P3.02c-007 Assessment of Dianhydrogalactitol in the Treatment of Relapsed or Refractory Non-Small Cell Lung Cancer: Topic: Targeted Therapy

Abstract

Non-small cell lung cancer (NSCLC) is treated with surgery and chemotherapy with either tyrosine kinase inhibitors (TKIs) or platinum-based regimens, but drug-resistance is frequent and long-term prognosis poor. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent with proven activity against NSCLC in clinical studies. VAL-083 has demonstrated superior activity to cisplatin in both in vitro and in vivo NSCLC models, including TKI-resistant NSCLC, and circumvents cisplatin-resistance in ovarian cancer cells. VAL-083 is approved for the treatment of lung cancer in China; however, clinical adoption is limited by lack of modern data related to mechanism-of-action and utility in the context of standard-of-care platinum-based chemotherapy. Here we aimed to investigate in vitro i) the distinct mechanism-of-action of VAL-083, ii) VAL-083 cytotoxicity in a panel of NSCLC cell-lines with varying p53 status, and iii) the combination of VAL-083 with cisplatin or oxaliplatin. VAL-083 cytotoxicity was investigated in a panel of 11 human NSCLC cell-lines: 3 wild-type (H460, A549, H226), 6 mutant (H1975, SkLU1, H2122, H157, H1792, H23) and 2 null (H838, H1299) for p53. Cell-cycle and DNA damage was investigated by propidium iodide and immunofluorescent staining in synchronized cultures of H2122, H1792, A549. Cytotoxicity was determined by MTT assay. Combination potential for VAL-083 with cisplatin or oxaliplatin was investigated in H460, A549, H1975 (TKI-resistant) by determining superadditivity and synergy using the combination index (CI) <1 criteria. VAL-083 treatment caused persistent S/G2 cell-cycle arrest and cell-death. Furthermore, one-hour pulse treatment led to phosphorylation of DNA double-strand break sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X, suggesting activation of the homologous repair pathway. S/G2 phase cell-cycle arrest and increased γH2A.X in cancer cells persisted >72 hours after treatment, indicating irreversible DNA lesions. Importantly, VAL-083 was active against all cell-lines tested, irrespective of their p53 status, suggesting a mechanism-of-action that differs from other alkylating agents, including cisplatin. When combined with either cisplatin or oxaliplatin in vitro, VAL-083 demonstrated significant superadditivity (p<0.05) and synergism (CI<1) for both combinations in all NSCLC cell-lines. This strongly suggests non-overlapping modes-of-action between the platinum drugs and VAL-083 and demonstrates synergism in TKI-resistant cell-lines. This preclinical data strongly suggests VAL-083 as a potential treatment for platinum and TKI-resistant NSCLC. An open-label post-market clinical trial in China will investigate the activity of VAL-083 in relapsed/refractory NSCLC. Results will provide guidance to physicians under the context of VAL-083’s current approval in China, as well as serve as proof-of-concept for expanded development worldwide.