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Wolfgang Fendler: Thank you very much for inviting me. Also, for this aspect and this talk, some disclosures before I go in with details. And I thought I might start with the question, what are we talking about if we talk about early access, and early access specifically in Germany? Because I think there are some details about this to understand where the data comes from.

Early access in Germany is basically an individual clinical therapy indication based on a national law that allows nuclear medicine facilities, specifically nuclear medicine facilities, to use products that are not authorized for manufacturing and for sale. And that is a possibility for us to do clinical imaging and therapy based on those non-authorized products, which means they are basically not approved by the EMA—the highest authority—but we still have to stick to a lot of rules and regulations. So it's not totally outside the regulations.

We have to stick to pharmacy regulations. We have to report manufacturing. We have to get audited for manufacturing. We have to document all the manufacturing. We have to comply with GMP, GCP. We have to set up reimbursement also in the clinical space and the clinical setting to make sure that there's little to no risk for product quality if we do early access, and it should usually be last line following tumor board decisions after all approved therapies.

I just wanted to stress this—early access is not equal to compassionate use. It's a specific way of going in with an early treatment or imaging that has promising data. But compassionate use is a very defined system that's usually bound to an IND procedure of a newly approved product, and that's not the case for the German access.

So to put this simply, it's not the Wild West for early access in Germany, but it's more like the German-style Wild West—Wild West Germany. So of course, it's outside the approvals, but we try to stick to some rules as much as possible to get this to a high quality for the patient.

What are some key contributions to lutetium-PSMA from early access? Here are five points I want to go over with you together: dosimetry and alpha therapy (a very current topic), lutetium-PSMA for extensive bone disease, risk assessment before lutetium-PSMA, response assessment, and extended treatment. These are some of the topics that have been touched by early access programs and early access data.

Actinium-PSMA: Here's a meta-analysis of eight studies, all from the early access space—not only Germany, but also other countries (South Africa is in there)—that have shown a biochemical response rate of a 50% or more drop in PSA in 60% of patients. They also show patterns of response, which is typically higher for pre-chemotherapy as compared to post-chemotherapy or post-lutetium-PSMA space.

So this is important data for us to understand what is the value of actinium-PSMA, should we proceed into clinical trials, and how should we proceed into clinical trials? And I think this is very valuable data from early access.

There are some more specific indications that we have learned for alpha therapy—a clear highlight is toxicity of the salivary glands. More than 70% of patients had grade I to III xerostomia. We have now understood from all those trials that this is an issue. And this also comes from very early data on lutetium-PSMA use. This is a study from Munich, 2015, one of the earliest dosimetry trials, which already showed the salivary glands count for PSMA-directed treatment, and this is a potentially dose-limiting organ if we want to process and further develop these types of treatments.

To the second point there, from the early access programs, we have gained data on patient cohorts that are outside the prospective trials—patients with extensive bone marrow involvement. “Super scans” on bone scan were not enrolled in the VISION trial, but in a retrospective assessment, they can be looked at in patients that had extensive disease on PSMA-PET and more than 50% bone marrow involvement. And this trial looked into the response based on PCWG3, but also on the safety profile and overall survival in these patients. And you see some of the MIPs with the red marking of the bone marrow involvement, which is really extensive.

The retrospective trial, mostly in an early access setting, could show that there is significant response. Most of the patients demonstrated a ≥50% PSA drop. In those patients who demonstrated a PSA drop, they also showed a median overall survival of 12.5 months, which is not very far from the VISION data, which was 15.3 months.

Also, looking at the safety profile, anemia was an issue in 22% of patients. But other adverse events for bone marrow were less than 20%—18% thrombocytopenia, 8% neutropenia for all events (related or unrelated)—so that's quite manageable in a clinical setting. And the trial could clearly highlight that lutetium-PSMA, also in these patients with diffuse marrow involvement, leads to meaningful anti-tumor activity. It shows a quite acceptable safety profile similar to the VISION trial, and these patients should further be considered for clinical decision-making, but also for future clinical trials.

The third point: What can we learn from clinical routine data—also mostly early access programs—in terms of risk profiling these patients? This is a joint study you see here: UCLA, of course, Technical University. So it's a mixture of mostly early access patients, but also some prospective patients in there, which led to creation of this risk nomogram for lutetium-PSMA.

