ASCO: J&J's radioligand shows promise, but 4 deaths raise concerns

JNJ-6420 is an innovative radioligand therapy targeting prostate cancer cells. Developed as an anti-hK2 antibody-based treatment, it aims to deliver high-energy, short-range alpha-particle emitters directly to cancerous cells. Johnson & Johnson's novel radiopharmaceutical showed promising yet mixed results in its early-stage trial, marked by significant therapeutic responses but also marred by patient fatalities.

Study Design and Objectives

The Phase 1 dose-escalation study was designed to test the safety and efficacy of JNJ-6420 in patients with metastatic castration-resistant prostate cancer. All participants had previously undergone at least one androgen receptor pathway inhibitor treatment. The primary goals were to assess the drug's safety profile and to identify an optimal dosage for Phase 2 trials. Participants were divided into two groups: one with a fixed dosing schedule ranging from 50 μCi to 300 μCi, and another capped at a cumulative dose of 500 μCi.

Safety and Adverse Events

As of January 5, data from 64 patients who had received at least one dose of JNJ-6420 were reviewed. Detailed safety data was available for 57 patients treated with 150 μCi doses. While the treatment induced Grade 3 or higher treatment-emergent adverse events (TEAEs) in 61% of patients, serious TEAEs were reported in 37%. Nearly all participants experienced some form of adverse event.

Tragically, there were four patient deaths linked to the treatment. Two fatalities were attributed to interstitial lung disease (ILD), one to COVID-19-related respiratory failure, and another to decreased appetite and hypotension. ILD, a condition characterized by lung tissue scarring, is a known risk in oncology treatments, especially those involving antibody-drug conjugates. Both ILD-related deaths occurred in patients who had received cumulative doses of 750 μCi or more.

Managing Risks

To mitigate the risks of ILD and thrombocytopenia (reported in 63% of TEAEs), study investigators recommend a cumulative dose cap and an adaptive dosing schedule. The cases of ILD predominantly appeared in patients who had received cumulative doses of 500 μCi or more before the introduction of pulmonary function surveillance measures.

Therapeutic Responses

Despite the safety concerns, the study demonstrated encouraging therapeutic outcomes. A PSA50 rate of 45.6% was observed, indicating a significant reduction in prostate-specific antigen levels, a primary biomarker in prostate cancer. This reduction is often correlated with prolonged overall survival.

Among the patients, one achieved a complete response, two had partial responses, and three exhibited confirmed objective responses. Participants receiving doses of 150 μCi or higher showed prolonged clinical, biochemical, and radiographic responses, with some benefits lasting up to 112 weeks.

Industry Context

The promising results of JNJ-6420 come amid a surge of interest in radiopharmaceuticals within the pharmaceutical industry. Novartis leads the field with its approved drugs, Pluvicto and Lutathera. Competitors are also making significant strides; Eli Lilly acquired Point Biopharma for $1.4 billion and partnered with Aktis Oncology in a $60 million deal to develop new products. AstraZeneca entered the market by purchasing Fusion Pharmaceuticals for $2 billion, while Bristol Myers Squibb acquired RayzeBio for $4.1 billion in December 2023.

Conclusion

The early-stage trial of JNJ-6420 has shown both profound therapeutic potential and serious safety concerns. With adaptive dosing strategies and cumulative dose caps, further trials could refine the treatment to maximize benefits while minimizing risks. The continued interest and investment in radiopharmaceuticals by major pharmaceutical companies underscore the potential of therapies like JNJ-6420 to revolutionize cancer treatment.

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