(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) held in Lugano, Switzerland between April 25th and 27th was host to PSMA for Diagnostic and Treatment session. Dr. Louise Emmett discussed radioligand therapy dosing in special situations and toxicity.
In prospective trials, the ‘exclusion criteria’ for 177Lu-PSMA dose reductions have included:
- Creatinine clearance ≥ 40 ml/min
- Platelet counts ≥ 100 x 109/L
- Hgb ≥ 90 g/L (no red blood cell transfusions in the prior 4 weeks)
- Neutrophil counts > 1.5 x 109/L
- ‘Superscan’ appearance on imaging (exclusion criterion in VISION, but not TheraP)
What are the usual criteria for considering a 177Lu-PSMA dose reduction in the event adverse effects occur?
- 20% dose reduction for participants who have a dose-limiting toxicity in the preceding cycle.
- Nadir platelet count <100 x 109/L
- Nadir neutrophil count <1.0 x 109/L
Dose delays for Lu-PSMA in prospective trials have been considered if the platelet count is declining and less than 100 x 109/L.
What is the toxicity of Lu-PSMA in comparison to other agents in the mCRPC setting? Exposure-adjusted analysis of treatment-emergent adverse events in the VISION trial demonstrated that patients receiving 177Lu-PSMA-617 had a significantly increased incidence of:
- Bone marrow toxicity
- Anemia (Grade ≥3: 16.7% vs 14%)
- Thrombocytopenia (Grade ≥3: 42% vs 2%)
- Neutropenia (Grade ≥3: 18% vs 1%)
- Acute kidney injury (Grade ≥3: 16% vs 5%)
What is the efficacy and safety of 177Lu-PSMA in patients with diffuse bone marrow involvement? A multicenter retrospective analysis published by Gafita et al. in 2020 evaluated 177Lu-PSMA in 390 patients, of whom 43 had diffuse marrow involvement. Their baseline PSA was 1,000 ng/ml, and they received a median of 4 cycles. The PSA50 response rate was 58%, with a median time to progression of 8.3 months and a median overall survival of 11.6 months. Grade 3 anemia and thrombocytopenia were observed in 22% (VISION: 16.7%) and 17% (VISION: 10%) of patients, respectively.1 While these outcomes suggest worse adverse event outcomes for Lu-PSMA in this cohort of patients, the increased incidence of severe anemia and thrombocytopenia may be secondary to the underlying disease process, as opposed to the radionuclide itself. As such, reducing the dose of 177Lu-PSMA in these patients may have the undesired effect of worsening marrow toxicity outcomes via facilitating disease progression. Accordingly, Dr. Emmett framed the approach to dose reduction for marrow toxicity as follows:
- Consider the marrow compromise present before commencing 177Lu-PSMA
- Consider the marrow compromise emerging after commencing 177Lu-PSMA
How high can we go with the 177Lu-PSMA dose? In 2019, Tagawa et al. published the results of a dose escalation study in 56 men with mCRPC. Patients received a single fractionated dose of 177Lu-PSMA-617 on days 1 and 15. 27 of 56 patients received a maximum dose of 22 Gbq. Notably, there were no PSMA PET criteria for inclusion. A PSA50 decline was observed in 54% of patients. The median PSA progression-free survival was 5.6 months, and the median radiographic progression-free survival was 9.6 months. The median overall survival was 15.2 months. With regards to adverse events, grade 1–2 thrombocytopenia was observed in 34% of patients. Grade 1–2 anemia was observed in 20%, with 8% having grade ≥3 toxicity.
Dr. Emmett noted that when considering Lu-PSMA therapy in these patients, it is important to consider the likelihood of treatment benefit in these patients and correlate that with subsequent adverse events that may occur secondary to the underlying malignancy, as opposed to the treatment itself. Recently, Swiha et al.2 developed a 4-category score incorporating both heterogeneity and intensity of tumors (HIT) using a combination of heterogeneity and intensity:
- Category 1: SUVmax <15
- Category 2: SUVmax 15-79 with heterogeneous intensity
- Category 3: SUVmax 15-79 with homogenous intensity
- Category 4: SUVmax ≥80
As demonstrated in the Kaplan Meier curve below, patients in the higher category groups had superior outcomes with Lu-PSMA therapy. The median PSA progression-free survivals were:
- Category 1: 1 month
- Category 2: 4.1 month
- Category 3: 6.0 month
- Category 4: 8.5 month
Dr. Emmett then gave a case example of a patient in HIT category 1. This patient had marrow compromise after starting therapy. As seen below, the patient’s PSA rose between doses 1 and 4. This corresponded with the worsening of his hematologic parameters, as evidence by his decreasing hemoglobin and platelet counts. As demonstrated in the SPECT/CT below, the patient had clear evidence of disease progression with marrow infiltration. Thus, this patient is not likely experiencing treatment-related toxicity but is showing signs of underlying disease progression.
