AZD4573 Elicits Responses in Relapsed/Refractory Peripheral T-cell Lymphoma

Pier Luigi Zinzani, MD, PhD

Single-agent treatment with the CDK9 inhibitor AZD4573 produced clinical activity in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), according to an early analysis of a phase 2a trial (NCT05140382) presented at the 17th Annual International Conference on Malignant Lymphoma.¹

Among evaluable patients in the intent-to-treat (ITT) population who started treatment at least 8 weeks before data cutoff (n = 20), the objective response rate (ORR) was 15.0%, with all 3 responders achieving a complete response (CR). One CR lasted 1.8 months, and 2 CRs were ongoing at 2.3 months and 4.0 months, respectively.

Patients who received at least 1 or more target dose of AZD4573 at 12 mg (n = 17) experienced an ORR of 17.6%, and the ORR in patients who received 2 or more cycles of treatment (n = 9) was 33.3%.

“Preliminary results show encouraging clinical activity with AZD4573 monotherapy in patients with relapsed/refractory PTCL,” lead study author Pier Luigi Zinzani, MD, PhD, of the University of Bologna Institute of Hematology in Bologna, Italy, and colleagues, wrote in a poster presentation of the data.

Patients with relapsed/refractory PTCL have limited treatment options and poor survival outcomes. A prior first-in-human, phase 1 study (NCT03263637) in patients with hematologic malignancies determined the recommended phase 2 dose of AZD4573 as 12 mg once weekly.² In the phase 1 study, AZD4573 was found to have a manageable safety profile. Notably, no patients with PTCL were treated during the phase 1 study; however, 2 patients with diffuse large B-cell lymphoma responded to treatment.

In the ongoing phase 2a trial, investigators are evaluating the efficacy and safety of AZD4573 monotherapy in patients at least 18 years of age with relapsed/refractory PTCL who have an ECOG performance status of 0, 1, or 2 who received 1 or more prior lines of therapy, including an alkylating agent and/or anthracycline.¹ Moreover, patients must have fresh or archival tumor tissue at screening, and adequate hematological and organ function.

Key exclusion criteria include the presence of bulky disease 10 cm or greater or lactate dehydrogenase more than 3 times the upper limit of normal; a diagnosis of lymphoblastic/precursor T-cell lymphoma or leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, or cutaneous T-cell lymphoma; uncontrolled systemic disease; presence or history of central nervous system lymphoma, leptomeningeal disease, or spinal cord compression; or treatment with investigational drugs, cytotoxic chemotherapy, standard-of-care anti-lymphoma therapy, or radiation therapy within 14 days of study treatment initiation.

Patients treated thus far all received AZD4573 monotherapy. During an intra-patient ramp-up period in cycle 1, patients received 6 mg of AZD4573 on day 1, 9 mg on day 8, and 12 mg on days 15, 22, and 29. AZD4573 was given at 12 mg once weekly every 3 weeks thereafter. Notably, there is potential for a phase 2b expansion portion of the study with regulatory intent.

ORR per investigator assessment is serving as the primary end point. Secondary end points include CR rate, duration of response, progression-free survival (PFS), overall survival (OS), safety and tolerability, and plasma pharmacokinetics. Exploratory end points consist of the pharmacodynamic profile of AZD4573, urine plasma pharmacokinetics, assessment of biomarkers that may be associated with response or resistance to AZD4573, and the association between genetic polymorphisms and variations in patient outcomes.

At the March 8, 2023, data cutoff, 23 patients received at least 1 dose of AZD4573, and the median duration of follow-up was 2 months (range, 0.03-7.13). The median age was 62.0 years (range, 45-83), 65.2% of patients were male, and 60.9% of patients were White. The median number of prior lines of treatment was 3.0 (range, 1-9). Previous treatments included autologous hematopoietic stem cell transplant (21.7%) and allogeneic hematopoietic stem cell transplant (4.3%).

T-cell lymphoma subtypes included angioimmunoblastic T-cell lymphoma (30.4%), T-follicular helper/non-anaplastic large-cell lymphoma (13.0%), PTCL not otherwise specified (30.4%), ALK-negative anaplastic large-cell lymphoma (13.0%), and monomorphic epitheliotropic intestinal T-cell lymphoma (4.3%).

Additional data showed the median PFS in the ITT population was 1.9 months (95% CI, 1.22-2.04), and the 3-month PFS rate was 19.5% (95% CI, 4.96%-41.16%). Moreover, the median OS was not reached at the data cutoff, and the 3-month OS rate was 71.2% (95% CI, 46.62%-85.94%).

The safety analysis included the 23 patients who received 1 or more doses of AZD4573, and treatment-emergent adverse effects (TEAEs) occurred in 87.0% of patients, including 82.6% of patients who experienced grade 3 or higher TEAEs. Additionally, 87.0% of patients had AEs that were possibly related to AZD4573, and 65.2% of patients had grade 3 or higher AEs possibly related to the agent.

Additionally, serious TEAEs were reported in 69.6% of patients, and 56.5% experienced treatment-related serious TEAEs.

Three patients (13.0%) experienced AEs that led to death, and 2 of these deaths (8.7%) were considered possibly related to AZD4573. Notably, 2 instances of grade 5 septic shock were reported. Thirteen percent of patients discontinued treatment due AEs.

The most common grade 3 or higher TEAEs included neutropenia (52.2%), increased aspartate aminotransferase (26.1%), decreased white blood cell count (21.7%), increased alanine aminotransferase (13.0%), decreased neutrophil count (13.0%), septic shock (8.7%), anemia (8.7%), drug-induced liver injury (8.7%), thrombocytopenia (8.7%), acute kidney injury (8.7%), increased gamma-glutamyl transferase (8.7%), and decreased lymphocyte count (8.7%).

“AZD4573 monotherapy showed a manageable safety profile in patients with PTCL, consistent with findings from the previous phase 1 study,” study authors wrote.

Enrollment for the trial is ongoing.

References

1. Zinzani PL, Feldman T, Collins G, et al. Encouraging complete responses observed with CDK9 inhibitor AZD4573 in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL): early trial analysis. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Poster 425.
2. Brummendorf TH, Medd P, Koch R, et al. Safety, tolerability, pharmacokinetics (pk) and preliminary antitumor activity of the cyclin-dependent kinase-9 (CDK9) inhibitor AZD4573 in relapsed/refractory hematological malignancies: a phase 1 first-in-human study. Blood. 2022;140(suppl 1):3126–3127. doi:10.1182/blood-2022-167203