NUC-1031 Plus Cisplatin Versus GemCis for First-line Treatment of Advanced BTC, NuTide: 121

In the phase 3 Nutide:121 study, NUC-1031 plus cisplatin was compared with gemcitabine/cisplatin for first-line treatment of patients with advanced biliary tract cancer.

NUC-1031 is a novel agent that was developed by adding a phosphoramidate group to gemcitabine to enhance its function and overcome limitations.¹ Compared with gemcitabine, NUC-1031 has greater plasma stability (T_1/2, 8.3 hours vs 1.5 hours) and increased intracellular levels of active anticancer metabolite, dFdCTP (217 times greater).² The safety and dose selection of NUC-1031—625 mg/m² or 725 mg/m² plus cisplatin 25 mg/m²—were investigated in a phase 1b study in patients with biliary tract cancer (BTC) in the ABC-08 trial.³ The recommended phase 2 dose was determined to be 725 mg/m²; the overall response rate (ORR) was 44%, the complete response rate was 6%, and the partial response rate was 38%.³ The most common grade 3/4 treatment related adverse events were increased gamma-glutamyltransferase (42.9%) and alanine transaminase (11.1%), neutropenia (23.8%), leukopenia (11.1%), fatigue (19%), and diarrhea (11.1%).³ This evidence led to the development of the phase 3 trial, NuTide:121. Jennifer J. Knox, MD, MSc, FRCP(C), presented the findings from NuTide:121, a phase 3, randomized, open-label, multicenter study of NUC-1031 plus cisplatin versus gemcitabine/cisplatin (GemCis) for first-line treatment of patients with advanced BTC.

In general, GemCis had superior PFS and OS compared with NUC-1031 plus cisplatin; however, NUC-1031 plus cisplatin achieved higher ORR (BICR) but with inferior durability.⁴

The trial opened in November 2019 and encompassed 15 countries across North America, Europe, and Asia Pacific.⁴ The trial included patients with untreated, locally advanced or metastatic BTC who had a life expectancy of ≥16 weeks and an Eastern Cooperative Oncology Group performance status score of 0 or 1.4 Patients were randomized based on measurable disease, metastatic disease, anatomic site of disease, and geographic region.⁴ The primary end point was overall survival (OS) and ORR, and secondary end points included progression-free survival (PFS) and safety.⁴

A total of 773 patients were enrolled: 388 to NUC-1031 plus cisplatin and 385 to GemCis. Demographics in the NUC-1031 plus cisplatin group and the GemCis group were well balanced.⁴ From the safety population, patients in the NUC-1031 plus cisplatin group (n=383) received a median of 4.0 (range, 1-22) treatment cycles, and patients in the GemCis group (n=378) received a median of 6.0 (range, 1-25) treatment cycles.⁴ Blinded independent central review (BICR) ORR was 18.7% in the NUC-1031 plus cisplatin group and 12.4% in the GemCis group.⁴ The BICR complete response rate with NUC-1031 plus cisplatin was 1.1%, and it was 0% with GemCis.⁴ The BICR median duration of response was 6.4 months in the NUC-1031 plus cisplatin group and 12.3 months in the GemCis group.⁴ The NUC-1031 plus cisplatin group had a median PFS of 4.9 months versus 6.4 months with GemCis (hazard ratio [HR], 1.45; P<.001) and the median OS was 9.2 months with NUC-1031 plus cisplatin versus 12.6 months with GemCis (HR, 1.79; P<.001).⁴ The most common treatment emergent adverse events occurring in >10% of the safety population in the NUC-1031 plus cisplatin group were sepsis (2 patients), pneumonia (1 patient), and liver injury (1 patient). In the GemCis group, 1 patient had acute chronic kidney disease.⁴ In patients who discontinued therapy in ≤30 days of treatment, 56 (14.6%) patients withdrew from the study due to any adverse event (26 treatment-related) in the NUC-1031 plus cisplatin group, and 10 (2.6%) patients withdrew from the study due to any adverse event in the GemCis group (6 treatment-related).⁴

In general, GemCis had superior PFS and OS compared with NUC-1031 plus cisplatin; however, NUC-1031 plus cisplatin achieved higher ORR (BICR) but with inferior durability.⁴ The safety profiles between the 2 treatments were generally similar, with the exception of increased reversible liver toxicity with NUC-1031 plus cisplatin and a higher discontinuation rate with NUC-1031 plus cisplatin.⁴ Overall, results of this trial do not advance the treatment of BTC and are consistent with prior trials.

References

1. Slusarczyk M, Lopez MH, Balzarini J, et al. Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J Med Chem. 2014;57(4):1531-1542.
2. Blagden SP, Rizzuto I, Suppiah P, et al. Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study. Br J Cancer. 2018;119(7):815-822.
3. McNamara MG, Bridgewater J, Palmer DH, et al. A Phase Ib Study of NUC-1031 in combination with cisplatin for the first-line treatment of patients with advanced biliary tract cancer (ABC-08). Oncologist. 2021;26(4):e669-e678.
4. Knox JJ. Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). Presented at: ASCO 2023 Annual Meeting, June 2-6; Chicago, IL.