PURPOSE: First line treatment with platinum-based chemotherapy with or without immunotherapy improves survival in metastatic non-small cell lung cancer (NSCLC). Preclinical studies suggest that pharmacological ascorbate (P-AscH-) enhances tumor response to platinum therapy. Hence, we conducted a single-arm phase II study to evaluate the efficacy of P-AscH- in combination with platinum-doublet chemotherapy in patients with advanced stage NSCLC (NCT02420314). METHODS: Chemotherapy naïve advanced stage NSCLC patients with an ECOG PS of 0-2 were enrolled to receive 4-cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks (wks). Ascorbate (75 g) infusions were given twice a wk for 12-wks. The primary endpoint was to assess tumor objective response per RECIST v1.1. The trial was conducted as an optimal Simon two-stage design. After initial therapy, patients could receive maintenance or consolidation treatment. Secondary endpoints were to evaluate tolerability, progression-free survival (PFS) and overall survival (OS). Serum cytokines and chemokines were measured at baseline, C2d1, and C4d21± 7d. RESULTS: Forty subjects were enrolled. The study met its primary endpoint with 38 efficacy evaluable subjects. The objective response rate was 34.2%. All were confirmed partial responses (cPR). Disease control rate was 84.2% (stable disease + cPR). Median duration of follow up was 11.7 months (mo), mPFS was 5.7 mo (95% CI:4.2-6.7), and mOS was 12.5 mo (95% CI:7.5-21.4). Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 (cytopenia) events. These events were not attributed to P-AscH-. Common (≥5%) grade 3 TRAE included transient hypertension (27.5%), lymphopenia (22.5%), fatigue (7.5%), anemia (7.5%) and hypokalemia (5%). Cytokine and chemokines data suggest that protocol regimen elicited an immune response with multiple distinct cytokine signatures. Immunophenotyping of peripheral blood mononuclear cells (n=7) demonstrated a mean fold increase in effector CD8 T cells of 4.9 in patients with PFS ≥ 6 mo compare to 1.6 in patients with PFS < 6 mo. Assessments of serum iron profile and somatic alterations in KRAS, KEAP1, NFE2L2 and STK11 genes are underway. CONCLUSIONS: This phase II trial met the primary objective of improving the tumor response rate in advanced stage NSCLC by adding P-AscH- to platinum-based chemotherapy. P-AscH- appears to alter the host immune response. These promising findings warrant further investigation.
Citation Format: Muhammad Furqan, Taher Abu-Hejleh, Kellie L. Bodeker, Laura M. Pietrok, Stacey M. Hartwig, Mikaela M. Tremblay, Micaela G. Fosdick, Jon Houtman, Steven Varga, Casey F. Pulliam, Michael Petronek, Melissa A. Fath, Sarah L. Mott, Aaron D. Bossler, Andrew M. Bellizzi, Jun Zhang, Hariharasudan Mani, Varun Monga, Brian J. Smith, Joseph Cullen, Brett A. Wagner, Garry R. Buettner, John M. Buatti, Douglas R. Spitz, Bryan G. Allen. Pharmacological ascorbate enhances platinum-based chemotherapy responses in metastatic non-small cell lung cancer (NSCLC): A phase II clinical trial [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 CT164.