Iopofosine I 131 Earns FDA Breakthrough Designation for R/R Waldenström Macroglobulinemia

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The FDA has granted breakthrough therapy designation to iopofosine I 131 for the treatment of patients with relapsed/refractory Waldenström macroglobulinemia.¹

Iopofosine I 131 is a potential first-in-class, novel agent that features a phospholipid ether as a radioconjugate monotherapy. The therapy is being evaluated in patients with Waldenström macroglobulinemia in the phase 2 CLOVER WaM trial (NCT02952508).

“The FDA’s breakthrough therapy sesignation underscores the potential of iopofosine I 131 as it may offer substantial improvement on at least 1 clinically significant end point over available therapies to address the substantial unmet medical need in this life-threatening cancer,” James Caruso, president and chief executive officer of Cellectar Biosciences, stated in a news release. “With robust clinical data, a favorable safety profile, expedited review designations in the United States and Europe and a compelling commercial market potential, we believe iopofosine I 131 represents an attractive candidate for potential collaborations or partners seeking impactful innovation and accelerated development pathways.”

Data from CLOVER WaM presented at the 2024 ASH Annual Meeting have demonstrated that patients treated with iopofosine I 131 (n = 55) achieved an overall response rate (ORR) of 83.6%, including a major response rate (MRR) of 58.2%.² The complete response or very good partial response rate was 7.3%, and the clinical benefit rate was 98.2%.

Notably, the ORR was 81.4% in patients with MYD88 wild-type disease (n = 16) and 84.3% in patients harboring MYD88 mutations (n = 39). The MRRs in these respective groups were 50.1% and 59.0%. The ORRs for patients with CXCR4 mutations (n = 5) and TP53 mutations (n = 5) were 80.0% and 73.1%, respectively; the respective MRRs were 100% and 40.0%. Patients with chemoimmunotherapy-refractory disease (n = 26) and those who received a prior BTK inhibitor (n = 39) experienced respective ORRs of 73.1% and 76.9% and respective MRRs of 42.2% and 56.4%.

The study enrolled patients with histologically confirmed Waldenström macroglobulinemia who received at least 2 prior lines of therapy. Patients needed to have measurable immunoglobin levels above the upper level of normal or at least 1 measurable nodal lesion.

All patients received iopofosine I 131 at 15 mCi/m² on days 1 and 15 of cycle 1. Six weeks later, they received 2 additional doses on days 1 and 15 of cycle 2. Active evaluation occurred for up to 28 weeks following the initial dose, and the total treatment and evaluation period lasted 1 year.

MRR served as the trial’s primary end point. Secondary end points included ORR, treatment-free survival (TFS), duration of response (DOR), CBR, and safety. Long-term safety follow-up was planned for 3 years.

Additional data showed that the median progression-free survival was 50.7 weeks (95% CI, 39-68.1), and the median overall survival was not reached (NR). The median TFS was 62.3 weeks (95% CI, 39.3-NR), and the median DOR was 44.1 weeks (95% CI, 24.3-NR).

Regarding safety (n = 65), the most common any-grade treatment-emergent adverse effects (TEAEs) included thrombocytopenia (84.6%), neutropenia (83.1%), anemia (63.1%), decreased white blood cell count (33.8%), fatigue (33.8%), nausea (27.7%), diarrhea (20.0%), dyspnea (18.5%), headache (16.9%), dizziness (15.4%), decreased lymphocyte count (13.8%), epistaxis (13.8%), decreased appetite (13.8%), constipation (12.3%), and febrile neutropenia (10.8%).

The most common grade 3 or higher TEAEs reported in at least 10% of patients included thrombocytopenia (80.0%), neutropenia (69.2%), anemia (44.6%), decreased white blood cell count (27.7%), decreased lymphocyte count (13.8%), and febrile neutropenia (10.8%).

Fourteen patients died during the study, with deaths attributed to disease progression (n = 9), squamous cell carcinoma (n = 1), neutropenic infection (n = 1), non-neutropenic infection (n = 1), and unknown (n = 2). One patient experienced a secondary malignancy (myelodysplastic syndrome).

Iopofosine I 131 previously received fast track designation and orphan drug designation from the FDA.¹ The European Medicines Agency has also granted orphan drug designation to iopofosine I 131 for relapsed/refractory Waldenström macroglobulinemia and PRIME designation for Waldenström macroglobulinemia.

References

1. Cellectar granted U.S. FDA breakthrough therapy designation for iopofosine I 131 in Waldenstrom macroglobulinemia (WM). News release. Cellectar Biosciences. June 4, 2025. Accessed June 4, 2025. https://www.cellectar.com/news-media/press-releases/detail/359/cellectar-granted-u-s-fda-breakthrough-therapy-designation
2. Ailawadhi S, Gavriatopoulou M, Peterson J, et al. Iopofosine I 131 in previously treated patients with Waldenström macroglobulinemia (WM): efficacy and safety results from the international, multicenter, open-label phase 2 study (CLOVER-WaM). Blood. 2024;144(supplement 1):861. doi:10.1182/blood-2024-200277