Data Updates From the IMerge Trial

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, updated data were presented from the IMerge clinical trial (NCT02598661), which is investigating imetelstat in patients with low-risk myelodysplastic syndrome (MDS). In this Precision Medicine Perspectives series titled “Recent Updates in the Management of Lower-Risk Myelodysplastic Syndrome,” Abdulraheem Yacoub, MD, an expert hematologist at the University of Kansas Cancer Center in Kansas City, offers clinical insights on imetelstat and reviews the recent data on its efficacy in patients with low-risk MDS.

Targeted Oncology™: What is the mechanism of action of imetelstat?

Abdulraheem Yacoub, MD: Imetelstat is the first and only in-class drug that has a unique mechanism of action. It’s the first telomerase inhibitor that was ever designed, and it remains the only agent in that class that is being researched in blood cancers in general. It has a novel mechanism of action that is believed to be cancer specific. It spares normal tissue from toxicities and provides most of the activity to vulnerable cancers, such as leukemias and myelofibrosis.

Targeted Oncology: What was the study design and the patient population from the IMerge trial that was recently presented at the 2023 ASCO Annual Meeting?

Abdulraheem Yacoub, MD: The IMerge clinical trial [data were] presented at the 2023 American Society of Clinical Oncology [Annual Meeting] in Chicago by Amer Zeidan, MBBS, MHS, and his team. This study addressed patients with MDS and anemia and transfusion [dependence]. This is a patient population that has very few therapeutic options. Patients who have MDS live with their disease for an extended period, and anemia and transfusion [dependence are] a big burden and significant morbidity in these patients. Unfortunately, there are very few therapeutic options for these patients.

The IMerge clinical trial investigated the novel agent imetelstat in patients who have [not responded to] the standard-of-care therapy with ESA [erythropoiesis-stimulating agent] vs the control arm (placebo). The aim of this study was to describe the activity of imetelstat in this patient population. This study was based on a prior phase 2 study [with findings] that showed remarkable activity and disease-modifying features. The study was designed to investigate this activity in a randomized phase 3 global study to provide specific activity data and, hopefully, regulatory approval for this agent.

Targeted Oncology: What were the primary and secondary end points, and how were they defined in this trial?

Abdulraheem Yacoub, MD: Based on the previous known activity of imetelstat, we’ve realized that imetelstat is an active agent that improves anemia and disease-modifying features of the disease, in which it can result in reduction of the malignant clone in patients with low-risk MDS. And again, these are patients who will live with these diseases for many years, and they are under the morbidity of transfusions, which has a significant decrement in the quality of life. These patients are also at risk of disease transformation and progression to higher-risk MDS or AML [acute myeloid leukemia]. Both goals of care—improving the anemia and modifying the disease—are very important.

The primary end point of this study was to achieve transfusion independence for at least 8 weeks in the study. There were multiple secondary end points, including transfusion independence for a different period—for 24 weeks or even 1 year. The study was designed to test all these different intervals of transfusion independence. But there were also exploratory end points trying to identify whether therapy with imetelstat can be disease modifying by biomarkers of disease, such as allele burden and transformation to high-risk disease and high-risk AML and MDS.

Targeted Oncology: What is the durability of the response? Compare the outcomes at the 8-week mark vs the 24-week mark, and then how they compared across the subgroups.

Abdulraheem Yacoub, MD: This was a study that controlled imetelstat vs the control arm, placebo, in patients with anemia and transfusion dependence who have [not responded to] first-line therapy with ESA. The primary end point of the study was achieving transfusion independence for at least 8 weeks in patients who had been heavily transfusion dependent, averaging 6 units every 8 weeks. The primary end point was to go down to 0 transfusions in an 8-week time block. The primary end point was achieved in [approximately] 40% of patients in the study and in only 15% of the control arm, which made this a positive study [result]. So this is a positive study [result] that met the primary end point, with a very convincing statistical power demonstrating activity of imetelstat in the target patient population.