In total, these were 270 patients, again, mostly early access. And the trial could show that if you look at the various baseline characteristics of the patients—more than 20 characteristics have been looked at by statistical assessment—PSMA-PET factors play a huge role for the baseline risk. So SUVmean, total number of lesions, bone involvement, liver involvement—these have all been independently associated with overall survival and progression-free survival outcomes in these patients. And they have been combined in the nomogram for risk stratification based on mostly early access data.

The C-index was more than 70%. And if this is applied to the patients, we can see a nice stratification of overall survival under and after lutetium-PSMA, and also progression-free survival, both in the entire cohort and in the validation cohort of this joint multicenter setting. So in total, by the early access programs and also joint patient cohorts, we can create nomograms to predict overall survival and progression-free survival. We understand deeper that PSMA-PET is a companion imaging tool—most of the factors on PSMA-PET really risk-stratify patients very, very well—and we can use these nomograms in the clinic to understand better where the patient stands in terms of the risk profile.

The fourth point I want to make is we understand more about PSMA-PET response assessment. This is, again, a multicenter trial with UCLA, Technical University, and Essen support under the umbrella of Prostate Cancer Foundation, looking at response patterns of PSMA-PET under clinical lutetium-PSMA therapy. These patients underwent a PSMA-PET before starting lutetium-PSMA and after two cycles of lutetium-PSMA, and these are the imaging patterns that we can see in patients.

And this is the change in total tumor volume and the appearance of new lesions outlined in red here. So there's a mixture of patterns among these patients. Even for the patients that demonstrate decreasing tumor volume, we can see in 31% of these patients the appearance of new lesions. And this should all be taken into account when we talk about treatment response for these patients.

And what we could understand from those early joint cohorts is that if we combine those criteria and combine those aspects of changes under lutetium-PSMA, we can create imaging response criteria such as the RECIP 1.0 that tell us if a patient has a decrease of tumor volume by 30% or more without appearance of new lesions, that could be partial response. And if the tumor load increases by 20% or more and there are new lesions, this could be progressive disease.

And if this is applied to those patients in the clinical routine setting, we can see that the outcome, the overall survival, is drastically different, ranging from 22 months in partial response patients to eight months in progressive disease patients. And so those factors—those changes in PSMA-PET—they really are able to determine the response to lutetium-PSMA therapy.

The fifth aspect, the fifth key point I want to make, is that we can understand more about extended treatment. Unlabeled and in the VISION trial there have been up to six cycles of treatment. Outside this, with early access, of course, we have experience with much more treatment and continuous treatment.

We have analyzed cohorts that underwent either continuous PSMA therapy for persistent disease—more than six cycles, up to 14 or 18 cycles of treatment—and patients that underwent a rechallenge of lutetium-PSMA later on after initial good response. And looking into these patients with a long overall survival follow-up, we found that they have quite a favorable overall survival outcome—23 months for continuous treatment, 14 months for rechallenge treatment—and this is way beyond the VISION data.

Of course, these are highly selected patients, not the typical patient cohort. But if we select patients that are favorable responders and candidates for lutetium-PSMA, this can be a very good choice to also continue treatment or revisit lutetium-PSMA in those patients, also because the safety profile was quite favorable.

So some of the early key contributions to lutetium-PSMA practice is, in general, there are lessons to learn from early access PSMA-RLT, especially if it's done in a proper way, in a high-quality way, and if there are multicenter analyses to really join data sets—these can be quite solid data. These are five key points I want to make:

We understood about the lutetium-PSMA dosimetry. We could define the activity amount to be applied. We understood that salivary glands need attention, especially for alpha therapy. We understood that extensive bone involvement is not a hard stop for treatment—it can be done also under lutetium-PSMA therapy.

We understood some key features on PSMA-PET that determine the risk of patients dying earlier under lutetium-PSMA, and this could be used to risk-stratify patients also in the clinical routine setting.

Response assessment: This was not part of the prospective trials, but in the early access, we understood that changes on PSMA-PET can really be used to assess response and be implemented further in joint criteria. And then extended treatment is feasible and also leads to repeat responses in those patients and should be considered for prospective settings, but also for the clinical routine in the future.

And with this, thank you very much for your attention.