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Ana Ponce Kiess: It's my pleasure today to talk about the topic of finally moving beyond the 23 gray threshold to the kidney. These are my disclosures. So I'll just highlight what is the supposed 23 gray threshold and the importance of breaking the link between external beam and radioligand therapy, which Dr. Spratt did quite well for me. And some highlights from the 2024 FDA workshop—some currently available data retrospectively and implications for clinical trial design, dosimetry, and data sharing.

So the kidney—the 23 gray threshold is a dose limit for external beam radiotherapy of kidney mean absorbed dose to the whole kidney that was historically associated with the 5% risk of clinical nephropathy within five years. This was largely based on data—on whole abdominal radiotherapy, which we rarely do anymore—from the 1940s and '50s. As you can see, a wide field beam here. And one of these reports in particular showed that men who received this for seminoma, who received 23 gray in 25 daily doses, had a rate of clinical renal failure of 11%.

So this paper was cited by Emami in 1991 and then the QUANTEC Group in 2010, along with other data that was available for whole kidney dosing. And the QUANTEC Group was a working group that worked over about 10 years on quantitative analysis of normal tissue effects of radiotherapy in the clinic, and they analyzed each organ and constructed these normal tissue complication probability (NTCP) curves as a function of mean absorbed dose to each organ.

The definition of toxicity in most of these studies was clinical toxicity. So for this kidney study, clinical nephropathy usually had associated hypertension and symptoms. So it was likely CTCAE grade 4 toxicity, much more so than what we're seeing with PSMA-directed RLT. And based on the NTCP, the QUANTEC TD 5/5 dose—the avoidance dose—was actually quite a bit lower at 15 to 18 gray to the whole kidney. So they also highlighted the time course of this nephropathy that was gradual, progressive loss over many years, and not reversible in most cases.

So why is this relevant to this audience? Because the FDA guidance in 2011 and 2019 cite the 23 gray external beam threshold in concerns over late radiation nephritis in radiopharmaceuticals. And if you see the small text here from 2019, they actually cite the 23 gray threshold as a starting dose limit for first-in-human studies. But for many years, this was perceived as an upper dose limit for dose escalation and caused a lot of concern, both in academic and industry communities.

So of course, whole abdominal radiotherapy to the kidneys does not equal PSMA-targeted radioligand therapy exposure to the kidneys. And Dr. Spratt already went through some of the main differences between external beam radiation and radioligand therapy. The dose rate is 100 times higher. It's given over minutes versus days, long range passing all the way through the body. The dose distribution is planned. And then for RLT, very heterogeneous dose distribution—and for alphas, also higher LET and RBE.

So last year in March, within a few weeks of each other, these two editorials were published without us knowing about the other being published. But one by Dr. Hope and Dr. Hofman in Journal of Nuclear Medicine and others was entitled Rethinking Dosimetry: The Perils of Extrapolated EBRT Constraints to RNT. And then we had one from our RPT-TEC group, which is a normal tissue effects working group for radiopharmaceuticals led by George Sgouros about How Can Radiopharmaceutical Therapies Reach Their Full Potential?

And we just highlighted in this schematic the issue around not dose escalating to toxicity but capping at a dose limit and highlighting how that could limit efficacy and dose optimization for our field. So this very quickly came together as an FDA workshop, largely through the work of John Sunderland and SNMMI, to pull together this workshop last May with the FDA. That was very productive in terms of discussing dosimetry, dose optimization, renal toxicity, beta/alpha trial design.

And I think I could say that the group's consensus was that the EBRT thresholds should not be perceived as upper dose limits for escalation, although they still may be applicable as potential starting dose limits for first-in-human studies that have no other reference data. And we've seen many more studies now that have a clinical trial design that may ultimately exceed a cumulative 23 gray to the kidney that have been noted by Dr. Calais and Dr. Eiber—ReLUPSMA. There are also two dose escalation studies at the University of Michigan and Iowa that will likely exceed 23 gray to the kidney.

So I think we are beyond the 23 gray threshold now, and we're happy to see that. We have some really nice data coming out retrospectively from our European colleagues, as Dr. Eiber and Dr. Fendler talked about. These robust reports on retrospective kidney nephropathy after patients receiving extended cycles really add a lot to the field. And in this case report, they even did biopsies showing tubular injury and glomerular microangiopathy in patients who had 8 to 10 cycles of lutetium PSMA-I&T. And this is a more comprehensive report of 106 patients who had a median of six cycles and at least 12 months’ follow-up, which is critical for kidney toxicity.

They showed eGFR decreasing greater than 30% in 45% of the patients. And then a recent paper that just came out from Turkey as well showed in patients who had a kidney absorbed dose greater than 23 gray, they had significantly lower post-treatment CKD-EPI versus pretreatment. And there was a time course trend as well. So how can we translate some of these kidney concepts into clinical trials? I think we can now dose escalate to observe DLTs exceeding 23 gray mean absorbed dose to the kidney in Phase I and II.

We still have the importance of long-term follow-up for kidney toxicity in the Phase IV and registry programs. There were several discussions at the FDA workshop about the potential benefit of having two or more dosing regimens or dosage regimens in Phase II, or dose expansion to assess both efficacy and long-term safety with different regimens, and the need for earlier endpoints and biomarkers for renal toxicity. Finally, our RPT-TEC work group is still aiming to create NTCP curves for the kidney for PSMA RLT. There's a lack of published reports with detailed enough dosimetry and toxicity on our literature review, and this was also noted by the recent publication from the EANM Radiobiology Working Group as well

So we need patient-level data. We actually just executed, finally, a data sharing agreement with Novartis, so we really appreciate their partnership in this. And there are others that are now pending. So we have a data reporting template that we published as well. It basically comes from the ICRU 96 report that Dr. Spratt was just showing but lays it out very clearly what kind of data you need to collect in terms of administered activity, methodology, dosimetry, absorbed dose, and toxicity data to create these kinds of normal tissue complication probability curves.

So in conclusion, there's very significant differences between external beam radiotherapy and radioligand therapy that limit the applicability of both EBRT dose limits and dose response data to RLT. But luckily, the 23 gray threshold of kidney absorbed dose is no longer an upper limit for dose escalation, and we encourage standardized dose reporting and data sharing. Thank you.