What about renal toxicity? A retrospective analysis of 106 patients receiving ≥4 doses of Lu-PSMA I&T demonstrated the following median estimated glomerular filtration rate (eGFR) changes:3
- 3 months: -3.5%
- 6 months: -6.9%
- 12 months: -13.6%
- 24 months: -19.6%
The variables associated with impaired renal function at 12 months in these patients receiving Lu-PSMA I&T included:
- Hypertension
- Diabetes
- Age >65 years
What about the safety of Lu-PSMA in patients with compromised baseline renal function? A prospective registry analysis of 22 mCRPC patients with impaired renal function (mean eGFR: 45 +/- 10.7 mL/min) was published in 2021.4 These patients received between 2 to 6 cycles (median 5), with a median of 6.5 GBq per cycle. The end-of-treatment eGFR of 54.1 +/- 16.7 mL/min was significantly higher than that at baseline (p=0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of radioligand therapy.
Dr. Emmett noted that the delayed toxicity of radioligand therapy in these patients remains unclear. What are the long-term renal toxicity effects of Lu-PSMA? Is it ligand-dependent? Does Lu-PSMA induce myelodysplasia? We will gain invaluable data from trials evaluating LuPSMA in earlier line settings (e.g., PSMAfore, PSMAddition, SPLASH, ECLIPSE).
An emerging concept in radioligand therapy is adaptive dosing, as was employed in the ENZA-p trial of enzalutamide +/- 177Lu-PSMA-617 in the 1st line treatment for mCRPC. Radioligand-treated patients in this trial received adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6–8 weeks dependent on an interim PSMA-PET-CT (week 12).5
Dr. Emmett concluded her presentation with the following take-home messages:
- Marrow toxicity (grade 1-2) is common with PSMA-targeted radionuclide therapy
- Dose reduction at the first dose may exacerbate marrow failure – Are we treating high volume disease adequately?
- Severe marrow toxicity is most likely due to disease progression. Look for it!
- The use of composite biomarkers will help identify causes and determine the next best treatments.
- Renal toxicity is not a short-term issue. This topic needs better evaluation in current trials as we move treatment earlier in men who will live longer.
- Longer-term marrow and renal toxicities have not yet been defined.
Presented By: Louise Emmett, BSc(HONS), MBChB, FRACP, FAANMS, MD, The University of New South Wales (UNSW), Sydney, Australia
Written by: Rashid Sayyid, MD, MSc - Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference, Lugano, Switzerland, April 25th - April 27th, 2024
Related content: Optimizing Lutetium-PSMA Dosing in High-Volume Disease and Special Situations - Louise Emmett
References:
- Gafita A, Fendler WP, Hui W, et al. Efficacy and Safety of 177Lu-labeled Prostate-specific Membrane Antigen Radionuclide Treatment in Patients with Diffuse Bone Marrow Involvement: A Multicenter Retrospective Study. Eur Urol. 2020;78(2): 148-54.
- Swiha M, Papa N, Sabahi Z, et al. Development of a Visually Calculated SUVmean (HIT Score) on Screening PSMA PET/CT to Predict Treatment Response to 177Lu-PSMA Therapy: Comparison with Quantitative SUVmean and Patient Outcomes. J Nucl Med. 2024.
- Steinhelfer L, Lunger L, Cala L, et al. Long-Term Nephrotoxicity of 177Lu-PSMA Radioligand Therapy. J Nucl Med. 2024;65(1): 79-84.
- Rosar F, Kochems N, Bartholoma M, et al. Renal Safety of [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function. Cancers (Basel). 2021;13(12): 3095.
- Emmett L, Subramaniam S, Crumbaker M, et al. [177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024:S1470-2045(24)00135-9