Contributions
Abstract: EP928
Type: E-Poster Presentation
Session title: Myelodysplastic syndromes - Clinical
Background
Pevonedistat (PEV) combined with azacitidine (AZA) has demonstrated promising efficacy and a similar safety profile to that of AZA alone with no added myelosuppression, following evaluation in patients with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).
Aims
The objective of this pooled analysis was to assess the impact of PEV exposure on efficacy and safety.
Methods
The PEV exposure–efficacy analyses were conducted with data from NCT02610777, including overall survival (OS), complete response (CR), CR+partial response (PR) and event-free survival (EFS), in patients with higher-risk MDS/CMML who received PEV+AZA. The PEV exposure–safety analyses used pooled data from three studies (NCT01814826, NCT02782468 and NCT02610777), including ≥ grade 3 treatment-emergent adverse event (TEAE3), ≥ grade 3 neutropenia (NEU3), febrile neutropenia (FN), ≥ grade 3 aspartate aminotransferase elevation, ≥ grade 3 thrombocytopenia and ≥ grade 3 alanine aminotransferase elevation, in patients with higher-risk MDS/CMML and AML who received PEV+AZA. The exposure metrics for each patient were sourced from a previously developed population pharmacokinetic model using pooled data from eight phase 1/2 studies. Logistic regression was conducted to estimate PEV exposure–safety relationships for the toxicity endpoints, exposure–CR and exposure–CR+PR. The following covariates were assessed: age, sex, race, disease type and baseline Eastern Cooperate Oncology Group Performance Status (ECOG PS) score. The PEV exposure–survival for higher-risk MDS/CMML was assessed using Cox proportional-hazards models, with the following potential covariates: age, sex, disease type, baseline ECOG PS score and Revised International Prognostic Scoring System score (IPSS-R).
Results
In total, the exposure–efficacy analyses included 41 patients (median age, 74 years; male, 76%; Caucasian, 90%; median IPSS-R, 5.5), and the exposure–safety analyses included 135 patients (median age, 74 years; male, 64%; Caucasian, 82%). Following a starting dose of
20 mg/m2, there was a consistent clinical benefit in terms of OS, EFS, CR or CR+PR across the range of PEV exposures. Furthermore, PEV exposure was significantly related to the incidence of FN (p = 0.02), NEU3 (p = 0.003) and TEAE3 (p = 0.02), supporting PEV dose reductions for patients experiencing treatment-related adverse events.
Conclusion
These exposure–efficacy and exposure–safety results support a favorable benefit–risk profile of PEV 20 mg/m2 on days 1, 3 and 5 in combination with AZA 75 mg/m2 for 7 days in 28-day cycles. The study demonstrates consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2 and supports PEV dose reductions for patients with treatment-related adverse events.
Keyword(s): Acute myeloid leukemia, Azacitidine
Abstract: EP928
Type: E-Poster Presentation
Session title: Myelodysplastic syndromes - Clinical
Background
Pevonedistat (PEV) combined with azacitidine (AZA) has demonstrated promising efficacy and a similar safety profile to that of AZA alone with no added myelosuppression, following evaluation in patients with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).
Aims
The objective of this pooled analysis was to assess the impact of PEV exposure on efficacy and safety.
Methods
The PEV exposure–efficacy analyses were conducted with data from NCT02610777, including overall survival (OS), complete response (CR), CR+partial response (PR) and event-free survival (EFS), in patients with higher-risk MDS/CMML who received PEV+AZA. The PEV exposure–safety analyses used pooled data from three studies (NCT01814826, NCT02782468 and NCT02610777), including ≥ grade 3 treatment-emergent adverse event (TEAE3), ≥ grade 3 neutropenia (NEU3), febrile neutropenia (FN), ≥ grade 3 aspartate aminotransferase elevation, ≥ grade 3 thrombocytopenia and ≥ grade 3 alanine aminotransferase elevation, in patients with higher-risk MDS/CMML and AML who received PEV+AZA. The exposure metrics for each patient were sourced from a previously developed population pharmacokinetic model using pooled data from eight phase 1/2 studies. Logistic regression was conducted to estimate PEV exposure–safety relationships for the toxicity endpoints, exposure–CR and exposure–CR+PR. The following covariates were assessed: age, sex, race, disease type and baseline Eastern Cooperate Oncology Group Performance Status (ECOG PS) score. The PEV exposure–survival for higher-risk MDS/CMML was assessed using Cox proportional-hazards models, with the following potential covariates: age, sex, disease type, baseline ECOG PS score and Revised International Prognostic Scoring System score (IPSS-R).
Results
In total, the exposure–efficacy analyses included 41 patients (median age, 74 years; male, 76%; Caucasian, 90%; median IPSS-R, 5.5), and the exposure–safety analyses included 135 patients (median age, 74 years; male, 64%; Caucasian, 82%). Following a starting dose of
20 mg/m2, there was a consistent clinical benefit in terms of OS, EFS, CR or CR+PR across the range of PEV exposures. Furthermore, PEV exposure was significantly related to the incidence of FN (p = 0.02), NEU3 (p = 0.003) and TEAE3 (p = 0.02), supporting PEV dose reductions for patients experiencing treatment-related adverse events.
Conclusion
These exposure–efficacy and exposure–safety results support a favorable benefit–risk profile of PEV 20 mg/m2 on days 1, 3 and 5 in combination with AZA 75 mg/m2 for 7 days in 28-day cycles. The study demonstrates consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2 and supports PEV dose reductions for patients with treatment-related adverse events.
Keyword(s): Acute myeloid leukemia, Azacitidine