Cellectar Biosciences Reports Positive 12-Month Follow-Up Data from Phase 2b CLOVER WaM Study Demonstrating Durable Responses and Efficacy of Iopofosine I 131 in r/r Waldenström Macroglobulinemia

Cellectar's Iopofosine I 131 Shows Durable Responses in WM Phase 2b

Cellectar Biosciences announced positive 12-month follow-up data from its Phase 2b CLOVER WaM clinical trial evaluating iopofosine I 131 in 55 patients with relapsed or refractory (r/r) Waldenström macroglobulinemia (WM). The updated dataset, which includes a minimum of 12 months of follow-up for all enrolled patients as requested by the U.S. Food and Drug Administration (FDA), demonstrated an Overall Response Rate (ORR) of 83.6% and a Major Response Rate (MRR) of 61.8%, achieving the primary endpoint. The median Duration of Response (DoR) was 17.8 months, meeting a secondary endpoint. These results strengthen the regulatory positioning for accelerated approval and support the planned initiation of a confirmatory trial in the fourth quarter of 2026.

• The CLOVER WaM study demonstrated compelling efficacy in a heavily pretreated r/r WM patient population, with a median of four prior lines of therapy. Key results from the per protocol study population (n=55) included an 83.6% Overall Response Rate (ORR), a 61.8% Major Response Rate (MRR) which was the primary endpoint, and a median Duration of Response (DoR) of 17.8 months, a secondary endpoint. Responses deepened and remained durable, underscoring the potential of iopofosine I 131 as a meaningful, time-limited treatment option given its fixed-dose regimen.
• Iopofosine I 131 showed strong and consistent efficacy in difficult-to-treat BTKi-exposed (n=39) and BTKi-refractory (n=33) patient subgroups. In BTKi-exposed patients, the MRR was 64.1% with a median DoR of 18.2 months and median PFS of 15.9 months. Similar results were observed in BTKi-refractory patients, reinforcing the drug's potential to address a critical unmet need in the second-line setting and beyond, especially since there are no FDA-approved treatment options for patients progressing on BTKi therapy.
• The drug maintained a predictable and manageable safety profile, with adverse events being transient, low rates of infection (<10%), and no significant bleeding events, unlike other WM therapies. Cytopenias were the most common treatment-emergent adverse events. The mature 12-month follow-up data, incorporating surrogate endpoints and demonstration of durable responses in a high unmet need population, aligns with FDA expectations for accelerated approval, with plans for a confirmatory randomized study in a post-first line, post-BTKi population.

Addressing the Unmet Needs in Relapsed/Refractory WM

Current treatment approaches for Waldenström macroglobulinemia face significant challenges that limit optimal patient outcomes. Despite the availability of multiple effective therapeutic agents, the disease remains incurable and lacks consensus on preferred treatments in the relapsed setting. These limitations have driven extensive research into novel therapeutic strategies and combination approaches.

• Drug resistance and treatment discontinuation: BTK inhibitor resistance represents a major limitation, with ibrutinib discontinuation occurring in 27% of patients due to disease progression (14%), toxicity (8%), nonresponse (3%), and other factors, with cumulative discontinuation rates reaching 43% at 48 months

• Predictive biomarkers for treatment failure: Baseline platelet count ≤100 K/µL and tumor CXCR4 mutations are independently associated with 4-fold increased odds of ibrutinib discontinuation, while TP53 mutations correlate with shorter overall survival in chemo-free regimens

• Post-discontinuation disease management challenges: IgM rebound (≥25% increase) occurs in 73% of patients following ibrutinib discontinuation, with nearly half experiencing this within 4 weeks, necessitating close monitoring and consideration of continued therapy until next treatment initiation

• Toxicity profiles limiting therapeutic utility: Significant toxicity remains a major constraint, particularly with agents like idelalisib, despite demonstrated efficacy, highlighting the need for better-tolerated treatment options

• Suboptimal salvage therapy outcomes: Patients discontinuing ibrutinib due to disease progression have significantly shorter overall survival compared to those discontinuing for nonprogression events (21 versus 32 months; P = .046), though salvage therapy responses are higher when initiated within 2 weeks of stopping ibrutinib

• Limited role of stem cell transplantation: The therapeutic position of SCT in WM remains undefined due to insufficient patient data, leaving a gap in treatment options for appropriate candidates

CLOVER WaM's Durable Efficacy in Heavily Pretreated WM

Recent clinical evidence demonstrates the evolving therapeutic landscape for Waldenström macroglobulinemia, with particular emphasis on BTK inhibitor optimization and real-world treatment outcomes. These studies provide valuable insights into efficacy maintenance, safety profiles, and long-term disease management strategies across diverse patient populations.

