and this enables us to quantify the radiation dose both to normal tissues, and to tumors, this is something that you don't necessarily need to do in routine clinical practice, but it's particularly useful as we're developing these compounds.

And in the 30 patient Lancet cohort, all the men underwent imaging at 4, 24, 96 hours, and using some computation algorithms, we're able to produce these dose maps, where we can see the dose to tumor. So we can appreciate in this man, the adrenal metastases are lighting up in red. That means they received over 50 gray, and anything in the gray scale received 15 gray or less and we can see the off-target organs, the salivary glands, and the kidneys really received very low doses. And there's hardly any background uptake, almost all the radiation is going to tumor, which is what we want.

So, after our Phase II, single-arm study together with the ANZUP Cancer Trials Group, with funding from the Prostate Cancer Foundation of Australia, and Movember and some industry support from Endocyte and also ANZUP providing lutetium-177. We put together this Australian randomized trial, called the TheraP trial comparing  lutetium-177-617, PSMA-617 and cabazitaxel in a randomized trial, men with metastatic castration-resistant prostate cancer, who had progressed after docetaxel were eligible for this trial. All men underwent both PSMA and FDG PET/CT, and were then randomized to six cycles of lutetium PSMA or cabazitaxel at the doses scheduled that as you can see on this slide.

This was a 200 patient study in 11 sites around Australia, and the primary endpoint being PSA response and secondary endpoints as listed here. And we recently presented the first results of this trial at the ASCO 2020 Meeting in virtual format. And before I show you the results, I'll just highlight that we did carefully select men for this trial, on the left we can see a patient with widespread bony metastases, but relatively low PSMA expression at all sites, but high FDG uptake. FDG is a tracer, that image has sugar metabolism and it shows us perhaps sites that are more aggressive. And the intensity of PSMA uptake here was insufficient to meet our criteria for treatment.

And in the second patient, we can see a man who has high PSMA expression at some sites, but then other sites, particularly in the liver here, there is FDG positive PSMA negative disease that we call discordant sites. So only half the diseases are targetable and this man again, ineligible. And so when using PSMA FDG for selection, and this was a central selection through an imaging review panel around 28% of men were deemed ineligible. So we randomized 200 men, some of these men did have widely FDG avid disease, but all sites were PSMA avid and some men have PSMA positive, FDG negative disease.

This is the primary endpoint of their PSA response over 50%. So this occurred in 66% of men randomized to lutetium PSMA compared to 37% of men randomized to cabazitaxel. So at 29%, absolute greater PSA 50 response rate in those who were randomized to lutetium PSMA, really quite a big difference between these two arms. And we're pretty hopeful that these will translate into downstream benefits. At the time of this presentation, we did report PSA progression-free survival, which also favored lutetium PSMA with a hazard ratio of 0.69. And we really await for the follow-up of this cohort to define other endpoints including overall survival and quality of life.

And we were able to compare obviously adverse events between the two arms, and in terms of G34 adverse events that occurred in those men who received cabazitaxel, that occurred in 54% of men. This was not necessarily attributable to drug, just any grade 3 to 4 adverse events that occurred. And compared to 35% of those who received lutetium PSMA. So that tells us that there are less severe adverse effects with lutetium PSMA, despite those higher response rates that we saw. And only one man in this trial who received lutetium PSMA discontinued treatment early because of toxicity.

And here, we can also see the main toxicities of lutetium PSMA, it really is an extremely well-tolerated treatment. There were no episodes of febrile neutropenia, the main hematotoxicity is thrombocytopenia and we saw due to three to four, thrombocytopenia in 11% of men. And in some men, this was actually attributable to progressive marrow disease rather than necessarily drug. And the main lower grade side effects grade 1 or grade2 are dry mouth or dry eyes that's attributable to off-target the radiation of the salivary glands and the lacrimal glands. But most men received this therapy and really, it doesn't cause them many side effects at all.

