JNJ-6420 Elicits Responses in mCRPC, But Safety Concerns Arise

Michael J. Morris, MD

Although JNJ-69086420 (JNJ-6420) generated durable responses in patients with metastatic castration-resistant prostate cancer (mCRPC) after only 1 or 2 doses, manageable adverse effects (AEs) were observed with repeated dosing, according to data first-in-human phase 1 study (NCT04644770) presented at the 2024 ASCO Annual Meeting.

“JNJ-69086420 is an alpha emitting radioligand therapy that is the first to target hK2. It elicits deep and durable biochemical responses in metastatic CRPC. [Interstitial lung disease (ILD)] and thrombocytopenia were dose-limiting, but these are mitigated using the adaptive dosing schedule and dose cap,” Michael J. Morris, MD, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, said during his presentation of the data at the ASCO Annual Meeting.

As of the data cutoff date of April 22, 2024, 75 patients were enrolled in the study, including 37 who were in the standard dose-escalation cohort and given treatment every 8 to 12 weeks at fixed interval doses, 29 patients with the capped cumulative dose of 500 μCi that could be given as 250 μCi twice or 400 μCi once, and the rest of whom received adaptive dosing, which consisted of 250 μCi followed by a waiting period of more than 12 weeks, and 150 μCi, respecting the dosing cap of 500 μCi to 600 μCi.

At the 250 μCi dose level (n = 36), the objective response rate was 18%, including 1 complete response and 2 partial responses, in the 17 patients who had measurable disease. Deep and durable prostate-specific antigen (PSA) responses were seen, including a confirmed PSA50 response of 44% and a confirmed PSA90 response of 9%.

“In terms of duration, 28% of these patients had a duration of effect for greater than 6 months. But as you can see, patients had duration of disease control for 12 months, and 1 up to 27 months as well,” explained Morris.

Extended clinical, biochemical, and radiographic responses were observed in those treated with JNJ-6420 at doses of 150 μCi and higher. Evaluation of the recommended phase 2 dose (RP2D) is ongoing.

hK2, a novel target encoded by the KLK2 gene, is expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody-based targeted radiotherapy that delivers actinium-225. This is the first agent to target hK2/KLK2.

The first-in-human study sought to evaluate JNJ-6420 in heavily pretreated biomarker-unselected patients with mCRPC who were treated with 1 or more prior androgen receptor pathway inhibitors. JNJ-6420 was given via intravenous infusion and treatment was escalated from 50 μCi to 400 μCi every 8 to 12 weeks in the outpatient setting with no residential radioprotective restrictions.

Enrollment was open to patients with mCRPC confirmed by a tissue biopsy, and those who have received prior treatment with at least 1 androgen receptor–targeted therapy, such as abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa). The study is further divided into different parts based on prior chemotherapy experience:

• Part 1: Prior taxane-based chemotherapy or other chemotherapy is allowed but not required.
• Part 2a: Prior taxane-based chemotherapy or other chemotherapy is required.
• Part 2b: No prior taxane-based chemotherapy or other chemotherapy is allowed.
• Part 2c: mCRPC that has progressed despite prior treatment with lutetium Lu-177 vipivotide tetraxetan (Pluvicto).

All patients must have undergone surgical castration or be receiving ongoing medical castration therapy with a gonadotropin-releasing hormone analog (either agonist or antagonist) before starting the study drug and continuing throughout treatment, and have completed any prior palliative radiotherapy at least 2 weeks before starting JNJ-6420. An exception is allowed for palliative radiotherapy for pain, which can be used anytime before the first dose. Further patients must have an ECOG performance status of 0 or 1, and adequate organ function. Patients with prior radioisotopic therapy were excluded from the study.

The primary end points of the study are safety, including the number of patients with an AE, and determining a RP2D. Secondary end points of the trial include percentage of patients with PSA response, objective response rate, number of patients with anti-JNJ-6420 antibodies, and pharmacokinetics.

Of the 75 patients in the study, the median age was 68 years (range, 46-84), the median number of prior therapies was 4 (range, 0-12), and while all patients received a prior androgen receptor pathway inhibitor, 40 patients (53%) received 2 or more. A total of 49 patients (65%) received any taxane-based chemotherapy, 28 (37%) received 1 taxane-based chemotherapy, and 21 (28%) received 2 or more. Further, 5% (n = 4) had liver metastases.

For safety, any-grade treatment-emergent AEs (TEAEs) were seen in 96.0% of patients, with the most common including thrombocytopenia (58.7%), fatigue (53.3%), and anemia (48.0%). Grade 3 and higher TEAEs were observed in 61.3% of patients, including anemia (25.3%), thrombocytopenia (17.3%), hypertension (9.3%), leukopenia (8.0%), ILD (5.3%), and more.

“We also saw some persistent grade 3 and 4 thrombocytopenia using the original fixed dosing schedule at cumulative doses of greater than or equal to 500 μCi. This was significantly mitigated by reducing the dosing cycle to single doses of 200 and 400 μCi,” said Morris.

Serious TEAEs or treatment-related AEs (TRAEs) of any grade were seen in 32.0% and 16.0% of patients. A total of 14.7% and 12.0% of patients stopped treatment as a result of their TEAEs and TRAEs, respectively; these led to death in 6.7% and 5.3% of patients.

Morris added that for TEAEs, there were 4 grade 5 events, 1 of which was from COVID-19, 1 from failure to thrive, and 2 from ILD.

“In terms of the ILD, this was very much dose-related. All of the interstitial lung disease was seen at a dose of 600 or greater μCi. There is no ILD at 500 or less of a dose cumulatively,” added Morris.

Investigators are now moving on to assess patients treated with prior radioligand therapy as evaluation of the RP2D and adaptive dosing regimen continues.

Reference:

1. Morris MJ, Wong J, Nordquist L, et al. A phase 1 study of JNJ-69086420 (JNJ-6420), an actinium-225 (225Ac) -labeled antibody targeting human kallikrein 2 (hK2), for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42(suppl 16):abstr 5010. doi:10.1200/JCO.2024.42.16_suppl.5010