BACKGROUND: CBF2AT3-GLIS2 (CBF/GLIS) oncogenic fusion is the underlying genomic cause of "RAM" phenotype AML, a megakaryoblastic subtype exclusively seen in infants and young children. CBF/GLIS AML is a highly refractory and uniformly fatal subtype of AML with limited response to conventional chemotherapy. We have demonstrated that FR-α, a known target in ovarian cancer, is expressed in CBF/GLIS AML cells and this expression is causally linked to the fusion oncogene. STRO-002 is currently under clinical investigation for the treatment of relapsed/refractory ovarian and endometrial cancer (NCT03748186). Preclinical studies have tested and confirmed the potent in vitro and in vivo anti-leukemia activity of STRO-002 in CBF/GLIS AML cell lines and xenograft models (Le et al. ASH 2021). Based on these compelling preclinical pharmacology observations, Sutro Biopharma evaluated patients on a case-by-case basis for consideration of a single patient IND (compassionate use) program for pediatric patients with CBF/GLIS AML.
METHODS: Key criteria for consideration of STRO-002 were CBF2AT3-GLIS2 oncogenic fusion and FR-α expression by flow cytometry in AML sample. Key exclusion criteria were co-existent acute/uncontrolled infection and compromised organ function (pulmonary, hepatic, renal, etc). Between August 2021 and July 2022, 16 patients received STRO-002. Median age at treatment was 2 years (range 6 months-7 years). Median number of prior therapies was 3 (range 1-8). Eight patients had relapsed after stem cell transplant (SCT) and the remaining 8 had primary refractory (induction failure) or relapsed AML.
RESULTS: In the 16 patients treated, 10 received STRO-002 as monotherapy, and 6 received combination with chemotherapy (fludarabine/cytarabine, decitabine, methotrexate (MTX), or dasatinib). All 16 pts were evaluable for response, best observed response included 7 CRs with 6 MRD negative remissions. Of these CRs, 3 occurred after monotherapy and 4 with combination therapy: MTX/fludarabine/cytarabine (n = 1), decitabine/DLI (n = 1), fludarabine/cytarabine/G-CSF (n = 1) and dasatinib/DLI (n = 1). The remaining 9 patients had stable disease or transient decrease in disease burden. Of the 7 patients who achieved a CR, 4 proceeded to SCT, 2 are receiving DLI and 1 will receive consolidation therapy. Ten (63%) of the 16 evaluable patients are alive and the other 6 died of progressive disease. Follow-up is limited for the surviving patients.
Of note were 6 patients who achieved an MRD negative CR, two with primary refractory disease, and four who had relapsed after an allogeneic SCT. These six patients with significant disease had deep response to STRO-002 with MRD negative remission. One patient had a rapid decline in marrow blasts and had no evidence of disease by flow after 3 single agent every other week (QOW) doses of STRO-002. A second patient had a similarly rapid response to single agent STRO-002 with clearance of all detectable disease after a second QOW dose of STRO-002. ANC for both patients one week after last dose of STRO-002 was >1000. These patients were consolidated with allogeneic stem cell transplant or with DLI.
STRO-002 was generally well tolerated. Collection and review of treatment-emergent AEs (TEAEs) is ongoing. Treatment-related events ≥ grade 3 included neutrophil count decreased (n = 3), platelet count decreased (n = 3), anemia (n = 2), WBC decreased (n = 2), hyperbilirubinemia (n = 1), bacteremia (n = 1), febrile neutropenia (n = 1), urticaria (n = 1), generalized edema (n = 1), aspartate aminotransferase elevation (n = 1), alanine aminotransferase elevation (n = 1).
CONCLUSIONS: STRO-002 has promising activity in relapsed/refractory CBF2AT3-GLIS2 AML, a disease that tends to be highly refractory to all standard-of-care (SOC) therapies. Further, STRO-002 is well tolerated as a monotherapy agent and in combination with SOC therapies. Patients with low tumor burden were more likely to achieve CR and transition to SCT, DLI and CAR-T. Deep molecular and flow cytometric remission was achieved in a cohort of patients. Patients with primary refractory disease (no prior transplant), 1-3 prior lines of therapy, low disease burden, or without extramedullary disease appeared to have a more potent response to STRO-002.
Johnson:Servier Pharmaceuticals: Speakers Bureau. Murray:Sutro Biopharma: Current Employment. Butte:Sutro Biopharma: Current Employment, Current holder of stock options in a privately-held company. Molina:Sutro Biopharma: Current Employment, Current equity holder in publicly-traded company.
STRO-002 is an investigational folate receptor-alpha (FolRa)-targeting ADC that is currently undergoing Phase 1 clinical testing in ovarian and endometrial cancers.
Asterisk with author names denotes non-ASH members.