Approximately 30 percent of patients with high-risk myelodysplastic syndromes (HR-MDS) have been identified as a novel genomic subset who are retinoic acid receptor [alpha] positive (RARA+) (J Clin Oncol 2022; doi: 10.1200/JCO.2022.40.16_suppl.TPS7075). Treatment algorithms for patients with higher-risk disease are limited to allogeneic transplant or treatment with hypomethylating agents. However, the overexpression of RARA has been correlated to resistance to traditional treatment strategies in this patient population.
Recently, the FDA has granted orphan drug designation to tamibarotene, an oral selective RAR[alpha] agonist, for the treatment of MDS. Additionally, previous data in patients with acute myeloid leukemia (AML) set precedent demonstrating tamibarotene plus azacitidine elicited promising clinical response in patients with RARA+ disease (Haematologica 2019; doi: 10.3324/haematol.2018.192807).
These positive outcomes support the rationale to investigate tamibarotene plus azacitidine in HR-MDS. Consequently, tamibarotene (formerly SY-1425) is currently being evaluated in combination with azacitidine to azacitidine in combination with placebo in the SELECT-MDS-1 Phase III trial.
The interventional study will examine the combination in patients with newly diagnosed RARA+ higher-risk MDS who have not received treatment for this diagnosis. Patients must be RARA+ based on the investigational biomarker test, and newly diagnosed with HR-MDS by WHO classification classified by IPSS-R risk category as very high, high, or intermediate risk with a blast count >5 percent at study entry.
Assessment of the RARA biomarker for study eligibility will be done by collection of blood samples from potential study participants at the pre-screening visit and testing at a central laboratory. Approximately 190 participants who meet eligibility requirements will be randomized 2:1, providing 90 percent power to detect the difference in CR rates between the investigational and control arms.
In the tamibarotene plus azacitidine arm, participants will receive 6 mg of oral tamibarotene twice per day on Days 8-28 of each 28-day cycle, and prior data have shown this regimen to be tolerable. Azacitidine will be administered at 75 mg/m2 intravenously or subcutaneously on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally Days 8-28 of each 28-day cycle.
The primary goal of the study is to compare the complete remission rate between tamibarotene plus azacitidine versus azacitidine plus placebo. Secondary endpoints include objective response rate, event-free survival, overall survival, transfusion independence rate, time to and duration of initial and complete responses, and safety. The SELECT-MDS-1 trial opened in February 2021 and recruitment is ongoing with sites located in North America, Israel, and Europe. The trial is estimated to be completed in February 2029.
Oncology Times chatted with Shyam A. Patel, MD, PhD, for his perspectives on the ongoing SELECT-MDS-1 trial. He is Assistant Professor of Hematology/Oncology at the UMass Chan Medical School and UMass Memorial Medical Center. His research area includes a focus on the clinico-genomic profiling and clonal dynamic modeling of MDS.
Oncology Times: How are patients with higher-risk MDS identified?
Patel: "Patients with high-risk MDS are identified based on the Molecular International Prognostic Scoring System (IPSS-M) developed by Dr. Papaemmanuil's team (NEJM Evid 2022; https://doi.org/10.1056/EVIDoa2200008). This model improves prognostic discrimination for MDS across multiple clinical endpoints and supersedes the decade-only IPSS-R model (Blood 2012;120:2454-2465) and the quarter century-old IPSS model (Blood 1997;89:2079-2088).
"The current IPSS-M model subdivides patients into six total categories based on molecular diagnostics and prognostics. High-risk MDS is now specifically divided into one of three subgroups-Moderate High, High, and Very High. Precision prognostication for high-risk MDS is based on adjusted hazard ratios for leukemia-free survival for specific gene mutations known to recur in MDS and acute myeloid leukemia. This model improves upon the original models, which accounted for only blast count, karyotype, and cytopenia."
Oncology Times: Approximately 30 percent of patients with MDS are identified as RARA+. What are some of the challenges treating patients who are RARA-positive with newly diagnosed HR-MDS?
Patel: "Some of the challenges to treatment of patients with RARA+ high-risk MDS include some degree of resistance to venetoclax. RARA expression might also confer resistance to hypomethylating agents. These patients also have a decreased response rate to conventional chemotherapy, which can be quite toxic with unfavorable risk-benefit ratio. Another challenge is the limited curative potential of RARA agonists. We do not have long-term data for depth of efficacy of RARA agonists, but RARA-positive patients may still need to undergo allogeneic stem cell transplant with curative intent."
Oncology Times: How does the SELECT-MDS-1 study represent a significant advance in the way we view the treatment strategy of patients with high-risk MDS?
Patel: "The pre-clinical data that set the precedence for the rationale for SELECT-MDS-1 comes from the laboratory of Dr. Ravindra Majeti at Stanford University. The presence of a RARA superenhancer in myeloid neoplasms was found to confer sensitivity to the selective RARA agonist tamibarotene (Cancer Discov 2017;7:1136-53). Translational efforts over the recent years have led to the SELECT-MDS-1 trial, which represents a significant advance in the way we view treatment strategies for high-risk MDS. This is because the trial focuses on a subgroup of patients with MDS with a defined phenotype-specific vulnerability to a RARA agonist called tamibarotene. This RARA agonist might change the treatment landscape for this subset of high-risk MDS. Current FDA-approved medications for MDS are limited and are not precision-based in many cases, aside from luspatercept or lenalidomide. The SELECT-MDS-1 trial may help provide patients with better options in the near future."
Oncology Times: What are some possible adverse effects when treating patients receiving hypomethylating agents in combination with their RARA antagonist?
Patel: "The most common adverse effects of tamibarotene include decreased appetite, hypertriglyceridemia, and nausea/constipation (incidence ~40% for each). Possible adverse effects may include differentiation syndrome, which is due to cytokine release from maturing blasts. This is similar to differentiation syndrome from first-generation pan-retinoids such as all-trans retinoic acid, as well as IDH1/2 mutation-directed targeted agents such as enasidenib or ivosidenib, which are used to treat various subentities of AML. Differentiation syndrome may manifest as dyspnea, hypoxia, weight gain, and edema. Anemia (Grades 1 and 2) occurs in about 20 percent of patients receiving tamibarotene."
Dibash Kumar Das is a contributing writer.