Novel RARα Agonist Combo Induces Clinical Activity in Heavily Pretreated R/R AML


The addition of the oral selective RARα agonist SY-1425 to azacitidine induced clinical activity as treatment of patients with heavily pretreated relapsed/refractory acute myeloid leukemia with RARA positivity.

Eytan M. Stein, MD

Eytan M. Stein, MD

The addition of the oral selective RARα agonist SY-1425 to azacitidine induced clinical activity as treatment of patients with heavily pretreated relapsed/refractory acute myeloid leukemia with RARA positivity and demonstrated acceptable tolerability in a phase 2 study (NCT02807558), according to findings presented during the 2020 ASH Annual Meeting.1

Results showed that the regimen elicited an overall response rate (ORR) of 19% among 21 patients who were determined to be evaluable for response. Of the 4 patients who responded to the treatment, 1 achieved a complete remission (CR) and 2 experienced a complete remission with incomplete hematologic recovery (CRi). One patient achieved a morphologic leukemia-free state (MLFS).

Notably, responses were reported in 43% of patients (n = 3/7) who were naïve to a hypomethylating agent (HMA) and venetoclax (Venclexta). A response was also observed in 1 of 8 patients who had previously received treatment with HMA and venetoclax prior to study entry. This patient receive HMA and venetoclax, stopped venetoclax, received the doublet, and then achieved a response.

“RARA-positive AML is a novel patient subset with an actionable target for treatment with SY-1425. There’s a subset of patients with non–acute myelogenous leukemia (APL) AML who are characterized by overexpression of the RARA gene; this occurs in approximately 30% of patients with AML,” Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, said during a virtual presentation at the meeting. “As everyone knows, there’s a high unmet medical need for new effective therapies in relapsed/refractory AML, particularly for those who relapse after receiving HMA and venetoclax.”

Preclinical findings have indicated synergy between SY-1425 and azacitidine, providing the rationale to examine the combination in patients with myeloid malignancies who have RARA positivity.2 Moreover, early data with the doublet showed that among 18 response-evaluable patients with newly diagnosed unfit AML and RARA positivity, the ORR was 67% (n = 12/18), with 61% of patients achieving CRs and 6% of patients experiencing a MLFS.3,4

These data led to the multicenter, open-label, phase 2 trial, which enrolled patients with relapsed/refractory non-APL AML who were screened for the RARA biomarker with a peripheral blood–based test. Of those who were screened, 28 patients were found to be RARA positive; these patients were given intravenous or subcutaneous azacitidine at a dose of 75 mg/m2 on days 1 through 7 followed by oral SY-1425 at a daily dose of 6 mg/m2 on day 8 through day 28 of a 28-day treatment cycle.

The primary end point of the trial was ORR per International Working Group criteria. The secondary objectives of the trial include composite CR rate, time to response, duration of response, transfusion independence, and overall survival (OS), as well as safety and tolerability.

The median age of participants was 74 years (range, 30-87), and 46% (n = 13) were male. Patients had received a median of 2 prior lines of treatment. More than half patients, or 64% (n = 18) had received previous treatment with a HMA, while 32% (n = 9) had received venetoclax combinations. Thirty-six percent (n = 10) of patients were naïve to HMA and venetoclax. Half of patients (n = 14) had previously received prior intensive induction treatment, and 21% (n = 6) had previously undergone stem cell transplant. With regard to AML cytogenetic risk, 11% had favorable-risk disease, 29% were of intermediate risk, 21% were for poor risk, and 39% had this information missing.

Twenty-three of the 28 patients included on the trial ended up discontinuing treatment. Ten discontinued due to disease progression, 4 due to toxicities, 4 due to death, 2 due to treatment failure, 1 due to noncompliance, and 2 due to other reasons.

Additional results revealed that the median time to response was fairly short, at 1.4 months (range, 1.0-5.6). Two patients continue on the regimen; 1 was in a CR at month 9 and 1 had MLFS at month 8 of treatment. Two patients discontinued treatment about 1 month following their initial response.

