A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes

Abstract

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase inhibitory immune checkpoint (ICP) molecule expression. We conducted the first randomized phase 2 study of azacitidine plus the ICP inhibitor durvalumab versus azacitidine monotherapy as first-line treatment of higher-risk myelodysplastic syndromes (HR-MDS). Patients (N=84) received azacitidine 75 mg/m2 subcutaneously (days 1-7) with (Arm A) or without (Arm B) durvalumab 1500 mg intravenously on day 1 every 4 weeks. After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arms A and B received a median of 7.9 and 7.0 treatment cycles, respectively, with 73.7% and 65.9% completing ≥4 cycles. The overall response rate (primary endpoint) was 61.9% in Arm A (26/42) and 47.6% in Arm B (20/42; P=0.18), and median overall survival was 11.6 months (95% CI: 9.5, nonevaluable) versus 16.7 months (95% CI: 9.8, 23.5) (P=0.74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (A) and 81% (B). Grade 3 or 4 hematologic AEs were reported in (Arm A vs B) 89.5% vs 68.3% of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased PD-L1 (CD274) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining durvalumab and azacitidine in patients with HR-MDS was feasible, but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. ClinicalTrials.gov: NCT02775903

Dynamics of PD-1 expression are associated with treatment efficacy and prognosis in patients with intermediate/high-risk myelodysplastic syndromes under hypomethylating treatment

“…In this context, many combined therapies using HMA with novel drugs were designed for long-term synergistic effects and prolonged survival in treating MDS ( 26 , 37 ). These combinations included HMA plus immune checkpoint inhibitors (anti-PD-1/PD-L1) ( 38 , 39 ), HMA plus histone deacetylase inhibitors (HDACi) ( 40 , 41 ), and HMA plus immunosuppressive agent (lenalidomide) ( 42 , 43 ) and others. Combining HMA with immune checkpoint inhibitors is designed primarily to sensitize the antitumoral immune response of these therapies.…”

“…However, although some HMA-based combined therapies have demonstrated a favorable response rate in patients with higher-risk MDS, survival benefit was not achieved in these trials. At the same time, non-neglectable toxicities were frequently noted ( 38 , 39 ). A recent head-to-head study by Zeidan, A.M., et al.…”

“…A recent head-to-head study by Zeidan, A.M., et al. revealed the combination of azacitidine plus durvalumab (a PD-L1 inhibitor) leads to up to 89.5% grade 3-4 hematologic adverse events (AEs) in higher-risk MDS, while the incidence of grade 3-4 AEs remains 68.3% in patients treated with single azacitidine ( 39 ). Thus, a more rationally designed medication timing and dosage of these combinations will be especially important.…”

Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…In newly diagnosed HR-MDS, the FUSION-AML-001 trial failed to show improvement in patient outcomes with the use of azacitidine plus durvalumab compared to azacitidine alone. Of the 84 patients enrolled (42 in each arm), there was no significant difference in the ORR (61.9% vs. 47.6%, p = 0.18) and median OS (11.6 vs. 16.7 months; p = 0.74) between both arms [ 60 ]. Furthermore, toxicities, including hematologic adverse events and infections, were higher with the combination regimen (89.5% vs. 73.2% and 86.8% vs. 65.9%, respectively) [ 60 ].…”

“…Of the 84 patients enrolled (42 in each arm), there was no significant difference in the ORR (61.9% vs. 47.6%, p = 0.18) and median OS (11.6 vs. 16.7 months; p = 0.74) between both arms [ 60 ]. Furthermore, toxicities, including hematologic adverse events and infections, were higher with the combination regimen (89.5% vs. 73.2% and 86.8% vs. 65.9%, respectively) [ 60 ]. Similarly, atezolizumab alone and in combination with azacitidine failed to show clinical benefit in patients with R/R or HMA-naïve MDS [ 61 ].…”