Abstract 1276: A novel targeted oral insulin-like growth factor 1 (IGF-1) receptor inhibitor and its implications for patients with squamous cell lung carcinoma

Abstract

Background The incidence of lung cancer has increased throughout the twentieth century and is today the most common cancer in the Western World. Lung cancer is divided into two major histological subtypes, non-small cell lung cancer (NSCLC) accounting for approximately 80% of all lung cancer cases and small cell lung cancer (SCLC) accounting for approximately 20 % of all lung cancer cases. The median age at diagnosis is 68 years for patients with non-small cell lung cancer (NSCLC) and 20% of lung cancer deaths occur in patients aged 80 or more. The overall objective of the present abstract is to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related Insulin receptor and its impact in patients with especially NSCLC. Methods AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7-28 days of increasing BID doses of AXL1717. Results In the present abstract we describe our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with AXL 1717. Despite the fact that at inclusion these patients had already received third or fourth line treatment, treatment with AXL1717 resulted in more than seven months of treatment response within the study protocol and the reported patients did not develop any additional metastases. Furthermore, these patients demonstrated large central necrotic areas, which may suggest tumor response. Conclusion This first clinical study of AXL1717 has shown that the agent can be administrated safely orally to advanced stage cancer patients resulting in good bioavailability and tolerability. Encouraging signs of tumor response were seen in patients with NSCLC. Further update of these patients as well as a compilation of all included patients with NSCLC, as well as their toxicity, will be reported at the meeting Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2011-1276

The decline and fall of the IGF‐I receptor

“…Inhibitors of tyrosine kinase activity have the problem that they also inhibit the tyrosine kinase of related receptors, like the insulin receptor (InR), but this has been promptly hailed as a great advantage, as a number of investigators (Brierley et al, 2010) have convincingly shown that the InR is activated in cancer cells (see below). Targeting with PPP has been reported to actually inhibit non‐small cell lung carcinomas in humans (Ekman et al, 2011), although that report was limited to a few cases. Further studies on this compound are awaiting conclusions.…”

“…We have already mentioned that overlapping in the latter agents of the tyrosine kinases of both IGF‐1R and InR have already been greeted as an advantage, and we will discuss the role of the InR in human cancer (see below). The most interesting of the IGF‐IR inhibitors is probably the least known, PPP, which has been repeatedly shown to affect the IGF‐1R in cells in culture, in mice (Girnita et al, 2004) and in humans (Ekman et al, 2011). PPP has been considered an inhibitor of the IGF‐IR tyrosine kinase, albeit with some dissenters.…”

Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

“…Furthermore, PPP specifically blocks the phosphorylation of a tyrosine residue, Tyr1136, within the activation loop of the IGF-IR (9). PPP is currently being investigated in clinical trials (under the name AXL1717) and the results that have been presented to date suggest that it has at least some useful clinical activity and exhibits only modest toxicity (10)(11)(12). As such, it is quite different to previously tested IGF-IR antagonists in both respects.…”