Preliminary Biomarker Data from a Phase 1/2 Study of Golidocitinib Demonstrates Targeting JAK/STAT Pathway to Treat Peripheral T-Cell Lymphoma

Background Peripheral T-cell lymphoma (PTCL) is a group of heterogenous non-Hodgkin lymphomas originating from mature T lymphocytes. There is no consensus on treatment for patients with PTCL who failed 1^st line treatment (r/r PTCL). It has been well documented that many PTCL patients have elevated JAK/STAT pathway activities. Golidocitinib (AZD4205) is an orally available, JAK1-specific inhibitor currently in late-stage clinical development. We previously reported encouraging efficacy data from an ongoing phase 1/2 multicenter global study (#NCT04105010, JACKPOT8). Here we presented safety and efficacy data and the biomarker analysis of the samples collected from this study.

Method JACKPOT8 is a single arm, multicenter, multi-cohort global study. Patients with r/r PTCL were enrolled to receive golidocitinib at either 150 mg or 250 mg, once daily until disease progression or meeting pre-defined termination criteria. Antitumor efficacy was assessed according to Lugano criteria. All patients were requested to provide archived or freshly obtained tumor and plasma samples during the screening. Genome level mutation detection was carried out using next generation sequencing (NGS). JAK/STAT pathway activation was assessed according to pSTAT level.

Result At the cut-off date on May 31, 2021, 51 patients with r/r PTCL (21 PTCL-NOS, 20 AITL, 4 ALCL ALK-, 4 NKTCL, 2 MEITL) had been enrolled into the study and treated with golidocitinib at 150 mg (n = 35) or 250 mg (n = 16). Median number of prior treatment regimens was 2; 10 patients had a prior stem cell transplant. Overall, golidocitinib showed an acceptable safety profile. Grade 3 or above adverse events occurring in 10% or more of patients included neutropenia (29.4%), thrombocytopenia (15.7%), and pneumonia (11.8%). The majority of AEs were reversible or clinically manageable with dose modifications. Of all 49 patients who completed at least one investigator-based tumor response assessment, 21 achieved tumor response (ORR 42.9%), including 11 complete responses (CRs, 22.4%). Tumor samples from 20 patients were determined suitable for pSTAT3 IHC analysis. A positive trend between clinical activity and high level of pSTAT3 was observed (Table 1). Targeted genomic sequencing was carried out in samples from 19 patients. No genetic mutations associated with JAK/STAT pathway (including JAK1/2/3, STAT3/5A/5B/6) were identified in the tested samples.

Conclusion Golidocitinib demonstrated its promising potential as a novel targeted therapy for the treatment of PTCL. Clinical activity was observed across different subtypes. No apparent correlation between mutations in JAK/STAT pathway and clinical response was observed while baseline high pSTAT level seems to predict clinical benefit. Larger sample size is needed to confirm the findings.

Koh:Sanofi Genzyme: Research Funding. Wang:Dizal Pharmaceuticals: Current Employment, Current equity holder in private company.