SIERRA Results Do Not Support BLA Filing for 131I-Apamistamab in R/R AML

Findings from the phase 3 SIERRA trial (NCT02665065) were presented at the European Hematology Association (EHA) 2024 Hybrid Congress.

The FDA has determined that data from the phase 3 SIERRA Trial (NCT02665065) are not adequate to support a biologics license application (BLA) filing for induction and conditioning targeted radiotherapy agent, ¹³¹I-apamistamab (Iomab-B), in patients with active relapsed or refractory acute myeloid leukemia (AML), according to a press release from the drug’s developer, Actinium Phharmaceuticals.¹

Additionally, the FDA has advised the developer to attain overall survival (OS) benefit in a randomized head-to-head trial to support a BLA filing. This decision was announced in spite of the SIERRA trial meeting its primary end point of durable complete remission (dCR; P < .0001). Findings from the phase 3 trial were presented at the European Hematology Association (EHA) 2024 Hybrid Congress.²

Results from the trial show that 6-month dCR rates were 22% in the 131I-apamistamab group vs 0% in the conventional care (CC) group (95% CI, 12.29-34.73). Furthermore, all patients who received 131I-apamistamab underwent hematopoietic cell transplantation (HCT) vs only 18.2% of the conventional care arm.

"While this is not the outcome we expected, we will work with the FDA to further discuss specifics of the proposed randomized head-to-head clinical study to determine its strategic feasibility. The 12 oral presentations of the SIERRA results at prestigious bone marrow transplant, hematology and nuclear medicine medical conferences in the [United States] and [European Union] are an attestation of the strong interest from the transplant community for better conditioning regimens due to the high unmet need. We are grateful to the patients, their families, as well as the study investigators and their staff who participated in the SIERRA trial,” Avinash Desai, MD, chief medical officer at Actinium, said in the news release.¹

The multi-center, randomized, controlled phase 3 study enrolled 153 patients who were 55 years or older with active relapsed/refractory AML. Patients were randomly assigned 1:1 to receive CC (n = 77) or ¹³¹I-apamistamab with fludarabine and total body irradiation at 2 Gy before HCT (n = 76). Data cut-off occurred June 2022.

The primary end point of the trial was dCR, defined as the rate of complete response (CR)/CR with incomplete platelet recovery (CRp) at 6 months or greater. Secondary end points included OS and event-free survival (EFS).³

Of patients evaluable in the ¹³¹I-apamistamab arm (n = 59) and the CC arm (n = 64), 44 (74.6%) and 4 (6.3%) achieved CR or CRp, respectively. Additionally, the median duration of follow-up was 36.6 months (95% CI, 24.8-49.4) as of primary analysis cutoff. As of the January 2024 data cut-off, median OS was 6.3 (95% CI, 5.1-7.9) and 4.0 months (95% CI, 3.0-5.1) in the ¹³¹I-apamistamab and CC arms, respectively (HR, 0.69; 95% CI, 0.49-0.97; P = .0314).

Median OS had not been reached in the 13 patients who achieved a dCR with ¹³¹I-apamistamab (95% CI, 13.5-not reached [NR]), with 92.3% and 69.2% alive at 12 and 24 months, respectively. EFS was longer in the experimental vs CC arm (HR, 0.23; 95% CI, 0.15-0.34; P < .0001), with a higher EFS rate at 180 days after randomization observed at 25.8% and 0.3%, respectively. Furthermore, the ¹³¹I-apamistamab-led regimen with HCT was well tolerated with a favorable safety profile, including lower rates of sepsis and mucositis than patients undergoing CC HCT.

"We are disappointed that the positive results from the SIERRA trial are not deemed adequate by the FDA to support a BLA filing despite meeting the primary endpoint with statistical significance and producing positive efficacy and safety outcomes on several measures,” Sandesh Seth, Actinium's chairman and chief executive officer, said in the news release.¹

References

1. Actinium provides regulatory update on planned BLA filing and future plans for Iomab-B in the U.S. News release. Actinium Pharmaceuticals. August 5, 2024. Accessed August 5, 2024. https://tinyurl.com/48mtmjxv
2. Foran JM, Gyurkocza B, Nath R, et al. Long term efficacy results of the SIERRA trial: a phase 3 study of 131I-apamistamab-led allogeneic hematopoietic cell transplantation versus conventional care in older patients with active, R/R AML. Paper presented at: European Hematology Association (EHA) 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract P1377
3. Study of Iomab-B vs. conventional care in older subjects with active, relapsed or refractory acute myeloid leukemia (SIERRA). ClinicalTrials.gov. Updated July 19, 2023. Accessed August 5, 2024. https://clinicaltrials.gov/study/NCT02665065