FDA panel supports imetelstat for anemia in lower-risk myelodysplastic syndrome
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Key takeaways:
- Almost 40% of imetelstat-treated patients achieved a statistically significant benefit of red blood cell-transfusion independence.
- The committee voted that the benefits for responders outweigh the risks for nonresponders.
An FDA advisory committee voted 12-2 that the benefits of the investigational therapy imetelstat outweigh the risks for the treatment of transfusion-dependent anemia in certain adults with myelodysplastic syndromes.
Results of a phase 3 trial provided by the manufacturer for a new drug application showed imetelstat (Geron Corporation) — a telomerase inhibitor — conferred a significant clinical benefit for patients who achieved an 8-week red blood cell transfusion independence interval.
However, only approximately 40% of patients in the trial achieved such a response, leaving most patients with a statistically insignificant benefit from the drug. Voting members of the Oncologic Drugs Advisory Committee (ODAC) weighed the potential quality-of-life benefits the agent could provide the minority of patients with myelodysplastic syndromes (MDS) who responded, while also determining the potential risks for adverse events reported from the trial.
“While a significant minority of patients clearly benefited from imetelstat, the majority of patients do not derive benefit, and that combined with the increased toxicity of the agent — seen as infections and bleeding and platelet transfusions and other supportive measures — makes the data less clear to me that the risks totally outweigh the benefits for all patients treated,” Ravi A. Madan, MD, ODAC chairperson and head of the prostate cancer clinical research section of the Genitourinary Malignancies Branch at NCI’s Center for Cancer Research, said during a discussion following the vote.
“The data [are] very encouraging for the subset of patients who truly seem to benefit, and it seems to be life changing,” he added. “I think it will be important for the applicant and the academic collaborators in the future to really better define who this population is with biomarkers or other clinical parameters, and with the selection process they can bring the benefit to a vast majority of the patients treated.”
The voting question ODAC members considered asked if the benefits of imetelstat outweigh the risks for the treatment of transfusion-dependent anemia in adults with International Prognosis Scoring System low- to intermediate-risk MDS who had not responded to, stopped responding to or are ineligible for erythropoiesis-stimulating agents.
Imetelstat targets telomerase to inhibit uncontrolled malignant stem cell and progenitor cell proliferation in myeloid hematologic malignancies, ultimately leading to apoptosis of malignant cells and potential disease-modifying activity.
According to an FDA briefing document, results of a phase 3 trial provided by the manufacturer for the new drug application showed that imetelstat provided a significant red blood cell transfusion independence interval benefit of 51.6 weeks (95% CI, 26.9–83.9) compared with 13.3 weeks for placebo (95% CI, 8–24.9), but only among patients who achieved an 8-week red blood cell-transfusion independence response.
Instead, among the entire study population, researchers observed a red blood cell-transfusion independence interval of 5 weeks (95% CI, 4–7.7) with imetelstat and 3.9 weeks (95% CI, 3.6-4) with placebo; just 47 of the 118 patients (39.8%) in the imetelstat treatment arm achieved 8-week red blood cell-transfusion independence.
Results also showed increased adverse events among patients in the imetelstat arm. Study participants who received imetelstat over placebo experienced more frequent serious adverse events (32% vs. 22%), grade 3/grade 4 treatment-emergent adverse events (91% vs. 47%) and treatment emergent adverse events leading to any dose modification (86% vs. 25%).
Following the committee vote, some members asserted that because the trial met its primary endpoint of 8-week red blood cell transfusion independence compared with placebo, patients and oncologists can manage any potential increase in adverse events that occur from the agent.
“From my perspective, this trial met its primary endpoint and offers a new therapy for some patients who may have no other option depending on their MDS classification, and I felt that the benefits of improvement in transfusion independence outweighed the risks for cytopenias in a patient population and a blood cancer oncology community that is well versed in these adverse events and their management,” Neil Vasan, MD, PhD, assistant professor in the division of hematology and oncology at Herbert Irving Comprehensive Cancer Center, said during post-vote dialogue. “The discussion today, both by ODAC and the patient community, has shown that transfusion independence as a quality-of-life entity is complex and multifaceted, and I think this merits better clinical trial metrics and endpoints that I hope that we can address as a field in the future.”
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