BIBW 2992 Plus Simvastatin vs. BIBW 2992 in Previously Treated Patients With Advanced Non-adenocarcinomatous NSCLC

• Objective response rate [ Time Frame: each 8 weeks ] [ Designated as safety issue: No ]
  Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
  
  

• Disease Control Rate [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
  Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
  
  
• Progression-Free Survival [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
  Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
  
  
• Overall Survival [ Time Frame: every 12 weeks ] [ Designated as safety issue: No ]
  Overall survival (OS) will be calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurs first.
  
  
• Adverse event [ Time Frame: first drug intake until 28 days after last treatment administration ] [ Designated as safety issue: Yes ]
  For grading of adverse events CTC AE criteria (version 4.0) will be utilizedStatistical analysis and reporting of adverse events will concentrate on treatment-emergent adverse events. To this end, all adverse events occurring between first drug intake until 28 days (inclusive) after last treatment administration will be considered 'treatment-emergent'. Adverse events that start before first drug intake and deteriorate under treatment will also be considered as 'treatment-emergent'.
  
  
• Pharmacogenetic and biomarkers analyses [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
  The primary focus of predictive biomarker analyses is to investigate potential relationships of certain biomarkers with efficacy or safety endpoints. For this study, predictive efficacy analyses will be performed with such biomarkers as EGFR mutation status. EGFR mutation status will be measured in tumor samples and blood samples. In addition, plasma levels of IGFBP-3 and amphiregulin as well as gene polymorphisms related to the EGFR and IGF-1R pathways will be investigated.
  
  

One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that there are alternative mechanisms for persistent activating EGFR downstream signaling, including both RAS/Erk and PI3K/Akt kinase pathways. Therefore, simultaneous inhibition of both pathways would be necessary to reduce tumor cell survival more effectively. One of the candidate combinations is concurrent use of EGFR-TKIs and statins, which are irreversible inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Beside the cholesterol lowering effect, statins have been shown to induce apoptosis in several tumor types. It affects the synthesis of other products of the mevalonate pathway such as isoprenoids, which are used as substrates for prenylation. Attachment of isoprenoids to RAS proteins facilitates their anchoring to the cell membrane where they carried out their roles. By interrupting the biosynthesis of mevalonate, statins inhibit activation of RAS and downstream signaling cascades, including the RAF/MEK/ERK and PI3K/AKT, which play critical roles in regulation of cell survival and proliferation. Therefore, it seems to be a promising therapeutic approach overcoming tumor resistance to EGFR-TKIs, which is associated with RAS activation.

According to the recent clinical result of phase II trial, a randomized phase II study of gefitinib with or without simvastatin in previously treated patients with advanced NSCLC conducted by Han et al.37 gefitinib plus simvastatin combination produced higher response rates than gefitinib alone in patients with non-adenocarcinoma (5/13 [39%] v 1/13 [8%], P=0.06). This finding suggests that simvastatin may enhance sensitivity to gefitinib in non-adenocarcinoma that is relatively resistant to gefitinib. Moreover, by Mantha et al.35 demonstrated that the combination of gefitinib and lovastatin showed significant synergic cytotoxic effects in vitro in a total of 16 squamous cell carcinomas, NSCLC, and colon carcinoma cell lines. Of special interest, these cell lines did not possess the activating mutations of EGFR, which confer increased sensitivity to gefitinib. Nevertheless, combining lovastatin with gefitinib induced more significant inhibition of AKT activation than either agent alone. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib treatment regardless PTEN loss in glioblastoma cell lines. These results suggest that statins can augment EGFR inhibition.