Spliceosome mutations are associated with clinical response in a Phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia.
Background: PLK1 is overexpressed in acute myeloid leukemia (AML). A Phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. Patients and methods: A total of 44 R/R AML patients were treated with ONV+DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (n=32). A 10 gene expression-signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Results: 20% of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi) and 32% exhibited a =50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset.  By applying the signature to the BeatAML cohort (n=399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the Phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). Conclusion: PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations. Overall design: Peripheral blood samples from patients with relapsed or refractory AML were taken prior to treatment with the combination of the PLK1 inhibitor onvansertib and the hypomethylating agent decitabine. The samples were retrospectively used to explore potential biomarkers and gene signatures of response to the treatment.