Phase 2 Study of Pemetrexed and Itraconazole as Second-Line Therapy for Metastatic Nonsquamous Non–Small-Cell Lung Cancer

Abstract

Purpose Preclinical studies suggested that the oral anti-fungal agent itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent anti-angiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. Based on these data, we performed an exploratory clinical study assessing the efficacy of itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer. Patients/Methods The study enrolled patients with progressive non-squamous non-small cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to pemetrexed 500 mg/m2 IV day 1 with or without itraconazole 200 mg oral daily on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity. Results A total of 23 patients were enrolled; the study was stopped early due to increasing use of pemetrexed in the first line setting. Sixty-seven percent of patients were progression-free at 3 months on itraconazole plus pemetrexed vs. 29% on the control arm of pemetrexed alone (p=0.11). Median progression-free survivals were 5.5 months (itraconazole) vs. 2.8 months (control) (hazard ratio (HR)=0.399, p=0.089). Overall survival was longer in patients receiving itraconazole (median 32 months) vs. control (8 months) (HR=0.194, p=0.012). There were no evident differences in toxicity between the study arms. Conclusion Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.

Repurposing itraconazole as an anticancer agent

“…Phase III trials of the VEGFR inhibitor ramucirumab reported prolonged OS in non-small cell lung, gastric and colorectal cancer, (45)(46)(47)(48). Considering the results of the clinical trials using P-gp inhibitor or antiangiogenic agents (41,(43)(44)(45)(46)(47), the clinical efficacy of itracoanzole treatment in various types of cancer (Table II) implicated the additional anticancer activities, which was demonstrated in preclinical studies (Table I).…”

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

“…Upon validation of its antiangiogenic and antitumor activity in a number of models both in vitro and in vivo (8,10,11), it entered multiple phase 2 clinical trials for treating cancer. To date, the pilot trials in nonsmall cell lung cancer, prostate cancer, and basal cell carcinoma have been completed; itraconazole has been shown to increase the progression-free and overall survival of patients taking the drug (12)(13)(14). Additionally, retrospective studies assessing the outcomes of patients with ovarian cancer and recurrent triplenegative breast cancer taking itraconazole have revealed significant increases in overall survival (15)(16)(17), which are likely to be attributable, at least in part, to the antiangiogenic activity of itraconazole.…”

Repurposing itraconazole for the treatment of cancer

“…The suppression of tumour growth with itraconazole treatment has been demonstrated in non-small cell lung cancer xenografts (8,18). In one such study, growth was reduced by 72 and 79% (P<0.001) in two primary xenograft models (8).…”

“…As well as inhibiting cell proliferation in response to angiogenesis factors (VEGF and fibroblast growth factor), the migration and formation of tube networks were also prevented. These are necessary for capillary bed production; therefore, the area of tumour vascularity significantly decreased (8,18). In addition, itraconazole has been demonstrated to reduce pleural effusion volumes, the number of pleural tumour foci and VEGF-C levels in xenograft models with Lewis lung carcinoma (7).…”