Iopofosine I 131 Generates Efficacy Signals in Waldenström Macroglobulinemia

Sikander Ailawadhi, MD

Iopofosine I 131 (CLR 131) monotherapy elicited durable responses and was associated with a tolerable safety profile in patients with heavily pretreated, multi-class refractory Waldenström macroglobulinemia, according to topline data from the phase 2 CLOVER WaM trial (NCT02952508).¹

Findings showed that patients with Waldenström macroglobulinemia who had received a median of 4 prior therapies achieved an overall response rate of 75.6% with iopofosine I 131. The trial met its primary end point of major response rate (MRR), with an MRR of 61% (95% CI, 44.50%-75.80%; 2-sided P < .0001), and the disease control rate was 100%, which exceeded the protocol statistical hurdle of 20%. At a median follow-up of 8 months, the median duration of response (DOR) has not yet been reached, and the progression-free survival rate was 76%. Furthermore, the stringent complete remission rate was 8%.

These disease outcomes with iopofosine I 131 exceed those in real-world studies in patients with Waldenström macroglobulinemia. In the real world, treatment with standard therapy induced a 4% to 12% MRR and a DOR of approximately 6 months or less in patients who were less pretreated and less refractory to several drug classes.

“There is a critical need for new therapies with novel mechanisms of action to treat [patients with] Waldenström macroglobulinemia,” Sikander Ailawadhi, MD, a professor of medicine at Mayo Clinic in Jacksonville, Florida and lead investigator of CLOVER WaM, stated in a news release. “There are no approved treatments for patients post-BTK inhibitor therapy, where currently the expected response rate to salvage treatments is approximately 10%, and the expected DOR in those patients is less than 6 months. The results from this pivotal study utilizing just 4 doses of iopofosine monotherapy in heavily pretreated patients are very compelling, demonstrating deep and durable remissions. The combination of the safety profile and deep, durable responses with a high proportion of patients remaining treatment free is impressive.”

Iopofosine I 131 is a potential first-in-class, targeted radiotherapy for patients with relapsed/refractory Waldenström macroglobulinemia who have received at least 2 prior lines of therapy, including BTK inhibitors.

The single-arm, registrational CLOVER WaM trial enrolled 50 patients, 45 of whom met the criteria for a modified intention-to-treat (ITT) population, from which topline safety data are being reported, at a data cutoff of January 3, 2024. The topline efficacy-evaluable population (n = 41) included patients who received a total administered dose of iopofosine I 131 of more than 60 mCi and had at least 60 days of follow-up after their last dose of the drug.

In the modified ITT population, patients had a median age of 71 years and a median IgM level of 2185 prior to iopofosine treatment. Ninety percent of these patients were refractory to either a BTK inhibitor (n = 18/36; 50%) or an anti-CD20 therapy (n = 18/41; 40%). A total of 26.7% of patients were multiclass refractory and 80% of patients had previously received a BTK inhibitor.

Treatment with iopofosine I 131 was well tolerated, and the toxicity profile of this agent was consistent with previous reports. No treatment-related adverse effects (TRAEs) led to treatment discontinuation. Grade 3 or higher TRAEs observed in more than 10% of patients included thrombocytopenia (55%), neutropenia (37%), and anemia (26%). All patients recovered from cytopenias with no reports of aplastic sequalae. Investigators observed no clinically significant bleeding events. Two percent of patients experienced febrile neutropenia. No treatment-related deaths occurred in the trial.

“These inspiring topline data represent important and exciting news for the entirety of the Waldenström macroglobulinemia community battling this challenging disease,” Newton Guerin, president and chief executive officer (CEO) of the International Waldenstrom’s Macroglobulinemia Foundation, added in the news release. “[Patients with] Waldenström macroglobulinemia need new, clinically meaningful treatment modalities, and currently, there are limited options for patients who have received prior BTK inhibitor therapy. Iopofosine’s product profile is notable because of its novel mechanism of action, fixed 4-dose course of treatment completed within 75 days, and the promise of an enhanced quality of life for patients, including a prolonged treatment-free interval.”

CLOVER WaM is the pivotal expansion portion of the CLOVER-1 trial of iopofosine I 131 in patients with select B-cell malignancies.² CLOVER-WaM enrolled patients at least 18 years of age with Waldenström macroglobulinemia and an ECOG performance status of 0 to 2 who had a life expectancy of at least 6 months and had received at least 2 prior lines of therapy for Waldenström macroglobulinemia. Patients were required to have measurable IgM levels above the upper limit of normal or at least 1 measurable nodal lesion with a longest diameter of more than 15 mm or 1 measurable extranodal lesion with a longest diameter of more than 10 mm.

Patients were excluded if they had ongoing toxicities of grade 2 or higher from previous therapies, excluding alopecia; prior external-beam radiotherapy in which more than 20% of their total bone marrow received greater than 20 Gy; prior total-body or hemi-body irradiation; second malignancies in addition to Waldenström macroglobulinemia that were not in remission or required therapy in the 2 years prior to CLOVER-WaM enrollment; anticancer therapy within 2 weeks of initial infusion of iopofosine I 131; or the need for acute Waldenström macroglobulinemia treatment.

Previously, in 2020, the FDA granted a fast track designation to iopofosine I 131 for patients with lymphoplasmacytic lymphoma or Waldenström macroglobulinemia who had received 2 or more prior therapies, based on findings from CLOVER-1.³

“We are most grateful to the patients and their families, participating study sites, their staff, and our dedicated employees for the successful completion of this study,” James Caruso, president and CEO of Cellectar Biosciences, concluded in the news release.¹ “Their respective contributions may provide a meaningful new treatment option for patients where there currently are no approved therapies. Iopofosine’s high MRR and achievement of the study’s primary end point in [patients with] highly refractory Waldenström macroglobulinemia exhibits its potentially practice-changing clinical profile. We believe the currently impressive response rates and the DORs will continue to improve as the data mature. We plan to include these outcomes in our new drug application submission and will be requesting an accelerated approval based upon our Waldenström macroglobulinemia fast track designation.”

References

1. Cellectar Biosciences announces positive topline data achieving primary endpoint in pivotal clinical study of iopofosine I 131 in Waldenstrom’s macroglobulinemia. News release. Cellectar Biosciences. January 8, 2024. Accessed January 8, 2024. https://www.cellectar.com/news-media/press-releases/detail/320/cellectar-biosciences-announces-positive-topline-data
2. Study of iopofosine I 131 (CLR 131) in select B-cell malignancies (CLOVER-1) and pivotal expansion in Waldenstrom macroglobulinemia (CLOVER-WaM). ClinicalTrials.gov. Updated January 8, 2024. Accessed January 8, 2024. https://clinicaltrials.gov/study/NCT02952508
3. Cellectar receives FDA fast track designation for CLR 131 in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia. News release. Cellectar Biosciences. May 26, 2020. Accessed January 8, 2024. https://www.cellectar.com/news-media/press-releases/detail/238/cellectar-receives-fda-fast-track-designation-forclr-131