The secondary end points included a similar goal of transfusion independence over more stringent or longer periods. By the same token, transfusion independence of the 16-week block was achieved in [approximately] 30% of patients, and transfusion independence for a 6-month block or a 24-week block was achieved in 28% of patients. Nearly one-third of patients achieved transfusion independence for a 6-month period. For some patients who had longer follow-up, we also noticed that nearly 15% of [patients] achieved transfusion independence for at least 1 year. So this is remarkably successful therapy in terms of efficacy of achieving transfusion independence, and some [patients] achieved transfusion independence for multiple blocks of time. Some patients continue to be in the study with a very durable period of transfusion independence.

For an intention-to-treat analysis, for patients who received the active therapy with imetelstat who achieved transfusion independence, the median [period] was nearly 51 weeks of transfusion independence, [whereas] patients who achieved transfusion independence in the placebo arm had a median [period] of only 13 weeks. In addition to the fact that many more [patients] achieved transfusion independence in the treatment arm, achieving transfusion independence in the treatment arm was a lot more durable than [in] the control arm.

The other high-value finding from the study is that the delta, or rise in hemoglobin [level], was substantial. There was an average of [nearly] a 3-g/dL rise in hemoglobin [level] in the responders. For patients who are transfusion independent, achieving transfusion independence is excellent. But to achieve a hemoglobin [level] in the range of 10 to 11 g/dL is remarkable, and it’s a true signal of activity that is unmistakable. This will result in substantial improvement in quality of life for those patients.

Targeted Oncology: How did the efficacy data compare across the different subgroups? Could you please talk about the variant allele fraction [VAF] reduction that was seen compared with the placebo group?

Abdulraheem Yacoub, MD: One observation noted in the study is that all patients who were enrolled in the study benefited equally and there was no subgroup of patients that predicted lack of response. Of note, although the study did not enrich for patients with ring sideroblasts, patients who happen to have low-risk MDS and anemia tend to have ring sideroblasts, so the study was enriched for patients with refractory anemia with ring sideroblasts. But all patients responded to the study [treatment] equally, and ring sideroblasts were not a predictor of response or lack of response in the study. There was no subgroup that was uniquely sensitive or resistant to therapy.

Another important, pertinent point is that a significant goal for patients with low-risk MDS is to be able to provide clinically beneficial therapy early on that can potentially [affect] the disease course. We refer to this as disease modifying: therapy you can apply now that would modify patients’ outcomes for the future. There are many surrogates for this, or biomarkers, that inform treating physicians that this therapy might have a signal of improving patients’ outcomes. One of the strongest biomarkers for this is the reduction of the mutation allele burden of the pathological mutations that drive MDS, such as SF3B1, TET2, ASXL1, and other mutations.

Uniquely in this study, active therapy with imetelstat in patients with therapy [has shown] statistically significant reduction in the allele burden, or VAF, of pathological mutations, such as SF3B1, TET2, DNMT3A1, and ASXL1. This signal being concordant with clinical benefit provides reassurance to treating physicians and investigators that therapy with this agent has the potential of improving disease outcomes in the long term by reducing the allele burden and disease burden of their cancer.

Targeted Oncology: How should clinicians view this information? What are some of the implications of the efficacy data of this trial?

Abdulraheem Yacoub, MD: The field of MDS has suffered from many negative [results from] clinical trials in the past, and we’ve had very few [results from] clinical trials that were positive. We are very excited to welcome these preliminary data for this clinical trial that show the study is meeting the primary and efficacy end points of this study. This is a welcome advancement for the field of MDS. Of course, we are always going to wait for the final manuscript and final presentation of the complete data when all patients have met their primary end point assessment. We’re looking forward to hearing the regulatory opinion on the data and safety data with long-term follow-up for these patients.

But hopefully, once all these processes are completed, this positive study [result] has proven that once this novel agent with a manageable safety profile is approved, it will be a very important tool for our patients with anemia and MDS. And it will be practice changing, in which patients with MDS and heavy transfusion independence who have [not responded to] the standard therapies are likely to have 1 more option of therapy that is impactful and durable and can result in a meaningful improvement in their quality of life and their transfusion dependence and potentially delay other therapies, such as chemotherapy or low-dose chemotherapy, in the future. This positive study [result] will be impactful in how we treat our patients in the future.