Introduction: Despite significant advances in systemic anticancer therapy (SACT) for non-small cell lung cancer (NSCLC), many patients still fail to respond to treatment or develop treatment resistance. Albumin, a biomarker of systemic inflammation and malnutrition, predicts survival in many cancers. We evaluated the prognostic significance of albumin in patients receiving first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC.Methods: All patients treated with first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC at a regional Scottish cancer centre were identified. Serum albumin at pre-treatment, after 12-weeks of treatment, and at the time of progressive disease were recorded. The relationship between albumin (≥ 35g/L v <35g/L) and overall survival (OS) was examined.Results: Data were available for 389 patients of both targeted therapy cohort (n = 159) and immunotherapy-based therapy cohort (n = 230). Pre-treatment albumin was predictive of OS in each cohort at HR1.82 (95%CI 1.23–2.7) (p =0.003) and HR2.55 (95%CI 1.78–3.65) (p < 0.001), respectively. Pre-treatment albumin <35 g/L was associated with a significantly higher relative risk of death within 12 weeks in each cohort at RR9.58 (95%CI 2.20–41.72, p = 0.003) and RR3.60 (95%CI 1.74–6.57, p < 0.001), respectively. The 12-week albumin was predictive of OS in each cohort at HR1.88 (95%CI 1.86–4.46) (p < 0.001) and HR2.67 (95%CI 1.74–4.08) (p < 0.001), respectively. 46 out of 133 (35%) evaluable patients treated with targeted therapy and 43 out of 169 (25%) treated with immunotherapy-based therapy crossed over albumin prognostic groups between pre-treatment and 12-week. The prognostic value of 12-week albumin was independent of pre-treatment albumin status. A majority of patients had albumin <35g/L at the time of progressive disease when it was also predictive of survival following progressive disease at HR2.48 (95%CI 1.61–3.82) (p < 0.001) and HR2.87 (95%CI 1.91–4.31) (p < 0.001) respectively).Conclusions: Albumin is a reliable prognostic factor in patients with metastatic NSCLC, predicting survival independent of the class of drug treatment at various time points during the patient journey. Tracking albumin concentrations during systemic therapy may indicate disease activity or treatment response over time.
Background: The novel ProTide NUC-7738 is a phosphoramidate transformation of 3'-deoxyadenosine (3'-dA or cordycepin), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3'-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3'-dATP, which inhibits DNA and RNA synthesis. Although 3'-dA has potent in vitro anti-tumor activity, it has not been successful in clinical studies due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 was designed to overcome the key cancer resistance mechanisms associated with 3'-dA. NUC-7738 is resistant to breakdown by ADA, enters cancer cells independently of the human equilibrative nucleoside transporter (hENT1) and it does not require adenosine kinase for phosphorylation. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors or lymphoma who have exhausted all standard treatment options. The primary objective is to determine the recommended phase 2 dose (RP2D) and schedule of NUC-7738. Secondary objectives include safety, pharmacokinetics and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and schedule of NUC-7738. Part 2 will further evaluate NUC-7738 in expansion cohorts of patients with advanced solid tumors or lymphomas. Results: As of 25 Sept 2020, 15 patients had received escalating doses of 14-600 mg/m2 (IV infusion from 30-120 mins) NUC-7738 q1w in Part 1. Patients had received a mean of 3 prior lines of therapy (range: 1 to 5), with melanoma (n=5) and lung (n=3) the most common primary tumor types enrolled. NUC-7738 was well tolerated, with no Grade 3 or 4 treatment-related AEs. No dose-limiting toxicities have been reported. Encouraging signals of anti-cancer activity were observed in three patients who continued to receive clinical benefit for over 6 months (1 patient remained on treatment for over 17 months). NUC-7738 has a predictable plasma PK profile, with a dose proportional increase in Cmax and AUC. High intracellular levels of the anti-cancer metabolite 3'-dATP in PBMCs were detected 2 hours after the start of infusion and maintained for at least 24 hours. Conclusion: NUC-7738 has shown promising anti-cancer activity and a favorable tolerability profile in patients with advanced, treatment-refractory tumors. Patients had high and durable intracellular levels of the anti-cancer metabolite 3'-dATP, supporting non-clinical data that NUC-7738 overcomes the key cancer resistance mechanisms associated with 3'-dA. Citation Format: Ruth Plummer, Farasat Kazmi, Noor Md Haris, Tze-en Ding, Francesca Aroldi, Michelle Myers, Stefan Symeonides, Sarah Blagden. NUC-7738, a novel ProTide transformation of 3′-deoxyadenosine, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT136.
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