SY-1425 plus azacitidine induces high response rate in AML subgroup
Click Here to Manage Email Alerts
SY-1425 plus azacitidine conferred high rates of complete response among patients with RARA-positive acute myeloid leukemia, according to study results presented at the virtual ASH Annual Meeting and Exposition.
The regimen also was generally well-tolerated, with no increased toxicities relative to either treatment as a single agent.
Approximately 30% of patients with AML are positive for RARA, according to researchers.
“RARA-positive AML is a novel patient subset with an actionable target for treatment with the oral selective agonist SY-1425 [Syros Pharmaceuticals],” Stephane de Botton, MD, PhD, researcher at Institut Gustave Roussy in France, said during a presentation. “Early data from this trial demonstrated a high complete response rate and rapid onset of responses in RARA-positive newly diagnosed unfit AML.
“There remains an unmet need for new, well-tolerated therapies,” de Botton added. “For example, one-third of newly diagnosed unfit [patients with AML] do not respond to upfront treatment with venetoclax [Venclexta; AbbVie, Genentech] plus azacitidine, and the majority of responders eventually relapse.”
The phase 2, multicenter, open-label trial evaluated the safety and efficacy of 6 mg/m2 daily SY-1425 plus 75 mg/m2 IV or subcutaneous azacitidine among 51 patients who were treatment-naive and unfit for intensive induction chemotherapy. Patients had RARA-positive (n = 22; median age, 77 years; 59% men) or RARA-negative (n = 29; median age, 76 years; 66% men) AML, with a significant proportion of patients having high blast counts and poor risk features.
ORR per International Working Group criteria served as the study’s primary objective. Secondary objectives included composite complete response rate, time to response, duration of response, transfusion independence, OS, safety and tolerability, and exploration of molecular and cytogenic characteristics associated with response.
The majority of patients (90%) discontinued treatment, mostly due to adverse events (31%) and progressive disease (27%).
Results showed the combination was generally well-tolerated, with no increased toxicities beyond those observed with either treatment as a single agent, and most nonhematologic adverse events were low-grade and reversible.
However, serious adverse events occurred among 42 patients, including febrile neutropenia in 14 patients, pyrexia in six patients, pneumonia in six patients and sepsis in five patients.
The ORR was 67% among RARA-positive patients compared with 43% among RARA-negative patients. In addition, the composite complete response rate was 61% in RARA-positive patients vs. 32% in RARA-negative patients, with complete response rates of 50% vs. 25%.
De Botton noted that the response rates for RARA-negative patients appeared comparable to those achieved with single-agent azacitidine.
Median duration of complete response was 10.8 months (95% CI, 2.9-15.2) in the RARA-positive group vs. 10.3 months (95% CI, 3.1 to not reached) in the RARA-negative group.
When the researchers looked at the association between International Working Group response with molecular cytogenetic risk in RARA-positive patients, they found that 12 of 18 patients achieved a response irrespective of mutation or cytogenetic risk. Responses also were observed among patients with both intermediate and poor cytogenetic risk, as well as among patients with TP53, ASXL1 and NPM1 mutations, which are associated with variable risks.
Further, 67% of RARA-positive patients did not require red blood cell and platelet transfusions for at least 8 weeks while on treatment and 86% who were dependent on transfusions at baseline converted to transfusion independence during treatment.
Median OS was 18 months (95% CI, 5.7 to not estimable) among RARA-positive patients with complete responses, which de Botton described as “remarkable.” Median OS for RARA-positive patients without complete response was 5.6 months (95% CI, 0.4-9).
Analyses of patient samples for a monocytic expression signature of nine well-established markers showed approximately 80% of RARA-positive patients in the trial had a monocytic phenotype associated with venetoclax resistance, which includes lower BCL2 and higher MCL1 expression. These patients appeared likely to respond to SY-1425, de Botton said.
“SY-1425 plus azacitidine demonstrates high complete response rates, including the majority with molecular and cytogenetic complete responses in RARA-positive AML, a novel subset of AML characterized by RARA overexpression,” de Botton said. “Further development is warranted in RARA-positive AML and other myeloid malignancies.”
Perspective
Back to Top
Jamie Koprivnikar, MD
This is a very exciting abstract, as our current standard of care for elderly or unfit individuals with AML is a “one-size-fits-all” regimen consisting of venetoclax in combination with a hypomethylating agent. This study focused specifically on the subgroup of patients with RARA-positive disease, who tend to have poor responses to the current standard therapy of venetoclax in combination with a hypomethylating agent, which is felt to be mediated by venetoclax resistance.
It is very interesting to note that the patient population enrolled on this trial had disease that we would anticipate to be quite refractory — up to 43% of these patients had secondary AML, which is much more difficult to treat. Despite this, the response rates were exceptional, at 67%. This was impressive. Similar to patients who would be treated with venetoclax, these patients tended to have a quick response to treatment, with a median time to complete response of 1.2 months. The rates of myelosuppression were similar to what we would have seen with azacitidine alone.
Although venetoclax-based therapy has vastly improved the outcome for individuals with AML who are unfit for intense induction, we do see increased rates of neutropenia and thrombocytopenia, which was not seen with this regimen. In addition, patients with RARA-positive disease tended to have monocytic features associated with their leukemia.
A future area of exploration would be whether this molecule could potentially be combined with intense induction regimens for patients who have overexpression of RARA and/or monocytic leukemias to improve outcomes for these patients, as well. There is certainly an unmet need.
Hackensack University Medical Center
Collapse
De Botton S, et al. Abstract 112. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
Click Here to Manage Email Alerts