ASCO 2024 preview – toxicity looms large for J&J

Radiopharmaceuticals are hot, particularly those employing actinium. But Johnson & Johnson’s first human data with its KLK2-targeting, actinium-labelled radiopharmaceutical JNJ-69086420 have been marred by several patient deaths, a just released ASCO abstract reveals.

The results could raise questions about J&J’s decision to go all in on this target – the group also has a Car-T project and T-cell engager against KLK2 – despite a lack of other industry activity here. 

The phase 1 study of JNJ-69086420 enrolled KLK2-unselected patients with metastatic castration-resistant prostate cancer (CRPC) who had received at least one prior androgen receptor pathway inhibitor. In the dose-escalation portion of the study, prior chemotherapy was allowed but not required, while prior radiopharmaceutical therapy was an exclusion criterion.

Patients received escalating doses of 50-400μCi every 8-12 weeks, and the ASCO abstract focuses on 57 subjects in the 150μCi or higher cohorts. Among these there were four deaths resulting from treatment-related adverse events, though the abstract doesn't provide further information on these.

The trial saw a 16% rate of discontinuation due to treatment-related adverse events. Common treatment-emergent adverse events were thrombocytopenia, at 63%, and interstitial lung disease, at 9%.

Middling efficacy

As for efficacy, there were two confirmed partial and one complete response among 24 efficacy-evaluable patients, giving an ORR of 13%. The PSA50 response rate was 46%.

So far the data look middling among the recent crop of early-stage contenders in relapsed CRPC, with the usual caveats about cross-trial comparisons. Perhaps J&J will hope for better when it starts dose expansion.

Novartis’s PMSA-targeting radiopharmaceutical Pluvicto is already approved for mCRPC after androgen receptor inhibitors and chemo. The Vision trial found an ORR of 30% with Pluvicto here; however, this was in PSMA-positive patients, so isn't comparable. Novartis also hopes to get Pluvicto approved in the pre-chemo setting, based on the PSMAfore study.

More options are needed for PSMA-negative patients, and it will be interesting to see if JNJ-69086420’s ASCO presentation includes any details on this subgroup, if indeed PSMA positivity was tested. KLK2 is an obvious biomarker here, so any detail on patients' KLK2 expression status will also be of note.

Based on the data released so far it looks like J&J might struggle to find a therapeutic window for the project. If this turns out to be a problem with the target the group’s other KLK2 project could also suffer. 

The ASCO annual meeting takes place in Chicago on 31 May to 4 June.