Latest Updates on Nintedanib development: ASCO-2017 Annual Meeting
Nintedanib is a small molecule drug developed by Boehringer Ingelheim and marketed under the brand names Ofev and Vargatef for the treatment of idiopathic pulmonary fibrosis (IPF) and some types of lung cancer. It is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) and is currently under clinical development in Oncology.
Non-small cell lung cancer (KCSG LU14-2 Trial)
Non-small-cell lung carcinoma (NSCLC) is a type of epithelial lung cancer and accounts for about 85% of all lung cancers. In this trial, patients with NSCLC were eligible if they failed at least one prior systemic treatment. Clinical outcomes of nintedanib plus docetaxel for refractory Non-small cell lung cancer patients harboring EGFR mutation (mut-EGFR) showed that, 23 out of 62 patients had activating EGFR mutations and progressed during prior EGFR-TKI treatment. The majority of patients were heavily pretreated, with 43.7% received nintedanib plus docetaxel as ≥ 4th line therapy. 4 patients had prior bevacizumab treatment. Objective response rate (ORR) was reported 22.9%, PFS was 3.9 months (95% CI 3.1-4.6) and OS was 9.5 months (95% CI 5.3-13.7). Depending on EGFR mutation status, ORR in mut-EGFR group was found to be higher than wt-EGFR group (30.4% vs 20%) and median PFS in mut-EGFR group was significantly longer than wt-EGFR group (6.1 vs 3.3 months). Common grade 3/4 adverse events were neutropenia (58.3%) and reversible elevated liver enzyme (18.8%) with no death reported. It suggested that, nintedanib plus docetaxel showed measurable clinical activity with good tolerability for refractory NSCLC patients and this combination may be a recommendable regimen for EGFR-TKI-resistant mut-EGFR NSCLC.
Mesothelioma (LUME-Meso Trial)
Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs. In this trial, Patients with unresectable Mesothelioma were randomized 1:1 to receive ≤6 cycles Pemetrexed/Cisplatin (Day 1) plus Nintedanib or Placebo (Days 2–21), followed by Nintedanib or Placebo monotherapy until disease progression or toxicity. Overall survival showed better treatment with a median OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] Nintedanib vs 15.2 [12.2–23.6] Placebo). PFS results (HR=0.54; 95% CI 0.33–0.87) also showed greatest benefit for epithelioid patients (HR=0.49; 95% CI 0.30–0.82) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] Nintedanib vs 5.7 [5.5–7.0] Placebo). Grade ≥3 adverse events included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0). Survival endpoints results (OS and PFS) showed that, greater clinical benefit was observed in patients with epithelioid histology.
Endometrial cancer (NSGO ENGOT-EN1/FANDANGO trial)
Endometrial cancer is a cancer that arises from the endometrium, the lining of the uterus. Endometrial cancer (EC) patients with advanced and recurrent disease relapse despite treatment with combination chemotherapy and have a short progression-free survival. This placebo-controlled, multicenter, two-arm, phase 2 trial compares nintedanib versus placebo as concomitant and maintenance therapy in combination with chemotherapy in patients with advanced or recurrent Endometrial cancer. The primary objective of this trial is to evaluate efficacy of nintedanib against placebo in combination with chemotherapy, defined by PFS. Approximately, 148 patients will be randomized 1:1 to receive nintedanib 200mg twice daily or placebo (days 2-21) during chemotherapy (six cycles of Carboplatin and paclitaxel every 21 days). Nintedanib/placebo is continued until disease progression, unacceptable toxicity or withdrawal. Secondary endpoints include time to therapy, overall survival (OS), objective response rate (ORR) and disease control rate (DCR).
Advanced solid tumors
Nintedanib is an oral triple kinase inhibitor and is being used in combination with other inhibitors. In this trial, combination of Nintedanib and Bevacizumab which will block VEGF as well as salvage pathway of angiogenesis (PDGFR and FGFR) will be used. This is a phase 1b, open label trial with primary objective to evaluate the safety and tolerability of this combination. The secondary objective is to determine clinical efficacy ORR, PFS, and evaluation of plasma levels of angiogenic and anti-angiogenic biomarkers like VEGF, PDGF, VEGF-R and FGF. Patients in cohort I will be treated with Bevacizumab 15 mg/kg (day 1) intravenously every 3 weeks and Nintedanib 150 mg orally twice daily (days 2-21). In the absence of dose limiting toxicities, Nintedanib dose will be increased to 200 mg PO BID in cohort II. The trial will enroll approx 18 patients. Cohorts I has been completed without DLTs. Cohort II has enrolled 10 patients.
Nintedanib (Ofev) is a drug which is approved in some types of conditions and showed promise in various types of cancer as well, indicating that this multiple growth factors inhibitor has high potential in oncology.
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By Dr. Rupesh Tyagi
Senior Research Analyst, Science and Research @ Innoplexus