Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here today with Professor Louise Emmett, who is joining me from the University of New South Wales in Sydney, and also recently from the APCCC in Lugano, Switzerland, where she gave a wonderful talk to help us understand how we think through radiopharmaceuticals, especially in times when we may have a patient who is more frail or has some complications that we need to try extra hard to avoid.

Thank you so much for being here with me today, Professor Emmett.

Louise Emmett: Oh, such a pleasure. Thanks for asking me.

Alicia Morgans: Wonderful. So, Louise, I'd love for you to give us a brief overview of your talk and then I'll ask some questions when you're through.

Louise Emmett: Thanks so much for asking me to talk today. I'm going to talk about dosing of radioligand therapy in special situations and/or toxicity, focusing really on high-volume disease and, in terms of toxicity, looking at marrow toxicity and kidney toxicity.

In the prospective trials that we've done with Lutetium and PSMA to date, we've had very conservative enrollment criteria for marrow. In fact, in the VISION trial, they actually excluded men with very high-volume disease or a super scan appearance. We also have pretty conservative dose reductions. So we get a 20% dose reduction if we have a dose-limiting toxicity for marrow and also dose delays for platelets. The question is, is this what we should be doing with our patients? Are these the levels at which we should not be treating?

There is some good evidence for this at the moment. There's a nice multicenter retrospective study that looked at men who have really high-volume disease, and they looked at 43 patients who got a median of four cycles. These patients actually did quite well. They had a 58% PSA, 50% response rate. They had a good time to pain progression of 8.3 months. The grade three anemia was actually pretty similar to what was seen in VISION. So anemia was 22% of patients had grade three versus 16.7% in VISION. Thrombocytopenia was 17% compared to 10% in VISION. So it definitely looks like we can take these patients with high-volume disease and give them the option of Lutetium-PSMA even though it wasn't included in the trials.

One of the important things to understand with Lutetium-PSMA therapy is at the moment we are giving a standard dose of 7.4 gigabecquerels in just about all the trials that we're using. But the question is, are we giving enough of a dose to patients with high-volume disease? The 7.4 gigabecquerels was actually dependent on a dose estimation based on external beam radiotherapy to the kidneys. But if you look at these two men that I've got here, one with low-volume disease and one with high-volume disease, and you look at the salivary gland activity that you can see on these two images, the salivary gland activity is much higher in the man with low-volume disease than with high. That's because when you give 7.4 gigabecquerels, it almost gets diluted between all of the cells that are concentrating that activity, that radioactivity.

So the dose delivered to this patient with very high-volume disease at a cellular level, the radiation dose, it's probably much, much lower than the dose delivered to the cancer cells in the patient with the low-volume disease. This is something we really have to question: can we get better responses in men with high-volume disease by giving a different dose?

Scott Tagawa had a look to see how high the dose could be in a really nice dose-escalation study using a fractionated dose schedule. So, 56 men, they divided the dose into two, gave half of it day one, half of it day 15, and then no further doses. Then they looked at the 27 men who got the maximal dose of 22 gigabecquerels—so a very high dose compared to 7.4, but no dose-limiting toxicity. Those men who did get the 22 gigabecquerels had a 54% PSA 50% decline, a median PSA PFS of 5.6 months, which is actually longer than what we saw in therapy. Radiographic progression-free survival was 9.6 months with a very similar adverse event profile.

Those results are with only two doses instead of the six doses that we saw in the other trials. So really interesting. And on a multivariable analysis, they found the patients who had the best overall survival were actually associated with higher PSMA uptake on the PSMA PET, which we already know, but also with the higher dose on this dose escalation study. So really food for thought, particularly in men with high-volume disease.

I don't think all men with high-volume disease should be considered for treatment. We know that heterogeneity is actually a really big factor in terms of whether a patient will or will not respond. And this is a paper that was really dividing patients on a binary scale into having either heterogeneous or homogeneous disease.

And if you look at these two patients, this patient's got very bright uniform disease on the left. While this patient's got a few spots that are quite bright, a lot of the disease in the marrow is really low below the liver.

So the patient on the right would actually be eligible for treatment on the VISION criteria. But in my experience, almost certainly this patient's going to get a bit of grade one to two toxicity with the Lutetium directly, but almost no treatment response in most of the marrow and will certainly, almost certainly come into problems with marrow toxicity very, very early in the treatment. I would treat the patient on the left definitely with Lutetium-PSMA. This patient on the right, if they had any other available treatments, I would be recommending that instead.

I really divide marrow compromise or deciding whether to increase dose or decrease dose related to whether a patient's got a marrow compromise based on whether they had that when they started the treatment with Lutetium-PSMA or if they develop it after they started treatment with Lutetium-PSMA because it's quite different situations. This is a patient on a trial who's had four doses of Lutetium-PSMA and in fact the question was the PSA has been going up slowly, but they're developing quite significant marrow toxicity. So the hemoglobin has dropped from 113 down to 80. Platelets have gone from 240 down to 89. And the question is whether we should do a marrow to find in this patient whether this patient should have a dose reduction.

