Sojung Park

BACKGROUND: Phase 3 trials have shown that nintedanib reduces the decline in forced vital capacity (FVC) in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF) with acceptable safety profiles; however, its effects on advanced IPF are unclear. We investigated the efficacy and safety of nintedanib in patients with advanced IPF. METHODS: Prospective data were obtained from 108 IPF patients administered at least one dose of nintedanib. Of these patients, 47.2% had advanced IPF (FVC < 50% predicted, or diffusing capacity < 30% predicted). RESULTS: The median treatment duration was 42.2 weeks. Nintedanib significantly reduced the decline rate in both FVC (- 0.55% [before] vs. -0.32% [after] predicted/month, p = 0.020) and total lung capacity (TLC) (- 0.35% vs. -0.06% predicted/month, p < 0.001) in all patients. A significant improvement in FVC decline rate after treatment was also observed in the advanced group (- 0.77% vs. -0.22% predicted/month, p = 0.003), but not in the non-advanced group (- 0.41% vs. -0.33% predicted/month, p = 0.564). Adverse events occurred in 97.2% of the cohort, including diarrhoea (50.0%) and anorexia (45.4%). Following adjustment for treatment duration, no inter-group difference in odds ratio was observed for the occurrence of adverse events. However, the advanced group showed a higher frequency of treatment interruption (68.0% vs. 40.0%), mainly as a result of disease progression (47.1% vs. 36.4%). CONCLUSIONS: The efficacy and safety profiles of nintedanib in the advanced group were comparable to those in the non-advanced group except for a higher frequency of discontinuation, which may be due to the advanced status itself.

// Ji Hyun Park 1 , Yun Jung Choi 2, 3 , Seon Ye Kim 2, 3 , Jung-Eun Lee 2, 3 , Ki Jung Sung 2, 3 , Sojung Park 2 , Woo Sung Kim 2 , Joon Seon Song 4 , Chang-Min Choi 1, 2 , Young Hoon Sung 3, 5 , Jin Kyung Rho 3, 5 , Jae Cheol Lee 1 1 Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea 2 Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea 3 Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea 4 Department of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea 5 Department of Convergence Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea Correspondence to: Jin Kyung Rho, e-mail: jkrho@amc.seoul.kr Jae Cheol Lee, e-mail: jclee@amc.seoul.kr Keywords: 3rd generation, EGFR-TKI, IGF1R, resistance, NSCLC Received: December 07, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 21, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 09, 2016 ABSTRACT Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10&ndash;100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance.