Golidocitinib + Anti-PD-1 Shows Promise in IO Resistant Non-Small Cell Lung Cancer

Golidocitinib (DZD4205, previously known as AZD4205), an orally available, potent and highly selective Janus kinase 1 (JAK1) inhibitor being developed by Shanghai-based Dizal Pharmaceuticals and approved by the National Medical Products Administration (NMPA) of China for the treatment of relapsed or refractory Peripheral T-cell lymphomas (PTCLs), a group of rare blood cancers, showed synergistic anti-tumor effects in anti-PD-1-resistant non-small cell lung cancer (NSCLC), the most common type of lung cancer, when combined with a PD-1 antibody.[1]

The details of the trial design and the study results will be presented at the 2025 European Lung Cancer Congress (ELCC 2025) in Paris, France, March 26-29, 2025.

The European Lung Cancer Congress, a collaborative effort of the most important multidisciplinary medical societies representing thoracic oncology specialists working together to advance science, disseminate education, is designed to bring the latest clinical updates to benefit and improve the practice of lung cancer specialists worldwide.

JAK/STAT pathway
Recent studies showed that the dysregulated activation of the JAK/STAT pathway, which leads to the prolonged release of IFN-γ, is a significant contributor to the resistance to immune checkpoint inhibitors in cancer immunotherapy. Preclinical and clinical studies have further demonstrated that the combination of JAK inhibitors with PD-1 immunotherapy can reverse or delay onset of immunotherapy resistance by modulating the JAK/STAT pathway in Hodgkin’s lymphoma and NSCLC.

Golidocitinib has shown clinical benefits by effectively inhibiting the JAK/STAT pathway, leading to its approval for the treatment of relapsed/refractory peripheral T-cell lymphoma (r/r PTCL) in China. Furthermore, preclinical studies also show that the combination of Golidocitinib and PD-1 antibody has synergistic potentials for anti-tumor effects.

Building on these findings, an exploratory phase 1b clinical study combining golidocitinib with PD-1 antibodies was designed to explore the synergistic effects of this combined regimen in NSCLC patients who have failed from anti-PD-1 containing regimens. This study will enroll 30 locally advanced or metastatic NSCLC patients who have previously received anti-PD-1 monotherapy or anti-PD-1 therapy with platinum-containing chemotherapy regimens.

“Immunotherapy alone or with chemotherapy is commonly used as front line treatment for NSCLC patients without driver mutations. Unfortunately, resistance is inevitable and once the disease progresses, the prognosis is poor and treatment option is limited.” noted Xiaolin Zhang, PhD, Chief Executive Officer of Dizal.

“The findings we are presenting at ELCC 2025 highlight the potential for Golidocitinib-based combination regimen to delay or overcome the resistance. The preliminary results are very promising and justify further clinical validation,” Zhang added.

Sunvozertinib
In addition to the golidocitinib-based combination therapy, positive results from a Phase 2 study of sunvozertinib (DZD9008), an irreversible EGFR inhibitor targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity, in combination with anlotinib will also be presented. Sunvozertinib  combined with anlotinib was well tolerated and demonstrated encouraging antitumor activity in NSCLC patients with EGFR mutations who had failed prior EGFR-TKI therapies.

As of December 25, 2024, the objective response rate (ORR) and the disease control rate (DCR) were 33.3% and 100%, respectively, in this heavily pre-treated patient population. Enrollment is ongoing and detailed results will be updated at the congress.

Scheduled Presentations

__

Note: * In August 2023, sunvozertinib received approval from NMPA to treat advanced NSCLC with EGFR exon20ins after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M, and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins. Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug-related TEAEs (treatment-emergent adverse event) were Grade 1/2 in nature and clinically manageable. Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 Part B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR exon20ins. Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery and The Lancet Respiratory Medicine.

Clinical trials
Assessing An Oral Janus Kinase Inhibitor, AZD4205 as Monotherapy in Patients Who Have PTCL (JACKPOT8) – ClinicalTrials.gov ID NCT04105010
A Study of Sunvozertinib Combined With Anlotinib in Local Advanced or Metastatic Non-small Cell Lung Cancer WUKONG-9 – ClinicalTrials.gov ID NCT06182761Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer with EGFR or HER2 Mutation (WU-KONG1) – ClinicalTrials.gov ID NCT03974022
A Study of DZD9008 Versus Platinum-Based Doublet Chemotherapy in Local Advanced or Metastatic Non-small Cell Lung Cancer (WU-KONG28) – ClinicalTrials.gov ID NCT05668988

Reference
[1] Won-Seog Kim, Dok-Hyun Yoon, Hyeon-Seok Eom, Youngil Koh, Jae-Yong Kwak, Won-Sik Lee, Jong-Seok Lee, Ho-Jin Shin, Yuqin Song, Haiyan Yang, Mei Wang, Jingrun Li, Xubin Huang, Xueyuan Deng, Kan Chen, Zhenfan Yang, Jun Zhu; A Phase I/II Study (JACKPOT8) of DZD4205, a Selective JAK1 Inhibitor, in Refractory or Relapsed Peripheral T- Cell Lymphoma. Blood 2020; 136 (Supplement 1): 19–20. doi: https://doi.org/10.1182/blood-2020-134650
[2] Song Y, Yoon DH, Yang H, Cao J, Ji D, Koh Y, Jing H, Eom H, Kwak J, Lee W, Lee J, Shin H, Jin J, Wang M, Yang Z, Kim WS, Zhu J. Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas. Ann Oncol. 2023 Nov;34(11):1055-1063. doi: 10.1016/j.annonc.2023.08.013. Epub 2023 Sep 9. PMID: 37673210.
[3] Song Y, Malpica L, Cai Q, Zhao W, Zhou K, Wu J, Zhang H, Mehta-Shah N, Ding K, Liu Y, Li Z, Zhang L, Zheng M, Jin J, Yang H, Shuang Y, Yoon DH, Gao S, Li W, Zhai Z, Zou L, Xi Y, Koh Y, Li F, Prince M, Zhou H, Lin L, Liu H, Allen P, Roncolato F, Yang Z, Kim WS, Zhu J. 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. 2024 Jan;25(1):117-125. doi: 10.1016/S1470-2045(23)00589-2. Epub 2023 Dec 9. PMID: 38092009.

Featured image: © 2019 – 2025 Fotolia/Adobe. Used with permission

DOI