One of the things we use clinically a lot are the 3D SPECT/CT that we get 24 hours after each Lutetium injection. And this is the patient after the first dose, after the second dose and after the fourth dose. And you can see in this patient not only have they had a mild increase in PSA, but all of the marrow has started to coalesce. So you can see they've actually got PSMA expressive disease right throughout their humeri and their marrow in there. It's starting to look more like a bone scan.

This patient has quite marked progressive disease with a low PSMA expression. They don't need to have a dose reduction, they don't need a marrow trephine, they actually need not to be on Lutetium-PSMA treatment. They need alternative treatments to be considered. And in fact, if you look at the increase in volume, you probably could have told that dose two. At a stage when they still had decent marrow and other alternative treatments were still an option. So we need to be using everything that we have, all of our tools, PSA and SPECT/CT to see how these patients are progressing and how to treat them appropriately.

And then just quickly looking at renal toxicity as well. Renal toxicity wasn't a problem in VISION or TheraP, but we do know from some retrospective studies, this one from Germany, 106 patients, that the majority of patients actually get a moderate reduction in GFR over time. Because most patients are at the end stage of their disease, we don't have a lot of patients that we can follow out for a long period of time, but it's concerning to see that the median drop in GFR at 24 months in these 106 patients was 20%. And the risk factors for that were fairly classic risk factors: hypertension, diabetes, older age, or prior taxane chemotherapy.

So I would say Lutetium definitely does cause an impairment in the long-term in GFR, and we are going to need a lot more information from prospective trials to see how extensive that reduction in GFR is over a longer period, say, three or four years. And I think the data that we're going to get from all the prospective trials, PSMAFore, PSMAddition, SPLASH, ECLIPSE, will give us a lot of information on how toxic Lutetium-PSMA is to the kidneys and whether that will prevent us giving very high doses as we bring it earlier in the prostate cancer space.

One of the things that we really learned from ENZA-p is that we can do what we call adaptive dosing of Lutetium-PSMA, and that is this concept of using interim biomarkers such as an interim PSMA-PET to determine if we've completely lost the target, and if we don't have any PSMA target left, we don't have to give more doses. And that is a potential way of treating patients earlier, getting less radiation toxicity to organs such as kidneys and the potential risk of myeloid dysplasia. And I think we really need to look at how we can treat with Lutetium-PSMA using adaptive dosing, using interim biomarkers to avoid toxicity if we're going to be using radionuclide therapy in the hormone-sensitive space and even earlier in men with prostate cancer.

So really, in summary, marrow toxicity is quite common. We get grade one to two toxicity with Lutetium-PSMA, but if we dose reduce in patients who have marrow compromised due to very high-volume disease, then we're unlikely to treat very high-volume disease adequately. And in patients who have a reduction or marrow compromise after we start the Lutetium-PSMA, we really need to be very aware as to whether it's progressive disease. Sometimes the PSA is just not enough and we should look at multiple biomarkers to see that. I do think the progressive disease is the most likely cause of severe marrow toxicity in patients being treated. And of course, renal toxicity doesn't appear to be a short-term issue, but it potentially will be a long-term issue and something we need to look out for in the trials earlier in the prostate cancer space.

Alicia Morgans: Louise, thank you so much. That was fantastic. I wonder and so appreciate all that you were talking about with SPECT. I wonder if clinicians could use a PET scan or a PSMA-PET as a way to do the same assessment that you talked about where you showed that the cytopenias were happening not just because of exposure to treatment, but actually because of marrow infiltration and disease progression. Because many centers don't yet have ideal utilization of SPECT at their center, yet they're able to get maybe a repeat PSMA-PET, but maybe not the SPECT. Is that something they could do?

Louise Emmett: Totally. So I'm keen on introducing SPECT and I talk about it a lot because it's cheap, it's easy to do, it's readily available, we can do it worldwide, and it gives the same information more frequently than we get with a PET. But in the Enza-p trial, we actually did an interim PSMA-PET at day 92, so that was after the first two doses of Lutetium-PSMA. It's a really nice time point to use to get an interim PET because it's a very good time to see whether you've got response or progression and it helps identify radiation resistance versus radiation sensitivity. So absolutely, a PET and a SPECT are interchangeable, and if I had to choose when to do a PSMA-PET, it would be after the second dose.

People talk about PET not being reliable because of upregulation or downregulation of the PSMA receptor, but that's a kind of thing that happens much earlier. If you still have upregulation of your PSMA-PET at 12 weeks, that is progression.

Alicia Morgans: Yeah. So very important point and thank you for raising that as well. One of the other things that you talked about, and I don't know if you can answer this or not, is looking at that heterogeneous expression of PSMA versus the patient who's more consistent. Do you feel like something like that might help us anticipate which patients may have more cytopenias because perhaps they're still getting exposure to the marrow, but they're not actually having the disease response they need to have? Or are there things we can use to try to anticipate which patients may have more marrow toxicity?

