AZD5991 Demonstrates 'Limited Clinical Activity' in Most Hematologic Malignancies

AZD5991, an MCL-1 inhibitor, is associated with troponin elevation and low overall response rates in patients with relapsed or refractory hematologic malignancies, according to a recent study.

The phase I, open-label, multicenter, nonrandomized, first-in-human study was led by Pinkal Desai, MD, of Weill Cornell Medical College, and published in Clinical Cancer Research. Dr. Desai and colleagues “assessed the safety, tolerability, pharmacokinetics (PK), and antitumor activity of AZD5991 monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies.”

Sixty-one patients with hematologic malignancies received escalating doses of intravenous AZD5991 once or twice weekly, while 17 patients with acute myeloid leukemia or myelodysplastic syndromes (MDS) received escalating doses of AZD5991 plus venetoclax in either a three- or four-week cycle. The primary endpoints were safety and maximum tolerated dose, while secondary endpoints included plasma PK and antitumor activity.

All patients, except one in the monotherapy group, experienced at least one adverse event (AE). The most frequent AEs included diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Five patients experienced dose-limiting toxicities. Eleven deaths were attributed to disease progression, while five occurred due to AEs (cardiac arrest, sepsis, tumor lysis syndrome [TLS], and acute respiratory failure). TLS was not associated with AZD5991, the authors noted.

Three of five patients with MDS achieved an objective response. One achieved marrow complete remission (mCR) without hematologic improvement, one achieved partial remission after AZD5991 monotherapy, and one achieved mCR after AZD5991 plus venetoclax.

Troponin I or T elevation occurred in eight (10.3%) patients. According to a post-hoc retrospective analysis, elevated troponin T was observed in 14 of 31 (45%) patients before treatment and in 54 of 65 (83%) patients after treatment.

“Except in MDS, limited clinical activity was observed with AZD5991 monotherapy and in combination with venetoclax across different hematologic malignancies,” the researchers concluded. “Based on the retrospective analysis of troponin elevations and cardiovascular risk factors, as well as the risk-benefit profile of AZD5991, the study was ultimately terminated early.”

Reference:

Desai P, Lonial S, Cashen A, et al. A phase 1 first-in-human study of the mcl-1 inhibitor azd5991 in patients with relapsed/refractory hematologic malignancies. Clin Cancer Res. 2024. doi:10.1158/1078-0432.CCR-24-0028