JAK1 Inhibitor Shows ‘Remarkable’ Activity in T-Cell Lymphoma

Treatment with a novel, oral JAK1 tyrosine kinase inhibitor induced rapid and durable responses in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), findings from a single-arm phase II study showed.

Among 88 heavily pretreated patients evaluable for efficacy, 44% (95% CI 34-55) responded to single-agent golidocitinib, with 24% (95% CI 15-34) achieving a complete response, reported Jun Zhu, MD, of the Peking University Cancer Hospital and Institute in Beijing, and colleagues.

Moreover, the median duration of response with the selective JAK1-specific agent reached 20.7 months on independent review.

“Golidocitinib showed remarkable and durable anti-tumor activity,” the investigators concluded in Lancet Oncology. “Additionally, golidocitinib showed an acceptable and manageable safety profile in this patient population.”

In North America and Europe, PTCL accounts for about 5% to 10% of non-Hodgkin lymphoma cases, a proportion that more than doubles in Asia.

“Because of heterogenous immunophenotypes and an aggressive course of disease, there is no consensus on the standard treatment for relapsed or refractory peripheral T-cell lymphoma, and most patients have a very poor prognosis, with a 5-year survival rate lower than 30%,” wrote Zhu and co-authors.

Despite receiving accelerated approvals in relapsed or refractory PTCL, romidepsin (Istodax), pralatrexate (Folotyn), and belinostat (Beleodaq) have only shown moderate single-agent activity in this disease, according to the researchers.

In 2009, the FDA approved the histone deacetylase (HDAC) inhibitor romidepsin for PTCL, but that agent was subsequently withdrawn from the market in 2021 following a failed confirmatory trial. The agency approved the dihydrofolate reductase inhibitor pralatrexate in 2009 and the HDAC inhibitor belinostat in 2014, but neither drug has had a confirmatory trial — a source of frustration at FDA.

No JAK inhibitor is approved for PTCL, but prior research has suggested the class of agents could hold promise.

“Constitutive activation of the JAK-STAT pathway is important in T-cell malignancies,” explained Zhu and colleagues, noting that its blockade in clinical PTCL studies — with the JAK1/2 inhibitor ruxolitinib (Jakafi) and cerdulatinib, an investigational pan JAK/SYK inhibitor — has been associated with “encouraging anti-tumor activity.”

“JAK1 has been reported to be the primary driver of STAT3 phosphorylation and activation, and targeting other JAK family members is associated with increased toxicities — e.g., JAK2 inhibition-related serious anemia,” the study authors continued. “A selective JAK1 inhibitor could be a viable approach to effectively block the activation of the JAK-STAT pathway while minimizing toxicities.”

Zhu and co-authors said these phase II results will support a potential accelerated approval in PTCL. Dizal Pharmaceutical, the sponsor of golidocitinib (formerly DZD4205), has secured a fast-track designation from the FDA for speeding development and review of the agent in relapsed or refractory patients with this T-cell malignancy.

Another ongoing phase II study (NCT05963347) is evaluating golidocitinib in combination with cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisolone (CHOP); and a randomized trial is also planned to confirm the drug’s benefit in PTCL.

For the current study, investigators treated 104 adult relapsed or refractory PTCL patients across 49 centers in Australia, China, South Korea, and the U.S. with single-agent golidocitinib from 2021 to 2022. Of those, 88 were evaluable for efficacy. These patients had a median age of 58 years, 65% were men, and 94% were Asian.

PTCL not otherwise specified was the most common histologic subtype, in 57%, followed by angioimmunoblastic T-cell lymphoma in 18%, anaplastic large cell lymphoma in 11%, natural-killer T-cell lymphoma in 3%, and T-cell prolymphocytic leukemia in 1%. In the other 9%, the subtype was uncertain. Most (78%) had no bone marrow involvement at baseline, and a little more than half had increased serum lactate dehydrogenase.

Nearly three-fourths had received two or more prior lines of systemic therapy, including chemotherapy in all of the patients, an HDAC inhibitor in half, CD30-targeted therapy in 10% of the patients, and an ALK inhibitor in 1%.

Median follow-up for the current analysis was 13.3 months. Responses to golidocitinib were rapid, with a median time to first documented response of 1.4 months. The rate of radiographic complete tumor response on CT imaging was 29.5%. Beyond complete responses, 20% of patients achieved a partial response, 19% achieved stable disease, and 23% had progressive disease (14% were not evaluable).

Median progression-free survival was 5.6 months on independent review, and the estimated overall survival was 19.4 months.

In the safety cohort of all 104 patients receiving at least one dose of the JAK1 inhibitor, grade 3/4 drug-related adverse events (AEs) occurred in 59%, with the most common including decreases in neutrophil counts (29%), white blood cell counts (26%), lymphocyte counts (21%), and platelets (20%).

About a fourth of the patients had serious drug-related AEs, and three deaths occurred due to AEs of any kind (two from pneumonia and one due to confusional state).

Ian Ingram is Managing Editor at MedPage Today and helps cover oncology for the site.

Disclosures

Dizal Pharmaceutical funded the study.

Zhu had no disclosures. One co-author is employed by Dizal Pharmaceutical, and other co-authors reported relationships with Dizal, Antengene, AstraZeneca, BeiGene, BostonGene, Bristol Myers Squibb, Celgene, C4 Therapeutics, Corvus Pharmaceuticals, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Kyowa Kirin, Janssen, Novartis, Seattle Genetics, Secura Bio/Verastem, and Yingli Pharmaceuticals.

Primary Source

The Lancet Oncology

Source Reference: Song Y, et al “Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study” Lancet Oncol 2023; DOI: 10.1016/S1470-2045(23)00589-2.

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