Louise Emmett: Yeah, I absolutely think there are. And the example that I showed of a patient who's got... In the VISION trial, what they said was you had to have a single site above liver and they didn't exclude low expression in bone because they didn't know how to deal with it. But the problem is if you have a patient with a lot of low PSMA expression in bone where you don't expect to get a response, you'll get just enough Lutetium into those cells to maybe get a bit of marrow toxicity in the surrounding marrow, but you won't get cell death in those prostate cancer cells because we're just not getting enough dose there. And I think those patients are particularly at risk of marrow toxicity, they get the worst of both worlds. And I really try and put those patients onto other treatments. So heterogeneity I think is key. It's one of the things that SUV mean actually captures quantitatively, but it doesn't separate that out.

Alicia Morgans: Really important. Thank you for that. And let's talk a little bit about renal toxicity. So this is something I don't think we talk about quite enough, and I just so appreciate that you were highlighting it. And as you said, it's not just a now problem. This is going to be a delayed toxicity potentially that will have ongoing problems. How do we think about... If the median age of diagnosis of prostate cancer, at least in the United States, is 67, which is already in your high-risk group, how do we think about trying to protect these patients? Should we encourage good hydration? Do we give them fluids? What do we do to try to prevent this?

Louise Emmett: So I think that at the moment, the PSMA expression in the proximal tubules of the kidneys is the problem. And we don't get less PSMA expression with hydration or with this kind of thing. In the men that we've treated to date, I have to say that renal toxicity has not been a problem. I haven't had a single patient that I have treated with metastatic prostate cancer who has died from renal disease. They have all died from prostate cancer. So I think we need to be very careful not to overstate the problem with the kidneys, but if we're going to move it, and there's this big trend really to say, can we give Lutetium-PSMA or other PSMA targeted radionuclide therapies very early in the space and maybe we've got 10 or 15 years to live potentially. That's where we need to be super careful. We need to know, and we've got so much data coming out from PSMAddition, PSMAFore, ECLIPSE, SPLASH, we have different ligands. We'll be able to tell how much of a problem this is and what we need to do is to have great transparency over that data.

Alicia Morgans: So that makes quite a bit of sense. So thank you for that. And the final thing I want to ask is sort of as I was introducing, I mentioned frail patients, and I know you didn't speak specifically about them in your APCCC talk, but certainly you are an expert on delivering Lutetium and other radiopharmaceuticals to patients. I wonder if you can speak just a moment on how we can help reduce the toxicities that we do expect in these patients. Because in many situations, we are identifying patients that we believe are too frail for chemotherapy. They have a PSMA-PET scan that makes them a potential candidate for treatment with Lutetium-PSMA-617, and then how do we protect that patient as we want to actually care for them?

Louise Emmett: So we treat a lot of chemotherapy unfit patients, particularly older patients, patients who have mobility issues, patients who just won't be able to tolerate chemotherapy. And I actually think that Lutetium-PSMA is a great option for that patient group. But as you say, Lutetium-PSMA itself can have some toxicities. I don't think the mild dry mouth is particularly a toxicity. The renal toxicity is not going to be too bad for them. They do get fatigue, and we do need to be very aware that they're not progressing through their disease.

What we do a lot clinically is to give the first two doses. I loved what Tom Hope said at the APCCC. He said, "Everyone deserves two doses." And I think that's a really great way to go. You give a baseline dose, you give a six-week dose, and then you do an interim PET to make sure the patient's actually benefiting. I think in these frail patients, they need to be not losing weight. They need to be able to eat, they need to have good quality of life and not too much fatigue, and they need to be responding in order for us to be giving this treatment morally. And the two doses and checking to see what's happening will identify all of those patients who are not going to benefit.

Alicia Morgans: I think that's a wonderful strategy. And to your point, we can support them but make sure they're not clinically deteriorating, which suggests that they may not be responding and certainly do that scan after two doses to make sure that we're not seeing clear progression. And as you said, at that point, we should be able to see if there's increased PSMA activity, that's probably real progression. That is not a flare effect given the timeline.

So final message to listeners, what would it be on this particular topic?

Louise Emmett: I think Lutetium is a really well-tolerated treatment. I would ask people if they're sending patients for Lutetium-PSMA, not to send them too late so we don't end up with that marrow compromise at the start, which is really hard to pull patients back from, no matter what treatment you're using. So send patients early if you're going to send them. And then really monitor them, use as many biomarkers as you can to figure out what's happening with them. Because the more you have, the more you understand, the better you can treat.

Alicia Morgans: I think that's wonderful. And the final thing I would add to that is get to know and get to work with your nuclear medicine physician because this is absolutely a team sport and there is so much that can be learned and discussed and used to support our patients through treatment when we work well as a team.

So thank you so much for your time and your expertise, Louise.

Louise Emmett: Thanks, Alicia. Great to be here.