There's a second trial, the VISION trial. This is an industry lead trial run by Endocyte, now owned by Novartis, a very large 850 patient trial randomizing men who had progressed in a similar population after taxane-based therapy to either lutetium six cycles or best supportive best standard of care in a two-to-one randomized design. The primary endpoint of this study being overall survival. And this study has also finished recruitment and we really eagerly await the results of this trial. I think the VISION trial, which is a much larger trial, designed with FDA registration in mind, will really complement our Australian TheraP trial, which compares it to cabazitaxel and has slightly different endpoints.

I'd just like to highlight that, as this TheraP program has evolved in our center, we work very, very closely with our uro-oncology colleagues. So we have nuclear medicine who administers the lutetium therapy and assesses these patients, perhaps the suitability at working really closely with radiation oncologists and urologists. And this is some footage from our multidisciplinary team meetings that you can see, we've got this lovely display where we can look at anatomic imaging, histopathology and our nuclear medicine imaging combined with the patient's history. And this is very valuable. So, I would encourage centers that are perhaps thinking of commencing this therapy, to really get engaged in a tumor board or multidisciplinary team to optimize the selection and application of this therapy.

And so these are some take-home messages. Radiolabeled small molecules enable both imaging and therapy of prostate cancer. Lutetium PSMA certainly has striking efficacy in some men, who have progressed after standard therapies. TheraP randomized study demonstrated higher response rates and lower adverse events compared to cabazitaxel. We're awaiting further follow-up of the therapy cohort and critically the results of the Phase III VISION trial, to really define where this therapy sits in the management of prostate cancer. But I'm really hopeful that this is a new, highly effective therapy that hopefully in the not too distant future will become widely available globally. So, thank you very much.

Faculty Discussion: 

Phillip Koo: Thank you very much Dr. Hofman for that wonderful presentation on the therapeutic applications of these PSMA targeted therapies. First off, I just wanted to thank you so much for being a real pioneer when it comes to nuclear medicine physicians participating in clinical trials, and you've brought a real higher level of trial design and implementation on the diagnostic side and the therapeutic side as well. And proPSMA I think is a wonderful trial and all the other trials that you run including the therapeutic interventional trials that really represented our specialty so well.

And I couldn't agree with you more when we talk about the multidisciplinary programs and those teams. And I think we would all agree in today's day and age, a multidisciplinary program is more than just the radiation oncologists, [inaudible 00:16:20], or medical oncologists that can really ... The nuclear medicine, radiology, pathology are really core parts of that team, and patients benefit from that type of a relationship. So thank you. So first off I wanted to turn it over to Alicia for her comments and questions. But before I do that, I wanted to ask you, Alicia, often times when you're introducing a new type of therapy, this is whether we call it theranostics, radioligand therapies, it's a new class of drug, a new type of therapy.

There's always some resistance. From the medical oncologist perspective, do you see or anticipate any resistance or barriers to acceptance in the medical oncology community?

Alicia Morgans: I think that's a great question, Phil, and it gets to who's experiencing the resistance. Is the patient resisting? Is the clinician resisting? Are there other factors in the system that are resisting? Because it's really challenging to coordinate around delivering a therapy? So, I'll address each one. From a systems perspective, I think it can sometimes be a challenge if we have not already established those multidisciplinary pathways of coordinating between, either medical oncology or urology and either nuclear medicine, radiation oncology, depending on who gives these treatments.

I think that the reason that I'm actually hopeful that this will be a lesser challenge in our field is that we have had experience with radium using a drug that we know has a survival advantage, that is a radiopharmaceutical and had us over the last number of years, really solidify those pathways and ensure that people like you and Dr. Hofman are actually incorporated into our tumor boards even so, and radiation oncologists certainly as well. So, I think that will be a lesser barrier. For clinicians, there can be troubles in terms of understanding where do I best fit this therapy? How do I best manage the side effect profile?

