FDA ODAC Committee Votes In Favor of Benefit-Risk Profile of Imetelstat in Lower-Risk MDS

The FDA’s Oncologic Drugs Advisory Committee voted 12 to 2 that the benefits of imetelstat do outweigh its risks for the treatment of transfusion-dependent anemia in adult patients with International Prognostic Scoring System (IPSS) low- to intermediate-1–risk myelodysplastic syndrome (MDS) who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents (ESAs).¹

The committee discussed the benefit-risk profile of the agent as seen in the randomized, double-blind, phase 3 portion of the phase 2/3 IMerge/MDS3001 trial (NCT02598661). Results showed a significant improvement in the primary end point of 8-week red blood cell (RBC) transfusion independence (TI) with imetelstat (n = 118), at 39.8% (95% CI, 30.9%-49.3%) vs 15.0% (95% CI, 7.1%-26.6%) with placebo (n = 59; P <.001). A key secondary end point of 24-week RBC-TI was also met, occurring in 28.0% of patients on imetelstat vs 3.3% of patients on placebo (P ≤.001).² The sponsor Geron added that imetelstat demonstrated consistent and comparable benefit in 8-week RBC-TI across subgroups: WHO category (ring sideroblast [RS] positive, 45%; RS negative, 32%), prior RBC transfusion burden (4-6 units/8 weeks, 45%; >6 units/8 weeks, 34%), IPSS risk category (low, 40%; intermediate-1, 40%). 

However, the FDA questioned the magnitude and duration of RBC-TI in the absence of an improvement in overall survival (OS), response, and patient-reported outcomes (PROs).¹

On August 21, 2023, the FDA accepted for review the new drug application (NDA) for imetelstat for the treatment of transfusion-dependent anemia in patients with lower-risk MDS.³ The agency had assigned a Prescription Drug User Fee Act action date of June 16, 2024, and informed the company that an advisory committee meeting would be part of the NDA review.⁴

During the meeting, the committee first reviewed the design of the IMerge trial, which enrolled patients with IPSS low- or intermediate-1–risk, RBC transfusion–dependent MDS with disease that was relapsed/refractory to an ESA or had erythropoietin greater than 500 mU/mL. RBC transfusion dependence was defined as 4 or more units of RBCs per 8 weeks over the 16-week pre-study period.¹

Eligible patients were randomly assigned 2:1 to receive 7.1 mg/kg of intravenous imetelstat every 4 weeks (n = 118) or placebo (n = 60). Secondary end points were the 24-week RBC-TI, duration of TI, erythroid response (HI-E) per International Working Group (IWG) 2006 criteria, time to TI, MDS response per IWG 2006 criteria, OS, and safety. PROs and cytogenetic response were evaluated as exploratory end points.

Additional results from the trial showed that the magnitude of benefit in RBC-TI decreased over time. The 16-, 24-, and 52-week RBC-TI rates with imetelstat were 31.4% (95% CI, 23.1%-40.5%), 28.0% (95% CI, 20.1%-37.0%), and 13.6% (95% CI, 8.0%-21.1%), respectively, vs 6.7% (95% CI, 1.9%-16.2%), 3.3% (95% CI, 0.4%-11.5%), and 1.7% (95% CI, 0%-8.9%) with placebo, respectively.

Regarding the 8-week RBC-TI in responders, the median duration of the longest RBC-TI interval with imetelstat (n = 47) was 51.6 weeks (95% CI, 26.9-83.9) vs 13.3 weeks (95% CI, 8.0-24.9) with placebo (n = 9; HR, 0.23; 95% CI, 0.09-0.57; P < .001). However, in the entire study population, the median duration of the longest RBC-TI interval was 5.0 weeks (95% CI, 4.0-7.7) with imetelstat vs 3.9 weeks (95% CI, 3.6-4.0) with placebo.

The FDA also flagged that several other measures of clinical benefit failed to show an improvement with imetelstat. The rate of HI-E was 64% with imetelstat vs 52% with placebo, failing to show a significant difference between arms (P < .112). Additionally, neither complete or partial response occurred with either imetelstat or placebo. Stable disease was achieved by 69% of patients on imetelstat vs 68% of patients on placebo; progressive disease occurred in 6% and 3% of patients, respectively. Twenty-four percent and 28% of patients were not evaluable, largely owing to absent post-baseline bone marrow assessment.

