NuCana Reports Durable Responses with NUC-3373 Plus Pembrolizumab in Heavily Pre-treated Cancer Patients
Key Insights
NuCana (search)'s NUC-3373 combined with pembrolizumab demonstrated durable clinical activity in 12 heavily pre-treated patients with advanced solid tumors (search) who had previously failed PD-1 (search) inhibitor therapy.
A melanoma (search) patient achieved an 81% reduction in target lesions and remains progression-free at 23 months, while a bladder cancer (search) patient experienced 100% tumor lesion reduction and stayed on treatment for over 15 months.
Preclinical data published in PLOS ONE support the clinical findings, showing NUC-3373 promotes immunogenic cell death and enhances immune cell activation when combined with PD-1 (search) inhibition.
NuCana (search) plc has announced encouraging clinical data for its investigational cancer therapy NUC-3373 in combination with the PD-1 (search) inhibitor pembrolizumab, demonstrating durable responses in heavily pre-treated patients with advanced solid tumors (search). The results from the NuTide:303 Phase 1/2b modular study, published on medRxiv, show promising activity in patients who had exhausted standard treatment options and previously received PD-1 inhibitors.
Clinical Efficacy in Treatment-Resistant Patients
In Module 1 of the NuTide:303 study, 12 patients with advanced solid tumors (search) were treated with the NUC-3373 plus pembrolizumab combination. The patient population represented a challenging treatment scenario, having previously failed standard therapies including prior PD-1 (search) inhibitor treatment.
Two patients demonstrated particularly notable responses. A patient with urothelial carcinoma (search) of the bladder achieved a 100% reduction in tumor lesion size, classified as a partial response due to the presence of non-target lesions, and remained on treatment for over 15 months. Additionally, a patient with metastatic melanoma (search) who was resistant to prior pembrolizumab therapy experienced an 81% reduction in target lesions and continues to remain progression-free at 23 months.
Mechanistic Insights from Preclinical Studies
Complementary preclinical findings published in the peer-reviewed journal PLOS ONE provide mechanistic support for the observed clinical activity. The research demonstrates that NUC-3373 in model in vitro systems promotes the release of immunogenic damage-associated molecular patterns (DAMPs) and enhances activation of first-line defense immune cells, including natural killer (NK) cells.
Importantly, the preclinical data show that when combined with a PD-1 (search) inhibitor, NUC-3373 enhances tumor cell death by activating lymphocytes, regardless of the tumor's genomic stability status. This mechanism provides scientific rationale for the synergistic activity observed in the clinical setting.
Drug Development Strategy and Pipeline
NUC-3373 is a potent thymidylate synthase (search) inhibitor that induces DNA damage in cancer cells. The compound represents a new chemical entity derived from the nucleoside analog 5-fluorouracil, a widely used chemotherapy agent, but engineered using NuCana (search)'s proprietary ProTide technology to overcome limitations of conventional nucleoside analogs.
"It is becoming increasingly clear that the majority of future standards of care for advanced cancers will rely on combination regimens incorporating novel immuno-oncology backbones," said Professor David Harrison, Head of Translational Medicine at NuCana (search). "The combination of NUC-3373 with pembrolizumab has demonstrated both a favorable safety profile and evidence of efficacy and durable disease control in this patient cohort."
The NuTide:303 study is evaluating NUC-3373 in combination with pembrolizumab for patients with advanced solid tumors (search) and in combination with docetaxel for patients with lung cancer (search). NuCana (search) is currently evaluating optimal combinations and indications for further clinical studies of NUC-3373.
Company Pipeline and Financial Position
NuCana (search)'s pipeline includes two main assets: NUC-3373 and NUC-7738. NUC-7738 is a novel anti-cancer agent that disrupts RNA polyadenylation and is currently in the Phase 2 part of a Phase 1/2 study (NuTide:701), being evaluated both as monotherapy in patients with advanced solid tumors (search) and in combination with pembrolizumab in patients with melanoma (search).
Andrew Kay, NuCana (search)'s Executive Chairman, noted: "The complementary mechanisms of action of NUC-3373 and PD-1 (search) inhibition provide a strong rationale for synergy. We are currently evaluating optimal combinations and indications for further clinical studies of NUC-3373, while continuing to maintain our anticipated cash runway into 2029."
The company's ProTide technology platform is designed to transform widely prescribed chemotherapy agents into more effective and safer medicines by generating higher concentrations of anti-cancer metabolites specifically in cancer cells, addressing the significant shortcomings and poor tolerability associated with conventional nucleoside analogs.