And I think the data has shown from Dr. Hofman's presentations and others, that the side effects are actually relatively low, and that they should not, as far as we know at this time, be longstanding complications that will imminently change the quality of life for patients who end up using these treatments. So I do think that those are going to be manageable, and I think from a clinician's perspective, that will not be the biggest barrier. There are definitely questions about where to put lutetium, and I think that will be directed by our approvals to help us make those decisions, and as we see more and more trials come out, I'm sure that we will try to move this drug if we find it effective in most of advanced patients in a randomized Phase III like the one we're waiting for the VISION trial. I'm certain that we'll try to move it forward and thankfully Dr. Hofman and his team and others, are designing trials that will hopefully answer those questions.

Finally, we have to think about the patients. What are the barriers that they have? When patients use drugs like sipuleucel-T, there can be barriers in terms of getting to the Red Cross or getting to other facilities to try to coordinate, to make these things happen. These are certainly barriers that can be overcome, but these are things patients think about. When they think about chemotherapy, they can think about their experiences with other family members or their own impressions of what chemotherapy may be like, right or wrong, those can be barriers the patients need to work through and to talk with their clinicians about.

When it comes to lutetium, what I find most striking is that I don't meet a patient who seems to experience these types of barriers. Patients are so eager to think about this targeted therapy that again seems to be relatively well tolerated, that they nearly were breaking down our doors for the VISION trial. I'm sure Neal felt a similar pressure to try to get as many patients as possible under this study because, at least in Chicago, we had no other access. And by the time we got to the end, we had patients who were screening or were waiting to get on the screening list, who never ultimately were able to enroll because the trial enrolled so quickly.

So I think from a patient perspective, we won't see that barrier. And I'm hopeful for their sake, that we as a community of physicians and assistants can organize ourselves to effectively and properly deliver this therapy if it is approved as soon as possible.

One of these questions, actually, I posed to Dr. Morris earlier and to Dr. Tagawa thinking about how PSMA expression can change over the course of prostate cancer and how our different therapies can affect the expression at least in cell lines of this protein, that's really the target for this drug. And as we think about moving lutetium earlier and earlier in the disease, even into an adjuvant setting where we don't have PSMA evidence of measurable disease on a scan, what are your thoughts about potential challenges or limitations or are there none? Is this something that we should be able to do without a hitch?

Michael Hofman: Yeah, that's a great question, Alicia. I think as a new class of therapy, the best place to test it to start with is in men who have progressed after standard therapies, which is really what the VISION trial has done and the TheraP trial. And if both those trials are positive, I think we will have a new radiopharmaceutical that at least sits in that place, post docetaxel, post enzalutamide, or abiraterone quite firmly, probably prior to two cabazitaxel and given the at-large or that really high activity we see, we'd like to move it earlier. And we know because we scan patients with newly diagnosed prostate cancer and biochemical recurrence or early castration-resistant disease that we see high PSMA uptake on those PET scans, just like we do in the really advanced group.

If anything, sometimes the PSMA expression is even less heterogeneous early on, meaning that we don't get those signs of PSMA negative disease as commonly early on. So it may even be better placed early on. So I think it will be a step wise progression to do the clinical trials, to bring this treatment earlier and earlier and see what the results are. And I think the limitation that we see in the trials we've done to date is sometimes around durability of treatment, so very effective treatment, but when we stop the treatment, it may progress. So if we bring it earlier, is that going to be a big problem or will we see longer durations of response in more sensitive disease? 

Certainly from a radiobiological perspective, I think tumors that have not had as many lines of therapies may be more radiosensitive. So we may see better results. In our center, we have some phase I/II trials open, bringing the treatment all the way back to a small series, where we're giving a cycle or two of lutetium in men prior to prostatectomy, and then they're proceeding to have their prostate out. And we're seeing what the changes in these tumors will be. And we've just opened a 10 site Australian trial called the UpFrontPSMA trial, where men with newly diagnosed high volume castration sensitive disease will have two cycles of lutetium followed by docetaxel, randomized to docetaxel alone and after FDA approval occurs, there'll be a myriad of trials opening in this space.