Investigators also examined rates of transfusion independence of the patients who were treated on the trial. Results showed that 30% (n = 6/20) of patients were free of red blood cell and platelet transfusions for at least an 8-week interval while on the doublet. Notably, 27% (n = 3/11) of patients who had been dependent on transfusions at baseline were able to convert to independence while on treatment with SY-1425/azacitidine.

Moreover, the median OS in the heavily pretreated patient population was 5.9 months (95% CI, 3.1-9.9).

“What I found interesting was that when you look at all of the patients with stable disease [SD], they appear to be surviving for a prolonged period of time,” said Stein. “We know that these patients who have relapsed/refractory AML are typically an older population and their survival is generally quite low. This at least raises the question of whether those patients with SD experienced some improvement in their blood counts that allowed them to live longer than one might expect, but perhaps did not meet the formal criteria for a response.”

Stein added that this is the focus of an additional analysis that he is conducting with his colleagues.

With regard to safety, the doublet was found to be well tolerated. No increased toxicity was observed relative to the adverse effects that are typically observed with either agent when

used as monotherapies. Most of the non-hematologic toxicities were found to be low grade and reversible, Stein added.

The most commonly reported non-hematologic AEs that were reported in 20% or more patients included pruritus (17%, grade 1/2; 4%, grade 3 or higher), arthralgia (21%, grade 1/2), decreased appetite (21%, grade 1/2), vomiting (25%, grade 1/2; 4%, grade 3 or higher), diarrhea (28%, grade 1/2; 4%, grade 3 or higher), hypertriglyceridemia (11%, grade 1/2; 21%, grade 3 or higher), constipation (32%, grade 1/2), fatigue (28%, grade 1/2; 4%, grade 3 or higher), pyrexia (29%, grade 1/2; 7%, grade 3 or higher), and nausea (46%, grade 1/2).

“What stands out is that these patients have hypertriglyceridemia, which is a known AE with SY-1425,” said Stein.

The hematologic AEs reported in study participants were all grade 3 or greater in severity and included neutropenia (4%), leukopenia (7%), thrombocytopenia (14%), anemia (14%), and febrile neutropenia (36%).

Serious AEs were experienced by 19 patients, with febrile neutropenia reported most frequently; of the 7 patients who experienced this toxicity, 1 case was determined to be related to study treatment. Sepsis was the other most frequently reported SAE, and this occurred in 3 patients; none of these cases were related to study drug.

“There are hints here that this is a therapy that may find a place with the right patient population who has relapsed and refractory AML,” concluded Stein. “Because of this, we think that the clinical activity really does support the ongoing development of SY-1425 in RARA positive–myeloid malignancies.”


  1. Stein EM, De Botton S, Cluzeau T, et al. Initial results from a biomarker-directed phase 2 trial of SY-1425, a potent and selective RaRα agonist, in combination with azacitidine in relapsed/refractory acute myeloid leukemia. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 114.
  2. McKeown M, Johannessen L, Lee E, et al. Antitumor synergy with SY-1425, a selective RARα agonist, and hypomethylating agents in retinoic acid receptor pathway activated models of acute myeloid leukemia. Haematologica. 2019;104(4):e138-e142. doi:10.3324/haematol.2018.192807
  3. Jurdic JG, Raza A, Vlad G, et al. Early results from a biomarker-directed phase 2 trial of Sy-1425 in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) demonstrate DHRS3 induction and myeloid differentiation following Sy-1425 treatment. Blood. 2017;130(suppl 1):2633. doi:10.1182/blood.v130.suppl1_1.2633.2633
  4. De Botton S, Cluzeau T, Vigil EV, et al. SY-1425, a potent and selective RARα agonist, in combination with azacitidine demonstrates a high complete response rate and a rapid onset of response in RARA-positive newly diagnosed unfit acute myeloid leukemia. Blood. 2020;136(suppl 1):4-5. doi:10.1182/blood-2020-134600
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