Encouraging complete responses (CRs) with CDK9 inhibitor AZD4573 in patients (pts) with relapsed/refractory (r/r) peripheral T‐cell Lymphoma (PTCL): Early trial analysis

Introduction: Pts with r/r PTCL have limited treatment options and poor outcomes to standard of care therapy. CDK9 regulates transcription elongation through phosphorylation of RNA polymerase II. AZD4573 is a highly potent and selective CDK9 inhibitor that downregulates short-lived transcripts and labile proteins such as MCL1, BFL1, and MYC, which are overexpressed in haematologic tumours including T cell lymphoma. Preclinical studies demonstrate that AZD4573 induces apoptosis and inhibits tumour growth of PTCL cell lines and patient samples in vitro and in vivo (Cidado, CCR 2020;26:922–34). In a phase 1, first-in-human study in pts with haematologic cancers, the recommended phase 2 dose of AZD4573 monotherapy was 12 mg IV QW (Brümmendorf, ASH 2022, abs 1353). Here we report the efficacy and safety of AZD4573 monotherapy in a phase 2a study of pts with r/r PTCL (NCT05140382). Methods: Pts in this single-arm, open-label study were ≥18 years old, had ECOG PS ≤2, and ≥1 prior line of therapy including an alkylating agent and/or anthracycline. Primary cutaneous and primary leukemic PTCL subtypes were excluded. Each pt received an intra-pt ramp-up of AZD4573: 6 mg on day 1, 9 mg on day 8, then the target dose of 12 mg on day 15, continuing QW thereafter. The primary objective was efficacy by investigator-assessed ORR (Lugano 2014 criteria); secondary objectives included efficacy by complete response (CR) rate, duration of response, progression-free survival and overall survival; safety and tolerability; and pharmacokinetics (PK). Results: Eighteen pts received AZD4573; median age was 63.0 years (range 45–83), 66.7% were male and median number of prior regimens was 3.0 (range: 1–9). At the 1 Feb 2023 data cutoff, efficacy was evaluable in 12 pts who had received at least one 12 mg dose. The ORR was 3/12 (25.0%, all CRs) in the efficacy-evaluable set (Table). The CRs lasted 7.7 wks to 17.4+ wks. An additional complete metabolic response (CMR) was observed in a pt after initial progressive disease (PD). Safety was evaluable in 18 pts who received ≥1 dose. Treatment-emergent adverse events (TEAEs) occurred in 16 pts (88.9%), all of which were Grade ≥3. Key Grade ≥3 TEAEs were neutropenia (55.6%) and increased AST (22.2%). Two pts (11.2%) discontinued due to TEAEs (hospitalisation and septic shock, n = 1 each). Serious TEAEs were reported in 72.2% and were deemed treatment-related by investigators in 61.1%. Grade 5 treatment-related AEs were reported in 2 pts (11.1%, both septic shock). AZD4573 exhibited linear PK (half-life ∼6 hrs) with dose-dependent increases in Cmax and AUC. Conclusions: Preliminary results show encouraging clinical activity with AZD4573 monotherapy in pts with r/r PTCL, including 3 CRs and one CMR after initial PD. Safety and PK profiles are consistent with the phase 1 study with no unexpected findings, and the study continues to expand in the PTCL population. Previously submitted to EHA 2023. Encore Abstract - previously submitted to EHA 2023 The research was funded by: AstraZeneca Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. L. Zinzani Consultant or advisory role: Takeda, BMS, MSD, Beigene, Roche, Incyte, Gilead Honoraria: Takeda, BMS, MSD, Beigene, Roche, Incyte, Gilead T. Feldman Consultant or advisory role: Kite, Seagen, ADCT, Gilead, AstraZeneca Other remuneration: Takeda, SecuraBio, Epizyme G. Collins Consultant or advisory role: Roche, Takeda, Beigene, AstraZeneca, Incyte, BMS Honoraria: Roche, Takeda, Incyte, Beigene, AstraZeneca, SecuraBio, Kite, Novartis Research funding: Pfizer, BMS, AstraZeneca, Amgen, Beigene J. Zain Consultant or advisory role: SecuraBio, Myeloid, Seattle Genetics Honoraria: Kyowa Kirin Research funding: SecuraBio, Myeloid, Seattle Genetics, CRSPR AstraZeneca A. Khot Honoraria: Janssen, Celgene/ BMS, Amgen, Mundipharma, Kyowa Kirin F. Morschhauser Consultant or advisory role: Genmab, Novartis, Gilead, Roche T. M. Kim Consultant or advisory role: Boryung, AstraZeneca/MedImmune, Takeda, Novartis, Janssen, Hanmi, and Regeneron Honoraria: Takeda, Janssen, Regeneron, Samsung Bioepis, and AstraZeneca Research funding: Boryung, Boehringer-Ingelheim, BMS, Bayer, AstraZeneca/MedImmune, Takeda, Roche/Genentech, Novartis, Janssen, Hanmi, Genmab, Merck Serono, Merck Sharp & Dohme, Regeneron, and Sanofi J. Roderick Employment or leadership position: AstraZeneca J. L. Yoon Employment or leadership position: AstraZeneca S. Sharma Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Saeh Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Dai Employment or leadership position: AstraZeneca R. Reyes Employment or leadership position: AstraZeneca R. F. Olsson Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Shortt Consultant or advisory role: Otsuka, Novartis, Astellas, Pfizer, BMS, Mundipharma Honoraria: Mundipharma (speakers bureau) Research funding: Amgen, BMS, Astex