(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on prostate cancer, and a presentation by Dr. Michael Morris discussing a phase 1 study of JNJ-69086420 (JNJ-6420), an actinium-225 (225Ac)-labeled antibody targeting human kallikrein 2, for metastatic castration-resistant prostate cancer (mCRPC).
Human kallikrein 2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. It is regulated by androgen receptor signaling, similar to PSA, and exists both as a secreted and membrane-associated form. JNJ-6420 is a first-in-class anti-human kallikrein 2 antibody-based targeted radiotherapy delivering 225Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells:
At the 2024 ASCO annual meeting, Dr. Morris and colleagues report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected patients with mCRPC who received ≥1 prior androgen receptor pathway inhibitor.
Key eligibility criteria for this trial is as follows:
- >= 1 androgen receptor pathway inhibitor
- Prior chemotherapy allowed
- No prior radiopharmaceutical therapy
- No super scans allowed
Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Several parts of this phase 1 trial are detailed as follows, with the adaptive dosing portion currently enrolling (n >= 9):
The primary objectives were safety and defining a recommended phase 2 dose, and secondary objectives included preliminary assessment of clinical activity.
As of April 22, 2024, 75 patients received ≥1 JNJ-6420 dose. The baseline characteristics show a heavily pretreated population, including 5% of patients with liver metastases:
Overall, 61.3% of patients experienced grade ≥3 treatment-emergent adverse events, and 32.0% had a serious treatment-emergent adverse events. Treatment-emergent adverse events of note included thrombocytopenia (58.7%) and interstitial lung disease (6.7%):
Persistent grade 3/4 thrombocytopenia was only observed on a fixed dosing schedule at cumulative doses >= 500 μCi, and only 1/26 (3.8%) grade 3 thrombocytopenia was noted without recovered following 250-400 μCi dose. Overall, among the interstitial lung disease events, two patients had fatal cases. Still, all interstitial lung disease cases were with doses >= 600 μCi, and no cases were associated with cumulative doses <= 500 μCi.
Grade ≥3 treatment-emergent adverse events (≥10%) included anemia (25.3%) and thrombocytopenia (17.5%). 14.7% of patients discontinued treatment due to treatment-emergent adverse events, including 6.7% of the cohort having treatment-emergent adverse events resulting in death. At the 250 μCi dose level (n=36), the PSA50 rate was 44%, 9% had a PSA90, and 18% of patients had RECIST objective response (1 complete response, 2 partial responses):
The duration of response and swimmers plot shows that JNJ-6420 induces deep and durable PSA responses:
Adaptive dosing is supported by single-dose data, showing durable single-dose responses for 6-12 months with 250 μCi:
Which is further supported by PSA responses with extended interval retreatment:
Dr. Morris concluded his presentation discussing a phase 1 study of JNJ-6420, an actinium-225 (225Ac) -labeled antibody targeting human kallikrein 2, for mCRPC with the following take-home messages:
- JNJ-6420, an alpha-emitting radiotherapy that is the first to target human kallikrein 2, elicited deep and durable biochemical responses in patients with mCRPC
- Interstitial lung disease and thrombocytopenia were dose-limiting, but these risks are mitigated with a cumulative dose cap and an adaptive dosing schedule
- Assessment in patients with prior radioligand therapy is ongoing as evaluation of the recommended phase 2 dose and adaptive dosing regimen continues
Presented by: Michael J. Morris, MD, Prostate Cancer Section Head, Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
Related content: hK2-Targeted Radioligand Shows Promise in Treating Advanced Prostate Cancer: Phase I Findings - Michael Morris