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™)

Introduction: Waldenström macroglobulinemia (WM)remains incurable with current therapies. Treatment options for patients beyond initial therapy are limited, underscoring the need for new agents with novel mechanisms of action. Iopofosine I 131 is a novel radiopharmaceutical composed of a lipid raft-targeting phospholipid ether covalently bound to ¹³¹I, a beta-emitting radioisotope. Herein, we report the results of the CLOVER-WaM study [NCT02952508] in patients with previously treated WM.

Methods: Eligible WM patients had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m² on days 1 and 15 of each 57-day cycle. Dose reduction to 10 mCi/m² was allowed in the second cycle in patients with incomplete hematologic recovery or if the expected total dose exceeded 132 mCi. Supportive care with growth factors and transfusions was permitted per treating physician discretion. The primary endpoint was major response rate (MRR, defined as partial response or better) as determined by the modified VI^th International Workshop on Waldenström Macroglobulinemia Response Criteria. Secondary endpoints included overall response rate (ORR), treatment-free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR, defined as stable disease or better). Efficacy endpoints were assessed in the modified intent-to-treat (mITT) population, defined as all patients who received ≥60 mCi total administered dose of iopofosine I 131. MRR was analyzed with a 95% 2-sided confidence interval (CI) using the Clopper-Pearson interval method. In this population, MRR >20% was considered statistically significant. Time-dependent efficacy endpoints were analyzed using the Kaplan-Meier method. Safety was evaluated using CTCAE v4.03 in patients who received >1 dose of iopofosine I 131. The data cut-off for this analysis was May 31, 2024.

Results: In 65 patients enrolled (safety population), the median age was 70 (range, 50-88) years; 48 (73.8%) were male, and 17 (26.2%) were female. Sixty-one (93.8%) were White, 1 (1.5%) was Black/African American, and 3 (4.6%) were other or unknown. Fifty-five patients met mITT criteria and were evaluable for efficacy. The median number of prior therapies was 4 (range, 2-15). Bruton's tyrosine kinase inhibitor (BTKi) exposure was noted in 39 (71%) patients, of whom 31 (56%) were BTKi-refractory. Sixteen (29%) patients had MYD88-wild type, and 5 (9%) had CXCR4-mutated disease. The MRR was 56.4% (95% CI, 42.3-69.7). ORR was 80%; among MYD88-wild type patients, ORR was 81%, and among post-BTKi patients, ORR was 72%. CBR was 98%. The median DOR and TFS were not reached at a median follow-up of 8.8 months, with an estimated 72% of responding patients remaining progression-free at 18 months. In the safety population, any-grade adverse events, regardless of causality, were reported in 57 (87%) patients. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurring in >10% of patients included thrombocytopenia (80%), neutropenia (69.2%), anemia (44.6%), lymphopenia (13.8%), infections (12.3%), and febrile neutropenia (10.8%). Adverse event-related death occurred in 1 patient due to bacterial sepsis.

Conclusion: Iopofosine I 131 demonstrated durable efficacy in previously treated WM patients, with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile across broad biologic and clinical subgroups, irrespective of risk stratification. Based on the results of this trial, iopofosine I 131 shows promise as a novel treatment for WM patients.

