Michael Kelly, MD, MPH, MS, Medical Director at Syros Pharmaceuticals discusses ASH 2020 abstract – 112 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.
Presenting:
A new genomically specified subset of non-APL AML patients (pts) has been identified with an actionable target characterized by RARA overexpression (McKeown, Cancer Discovery 2017). A new blood-based biomarker test that predicts sensitivity to SY-1425, an orally potent and selective RAR alpha agonist, can detect RARA-positive (RARA+) pts (Vigil, ESH 2017). RARA+ (de Botton, ESH 2019) is around 30 percent of newly diagnosed (ND) unfit AML pts, and recent evidence shows that RARA+ AML is associated with venetoclax resistance, which may indicate a new low prognostic risk (Fiore, ASH 2020). Clinical production of the combination (McKeown, Haematologica 2018), which is currently being tested in RARA+ ND unfit AMLL, was aided by preclinical synergy of SY-1425 with azacitidine (aza) (NCT02807558). In the RARA+ ND unfit AML cohort, early results from SY-1425 + aza demonstrated high response rates and a fast onset of responses (Cook, ASH 2018; de Botton, ESH 2019). Updated information for the fully registered cohort is provided here.
Methodology:
All pts received aza at 75 mg/m2 IV/SC daily on days 1-7 followed by SY-1425 at 6 mg/m2/day PO in divided doses twice daily on days 8-28 of each 28-day period. Both RARA+ and RARA-negative (RARA-) ND unfit AML pts were enrolled. The main aim was to classify behavior by the overall response rate (ORR) per IWG. Composite full response rate studies, time to response, comparison of responses between RARA+ and RARA- cohorts, independence of transfusion, and protection were also included.
Outcomes:
A total of 51 pts, 22 RARA+ and 29 RARA-, were treated, with data available up to 27 May 2020 being published. 32 (63 percent) male; median age 76 (60-91); 17 (33 percent) weak and 33 (65 percent) intermediate cytogenetic risk; 29 (57 percent) de novo and 22 (43 percent) secondary AML; and 33 (65 percent) > 30 percent marrow blasts were the baseline characteristics. Treatment period was up to 18.2 months, with treatment discontinuation mainly due to AE (33%), much of which was not treatment-related, and disease progression (22 percent ).
Among 18 response-evaluable RARA+ pts, the best response analysis showed an ORR of 67 percent (12/18), with 61 percent full responses (11/18; 9 CR, 2 CRi, 0 CRh) and 6 percent MLFS (1 pt). CRs showed a high rate of complete molecular or cytogenetic remissions (89 percent, 8/9) (3 molecular, 5 cytogenetic). At 1.2 months, the median time for initial complete response was rapid. In 13 (72 percent) of 18 TI assessable pts, transfusion independence (TI) was achieved, including conversion to TI in all 6 (100 percent) who were transfusion dependent at baseline.
The ORR and full response rate were lower out of 28 response-evaluable RARA- pts, and the time to initial response was longer compared to RARA+ pts. With full responses at 29 percent (8/28; 6 CR, 2 CRi, 0 CRh), ORR was 39 percent. The median amount of time for the initial maximum response was 2.9 months.
The combination’s AE profile is consistent with that stated earlier for single-agent SY-1425 or aza in AML. Decreased appetite (41 percent; 21/51 pts), hypertriglyceridemia (41 percent), nausea (39 percent), constipation (39 percent), exhaustion (35 percent), peripheral edema (35 percent), pyrexia (33 percent), and febrile neutropenia were the most common AEs (all grades/causality) (33 percent ). Grade 3 hematologic AEs included febrile neutropenia (33%), thrombocytopenia (24%), anaemia (20%) and neutropenia (16 percent ). Low-grade is the bulk of non-hematologic AEs. Febrile neutropenia (27 per cent), pyrexia (12 per cent), pneumonia (12 per cent), and sepsis were the most common SAEs (10 percent ).
Outcome:
Without evidence of increased toxicity of the mixture compared to either as a single agent, SY-1425 + aza was generally well tolerated. Importantly, in this group, rates of myelosuppression were comparable with single-agent aza. In the majority of RARA+ ND unfit AML pts, there was evidence of clinical activity with a high CR rate and rapid time to initial response, with evidence of clinical gain correlated with TI. Clinical results were confirmed by the use of the novel blood-based biomarker test to predict sensitivity to SY-1425 in AML pts, with higher response rates and a faster onset in RARA+ vs RARA- pts, whose responses were consistent with single-agent aza. In this genomically identified subset of AML pts, as well as other associated RARA+ pt populations, SY-1425 + aza shows promise as a novel targeted regimen for the treatment of RARA+ ND unfit AML and warrants further development. Updated data will be provided, including mature period of response and survival.