• ASPEN Study (BGB-3111-302) evaluated zanubrutinib versus ibrutinib in MYD88-mutated WM patients, demonstrating comparable efficacy with superior safety profile and leading to zanubrutinib approval for WM treatment

• LTE1 Extension Study (BGB-3111-LTE1) followed 47 patients transitioning from ibrutinib to zanubrutinib, showing 85% treatment continuation at 15.3 months median follow-up with 96% maintaining or improving disease response without compromising safety

• Chinese Histologic Transformation Study analyzed 15 WM patients who transformed to DLBCL, revealing that BTK inhibitor-based regimens after transformation significantly prolonged overall survival (p = 0.007) with median OS of 26.0 months

• Chinese CD20-Targeted Therapy Study compared four regimens (FCR, BR, R-CHOP, rituximab monotherapy) in 128 WM patients over 10 years, with FCR achieving longest OS (75.86 ± 22.05 months) but highest grade ≥3 adverse event rate (60%)

• German Claims Database Analysis of 593 WM cases (2010-2022) showed median OS of 7.9 years, with 70% initially managed with watch-and-wait approach and rituximab-based combinations as most common active treatment

• Finnish Nationwide Study (2007-2021) demonstrated improved survival outcomes over time between early (2007-2014) and late (2015-2021) cohorts, with infections and WM itself as major causes of death

Iopofosine I 131's Manageable Safety and Regulatory Path

Published safety and tolerability data for Iopofosine I 131 demonstrates a predictable and manageable toxicity profile across multiple studies spanning nearly a decade. The primary safety concerns are hematologic toxicities that are transient and resolve without long-term sequelae. Clinical experience ranges from single-agent administration to combination therapy with external beam radiation therapy.

• Grade 4 hematologic toxicities represent the primary safety signal, with the most recent 2025 head and neck cancer study reporting thrombocytopenia, leukopenia, and anemia in 8 of 12 participants, occurring predictably during weeks 6-8 and resolving within three weeks without sequelae

• Dose-limiting toxicities are consistently hematologic in nature, with the 2016 Phase 1b study identifying thrombocytopenia and neutropenia as DLTs at doses of 31.25 mCi/m² and above in the adaptive dose-escalation design

• Lower single doses demonstrate excellent tolerability, as evidenced in the 2015 Phase 1a study where 370 MBq single administrations were well tolerated across all eight subjects with no severe adverse events or dose-limiting toxicities reported

• Non-hematologic toxicity burden appears minimal, with the 2025 combination study showing no treatment-related grade 3-4 non-hematologic toxicities when CLR 131 was combined with external beam radiation therapy

• Myelosuppression follows expected patterns for radiopharmaceuticals, with predictable timing and recovery profiles that align with the known mechanism of action and radiation dosimetry predictions of approximately 400 mSv marrow dose at 740 MBq

Iopofosine I 131: Beyond WM and Future Potential

Iopofosine I 131 is being investigated across multiple cancer types beyond Waldenström macroglobulinemia, with the most advanced clinical development in head and neck cancer. These trials employ various intervention models ranging from monotherapy dose-escalation studies to combination approaches with external beam radiation therapy.

Iopofosine I 131 Data Bolster Accelerated Approval in r/r WM

The recent announcement from Cellectar Biosciences regarding the 12-month follow-up data from its Phase 2b CLOVER WaM trial marks a significant moment for patients battling relapsed or refractory Waldenström macroglobulinemia (r/r WM). With an impressive Overall Response Rate of 83.6% and a Major Response Rate of 61.8%, alongside a median Duration of Response of 17.8 months, iopofosine I 131 has demonstrated robust clinical activity in a patient population desperately in need of new therapeutic options. These results are particularly compelling given the challenging nature of r/r WM, where durable responses are highly valued.

Crucially, the successful completion of the FDA-requested 12-month follow-up for all 55 enrolled patients, coupled with the achievement of both primary and secondary endpoints, substantially strengthens the drug's regulatory positioning for accelerated approval. This could pave the way for iopofosine I 131 to reach the market sooner, offering a novel treatment mechanism to address a persistent unmet need. For Cellectar, this represents a significant de-risking event, validating their development strategy and potentially establishing a strong foothold in the orphan drug market.

However, the path forward is not without its considerations. While the Phase 2b data are highly encouraging, the efficacy and safety profile observed in 55 patients will need to be confirmed in a larger, more diverse population. The planned confirmatory trial, slated for the fourth quarter of 2026, will be pivotal. Failure to replicate these strong results or demonstrate sustained clinical benefit in this larger study could jeopardize full approval or even lead to the withdrawal of accelerated approval. Furthermore, the regulatory landscape for accelerated approvals is under increasing scrutiny, emphasizing the importance of timely and successful execution of confirmatory trials. Despite these considerations, the current data provide a strong foundation for iopofosine I 131 to emerge as a valuable addition to the r/r WM treatment paradigm, offering renewed hope for patients and clinicians alike.