So it will be an exciting area in the next five years with lots of new data coming out, but I'm quite hopeful that we will get even better results if it's used early on. We just need to be mindful of the toxicities of radiation. People will know from external beam radiation that the toxicities are often delayed. They can occur years down the track, unlike perhaps a drug where you'll see the side effect immediately. So we do need to be mindful of that. We don't see much toxicity in this end-stage group that has to some extent a limited life expectancy, but if we bring it back really early in men that are going to be alive for 10, 20 years, then we need to be very careful about how we study these.

Phillip Koo: Great. Thank you. So Neal, before I let you ask some questions, I wanted to get your thoughts, as someone who's had an impact on prostate cancer, the whole disease spectrum, how do you imagine this is going to fit into the practice of a urologist or urologic oncologist?

Neal Shore: So I loved the first time I really got to listen to Michael speak at APCCC last summer, which seems like an eternity ago, and really saw right away and not only his passion but the data and the relevance for using these newer technologies, PSMA PET specifically. There's no doubt that this is where we're entering into this hackney use of the word game-changer, but it clearly is a game-changer, both from a diagnostic standpoint for urologists, as well as for therapeutic. But I wanted to just ask Michael because he's had the luxury of having PSMA PET for several years for quite a long time.

And as he knows in the US, we've been way behind in terms of getting it approved, we only have about seven or eight centers in the entire country that have had access to PSMA PET. So, a question that we asked earlier, I asked it to one of the earlier sessions is, will PSMA PET essentially negate the use of conventional imaging? And if yes, or partially in Australia, is there a role anymore for doing conventional CT scan or technetium bone scan?

Michael Hofman: Yeah, that's a great question, Neal. I think it depends on the setting in a man with newly diagnosed high-risk prostate cancer. I think in Australia now men would receive a PSMA PET instead of a CT bone scan, even though it's not funded yet, if the hospital will pay for it on a local level, or patients will pay for it out of pocket, then many men will just have a PSMA PET and urologists are no longer doing a CT or a bone scan in that setting. And the proPSMA trial really provides quite compelling evidence that that's a better standard of care for our patients and probably the same in the biochemical recurrent setting, or the early castration resistance setting PSMA PET is replacing CT and bone scan.

In this group of men with more advanced metastatic disease, we definitely see 30% of patients that have low PSMA expression. So if you're going to rely on a PSMA PET alone, it may be misleading in those 30% of men that have lost PSMA expression as the disease becomes more aggressive or as disease heterogeneity evolves. And so I think a PSMA PET alone in these men with very advanced tumors is actually insufficient. And you can complement that with FDG, which is what we do, but that's quite luxurious to be able to afford both a PSMA and an FDG PET. I think that's probably perhaps the best standard of care, but it does need some more study.

And from a clinical trial perspective, if we think about Prostate Cancer Working Group with CT bone scans being performed every three months, that's been really well validated. And we certainly still incorporate that into all our clinical trials, whereas how to interpret PSMA PET in that setting is a little bit gray. I know we still struggle with that, and there is no consensus to find response criteria and so more work needs to be done in that space. But I think we'll see an evolution towards PSMA PET being a core part, even in that metastatic group.

Neal Shore: I wanted to delve a little bit into this discordant issue of FDG PET versus PSMA PET as you know and I want to also echo Alicia's comment about the VISION study. Boy, patients just were so enthusiastic about enrolling in that study and it accrued so quickly in the US and we knew that sites were so competitive because we had a pent up demand. Patients were really in need of another line of therapy. But having said that, as you know Michael, in that study, there was no FDG PET. There was a baseline PSMA PET. There were no follow-up PSMA PET.

And as your data is showing in TheraP, if we just think about from what I've been reading and hearing that the PSMA PET affinity is about 85%, when you combine your algorithm, it maybe drops down, you lose another 15% of patients down to about 70%. So what are your thoughts regarding CT scan looking at lymph nodes or up to a one centimeter side or pulmonary lesions of two centimeters, is that a fair assessment, do you think? Or do you feel that we need to do more with the FDG PET because to your point, that becomes a sort of a bit of a financial toxicity and accessibility for both of those scans.