Ailawadhi:Regeneron: Consultancy; Cellectar: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Beigene: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Johnson and Johnson: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Xencor: Research Funding; Ascentage: Research Funding; Abbvie: Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Pharmacuclics: Consultancy, Research Funding. Gavriatopoulou:Cellectar Biosciences: Research Funding; GSK: Consultancy, Honoraria; Integris: Honoraria; Takeda: Consultancy, Honoraria; BMS: Research Funding; AbbVie: Honoraria; Beigene: Research Funding; Amgen: Consultancy; Karyopharm: Consultancy; Genesis Pharma: Honoraria; Swixx: Honoraria; Janssen Cilag: Honoraria. Peterson:Cellectar Biosciences: Consultancy, Research Funding; Novocure: Research Funding; American College of Radiology: Other: Travel Funding; Florida Department of Health Advisory Council on Radiation: Other: Travel Funding, Safety Council; Florida Radiological Society Board: Other: Radiation Oncology Chair. Ntanasis-Stathopoulos:Cellectar Biosciences: Research Funding; AstraZeneca: Honoraria; Janssen-Cilag: Honoraria. El-Haddad:Cellectar Biosciences: Research Funding; Bayer Healthcare: Consultancy; Boston Scientific Corporation: Consultancy; C.R.Bard, Inc.: Consultancy; Canon Medical: Consultancy; Johnson & Johnson: Current holder of stock options in a privately-held company; Terumo Medical Corporation: Consultancy; North America Neuroendocrine Tumor Society: Other: Board of Directors; Patent Final: Other: Locking Breaks for Enteral Feeding Tube Retention. Grajales-Cruz:Sanofi: Honoraria, Other: Data Safety Monitoring/Advisory Board; Amgen: Honoraria; Pfizer: Honoraria, Other: Data Safety Monitoring/Advisory Board; Janssen: Honoraria, Other: Data Safety Monitoring/Advisory Board; Cellectar Biosciences: Honoraria, Other: Data Safety Monitoring/Advisory Board, Research Funding. Afrough:Bristol-Myers Squibb: Honoraria, Other: Data safety monitoring/advisory board; Sanofi: Honoraria, Other: Data safety monitoring/advisory board; Karyopharm: Honoraria, Other: Data Safety Monitoring/Advisory Board; Janssen: Research Funding; K36 Therapeutics: Research Funding; Adaptive Biotechnology: Research Funding; AbbVie: Research Funding. Levy:Cellectar Biosciences: Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seagen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Trotman:BeiGene: Research Funding; Cellectar: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Research Funding. Doucette:Physicians' Education Resource, LLC: Honoraria; Educational Concepts in Medicine: Honoraria; Oncology Nursing Society: Honoraria; Bristol-Myers Squibb: Honoraria, Other: Data Safety Monitoring/Advisory Board ; Cellectar Biosciences: Research Funding. Castillo:AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Mustang Bio: Consultancy; LOXO: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Cellectar Biosciences: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; AbbVie: Consultancy, Research Funding. Hernandez-Ilizaliturri:Novartis: Consultancy; Pharmacyclics: Consultancy; Kite Pharmaceuticals: Consultancy; Morphosys: Consultancy; Ipsen: Honoraria; Incyte: Consultancy, Honoraria; Gilead: Consultancy; Epizyme: Consultancy; Dava Oncology: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; ADC Therapeutics: Consultancy; Amgen: Consultancy; BioGene: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy, Research Funding; Cellectar Biosciences: Consultancy, Research Funding. Nooka:Cellectar Biosciences: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; Aduro Biotech: Research Funding; Amgen: Honoraria, Research Funding; Cellectis: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Honoraria, Other: Data safety monitoring/advisory board, Research Funding; K36 Therapeutics: Honoraria; Karyopharm: Research Funding; Kite Pharmaceuticals: Research Funding; Merck: Research Funding; ONK Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Sanofi: Honoraria; Sebia: Honoraria; Takeda: Honoraria, Research Funding; Arch Oncology: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria. D'Sa:Cellectar: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Boccia:Cellectar Biosciences: Consultancy, Research Funding; AbbVie: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; AbbVie: Consultancy, Honoraria; Genmab: Honoraria; Johnson & Johnson: Honoraria; Karyopharm: Honoraria; Pharmacosmos: Honoraria; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Parmar:Sanofi: Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring/Advisory Board, Research Funding. Fernández de Larrea:Cellectar Biosciences: Research Funding; BMS: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Expenses; Takeda: Honoraria, Research Funding; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Cengiz Seval:Cellectar Biosciences: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Menarini: Consultancy; BMS: Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novartis: Consultancy. Beber:Cellectar Biosciences: Honoraria, Other: Advisory Board, Research Funding; Beigene: Research Funding. Ramchandren:Cellectar Biosciences: Research Funding. Thomas:University of Texas MD Anderson Cancer Center: Current Employment; Sanofi: Research Funding; Mustang Bio: Consultancy, Honoraria; Cellectar Biosciences: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; X4 Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Janssen: Research Funding; Ascentage Pharma: Research Funding; Abbvie: Consultancy, Research Funding. Longcor:Cellectar Biosciences: Current Employment. Shustov:Cellectar Biosciences: Current Employment. Anderson:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; BMS: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.