As part of the open public hearing, a 67-year-old woman with MDS pleaded with the committee to consider the effects of an armamentarium without imetelstat, calling transfusion dependence “a nightmare,” adding that the amount of time required for transfusion equates to “a lot of life lost.”

Regarding survival in the trial, at the time of the primary analysis, the hazard ratio for OS was 1.07 (95% CI, 0.46-2.48). At the time of the updated analysis with over 2 years of follow-up the hazard ratio for OS was 0.98 (95% CI, 0.53-1.82). Median OS was 40.4 months (95% CI, 37.1–not estimable [NE]) with imetelstat and was NE (95% CI, 32.2-NE) with placebo. The FDA noted that although RBC transfusion density has shown an association with decreased OS, the association between a treatment-induced increased rate of RBC-TI and an improvement in OS has not been demonstrated in prospective studies.

Regarding exploratory end points, PRO analysis reflected no difference in the deterioration in FACIT fatigue at 43% with imetelstat vs 46% with placebo. However, the FDA highlighted that PROs—in addition to being exploratory—were assessed infrequently, with available data dropping to below 50% after cycle 8 of treatment. Additionally, 50% or greater reductions in variant allele frequency in SF3B1 (29.5% vs 2.6%), TET2 (34.3% vs 8.3%), DNMT3A (11.1% vs 0.0%), and ASXL1 (40.0% vs 16.7%) occurred in higher percentages of patients on imetelstat vs placebo, respectively. However, the FDA maintained that reduction in mutational burden is not a direct measure of clinical benefit.

In terms of safety, the median duration of therapy was 33.9 weeks (range, 0.1-141.1) with imetelstat vs 28.2 weeks (range, 0.1-116.1) with placebo. Patients in both arms received a median of 8 cycles of therapy.

Grade 3/4 adverse effects (AEs) occurred in 91% of patients on imetelstat vs 48% of patients on placebo; serious AEs occurred in 32% and 22% of patients, respectively. Ultimately, 14% of patients experienced AEs leading to imetelstat discontinuation. AE-related dose reduction or treatment delay occurred in 70% of patients on imetelstat vs 24% of patients on placebo.

The committee also reviewed the frequency of myelosuppression in the trial. Grade 3/4 cytopenia was significantly more common with imetelstat vs placebo, with decreased rates of neutrophil counts, leukocyte counts, and platelet counts of 71%, 53%, and 65%, vs 7%, 1.7%, and 8%, respectively. This resulted in a higher need for myeloid growth factor (35% vs 3%) and platelet transfusion (18% vs 2%) on treatment with imetelstat vs placebo, respectively. Despite these interventions, the rates of grade 3/4 infections and hemorrhage were 11% (all grade, 42%) and 2.5% (all grade, 21%) with imetelstat.

“The reality is that patients in this category would have otherwise gotten lenalidomide [Revlimid] or hypomethylating agents and what is expected there is neutropenia and thrombocytopenia––we would be getting weekly or bi-weekly labs, so the amount of interface and burden to patients is the same,” said Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts. “The reality is for next-line therapy after an ESA or luspatercept-aamt [Reblozyl] it will be regimens that do cause cytopenia, and that is the expectation in MDS. As a clinician in this field, this is how we take care of our patients, whether they’re on therapies or not.”

References

1. March 14, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/watch?v=Om-cKKBsMS4
2. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004
3. Geron announces FDA acceptance of new drug application for imetelstat for the treatment of lower risk MDS. News release. Geron. August 21, 2023. Accessed March 14, 2024. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-FDA-Acceptance-of-New-Drug-Application-for-Imetelstat-for-the-Treatment-of-Lower-Risk-MDS/default.aspx
4. Geron announces PDUFA date for imetelstat NDA in lower risk MDS. News release. Geron. August 22, 2023. Accessed March 14, 2024. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-PDUFA-Date-for-Imetelstat-NDA-in-Lower-Risk-MDS/default.aspx