Michael Hofman: Yes. So I think if you look at scans very carefully, so in my talk, I had a patient with liver metastasis, that were FDG positive PSMA negative. Now in that man, you don't necessarily need the FDG PET. If you do a contrast-enhanced CT, you will see progressive liver lesions with low PSMA uptake. And you can define that man as having significant disease with low PSMA uptake and perhaps not ideal for lutetium PSMA therapy. And the same is true for nodal disease and other visceral diseases such as lung. Where the CT falls down is for bony metastases. If they have discordance, so FDG positive PSMA, negative lesions in bone, they're usually missed, they're often not lytic. They're just invisible on the CT scan. If you were to do a whole-body MRI, you would see them but on a CT, they would be invisible. And probably this needs some further study. But in my experience, probably around half of our patients with so-called discordant disease within bone. So you will miss those if you don't do the FDG PET, but you'll certainly still do well. If you look closely at your CT scan and your PSMA PET.

Now, PSMA PET, the technique differs from center to center. If you don't perform it with intravenous contrast for the CT component, you may not see those liver metastases. So you need to have a high-quality CT in addition to the PSMA PET component if you are not doing an FDG PET. But I always come back to the fact that these scans are relatively inexpensive compared to the treatments that follow. None of the treatments we use in advanced castration metastatic disease are cheap. And to put a patient on a course of treatment where they're not going to benefit, I think it is better to get the correct answer upfront and to where a small additional cost to do more advanced diagnostics to begin with, get the most information to make the best-informed decision. That would be my preference. I think the financial toxicity argument falls apart when you take into account the cost of the treatment, in fact. So I would encourage referrers to evaluate patients properly and you get ease, but it does require experience that you get a complex set of images when you perform both the PSMA and an FDG PET. So we need our nuclear medicine specialists and radiologists to perhaps up-skill in how to look at these complex image data sets, put all the information together so that you as the referer know what to do with this. So there's certainly a lot of education to do on the imaging side as well.

Phillip Koo: Great. So the last question I have is you and several other groups, the UCSF, UCLA have published data about the change in management after getting a PSMA diagnostic test. I guess the biggest question following that is, do those management changes lead to an improvement in outcomes? So it seems like you're using a lot of this in your own multidisciplinary teams currently. How do you work through those questions that come up where oftentimes there aren't very good answers?

Michael Hofman: Yes. I guess the question is moving a little bit away from PSMA theranostics towards the use of PSMA PET in the earlier stages of prostate cancer, where you may be wanting to do a prostatectomy or radiation or very early on, and you see a metastasis in [inaudible 00:34:29] invisible on conventional imaging, should that change your management? And we certainly show that it does. And I think if you look at the proPSMA trial, the management impact is significant, and your point is valid, that it's very difficult to show that those changes in management improved downstream outcomes. But I think it's important to bear in mind that those studies are really very, very difficult to do.

The point of doing a scan is to get the most accurate information to inform a logical choice in the next treatment strategy. So if you have got a man with Gleason 10 prostate cancer and your CT bone scan's normal, but your PSMA PET scans shows 30 bone metastases, I think it's pretty clear that that patient does not need a prostatectomy and that that management change is appropriate. And then you can do the same thought experiment, but say in the PSMA PET shows a single bone metastasis, what should you do in that man? So you do get some gray areas and it results in lively discussion in our tumor board meetings.

And I think experience and some further studies will sort that out, but we need to bear in mind that there always will be some gray areas in medicine, but I think it's best for the patient. If the clinician, whether it's a urologist, medical oncologist, radiation oncologist is making a decision based on the most accurate data. And that's the most accurate staging, rather than the uncertainty of really treating blindly or not knowing what's going on. I think it stands to reason that more accurate staging will lead to more informed decisions that will improve outcomes.

Phillip Koo: I completely agree. Thank you so much. We really appreciate the time and just sharing all your knowledge and data with us, and we hope to speak with you again soon. Thank you.

Alicia Morgans: Thank you.

Michael Hofman: Thank you so much. Pleasure.