David Sallman, MD, Assistant Member of the Malignant Hematology Department at Moffitt Cancer Center and Research Institute, Tampa, Florida, commented on these findings for The ASCO Post.

“Although the hypomethylating agent azacitidine represents a standard of care for higher-risk myelodysplastic syndromes [MDS], approximately 50% of patients will not respond, and less than 20% of patients will have a complete remission; thus, novel therapies are urgently needed to improve outcomes in this patient population. However, multiple azacitidine combination trials to date have thus far failed to significantly improve outcomes over azacitidine monotherapy, with no new higher-risk MDS approvals in more than 14 years,” Dr. Sallman noted.

David Sallman, MD

He observed that the randomized phase II study presented by Ades and colleagues found the combination of pevonedistat and azacitidine to be safe, without exacerbation of hematologic toxicities, compared with azacitidine alone. “And of note, the combination did show significant activity as seen by a near doubling of complete remission rates, and these responses were durable and occurred in patients with adverse molecular features,” stated Dr. Sallman.

“In the higher-risk MDS subset, there was a 6-month improvement in event-free survival, ie, transformation to acute myeloid leukemia or death, although without an improvement in overall survival. However, the relevant importance of event-free survival (vs overall survival) in higher-risk MDS requires further investigation,” he suggested.

Phase III Study Underway

A randomized phase III study of this combination vs azacitidine alone in higher-risk MDS, chronic myelomonocytic leukemia, and oligoblastic acute myeloid leukemia, with a primary endpoint of event-free survival, is ongoing (PANTHER; ClinicalTrials.gov identifier NCT0326895). “This will be a pivotal trial to definitively answer whether the addition of pevonedistat indeed improves outcomes in patients with higher-risk MDS, although the data to date are encouraging,” Dr. Sallman commented. 

DISCLOSURE: Dr. Sallman has served as a consultant or advisor to Agios, BMS, Celyad, Incyte, Kite Phamra, Novartis, and Syndax; has participated in a speakers bureau for AbbVie, Agios, Incyte, and Novartis; has received institutional research funding from Celgene and Jazz; and holds a patent for LB-100.