Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies

Abstract

Background: Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies.

Methods: Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively.

Results: Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found.

Conclusions: Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.

Figure 1. Study Randomization Schema

Figure 2. Figure 2A. Median Docetaxel Concentrations

Docetaxel plasma concentration-time curves for patients receiving 30 mg/m² (n=3) and 36 mg/m² (n=10) are shown. Figure 2B. Effect of Lonafarnib on Docetaxel AUC Docetaxel exposure as measured by mean AUC with lonafarnib (n=10) and without (n=3) was compared following dose-normalization between the 30 and 36 mg/m² groups. P = 0.46 (2 sided Wilcoxon rank sum)

Figure 2. Figure 2A. Median Docetaxel Concentrations

Docetaxel plasma concentration-time curves for patients receiving 30 mg/m² (n=3) and 36 mg/m² (n=10) are shown. Figure 2B. Effect of Lonafarnib on Docetaxel AUC Docetaxel exposure as measured by mean AUC with lonafarnib (n=10) and without (n=3) was compared following dose-normalization between the 30 and 36 mg/m² groups. P = 0.46 (2 sided Wilcoxon rank sum)

Figure 3. Percent Tubulin Acetylation in Tumor Biopsies Before and After Treatment

Immunohistochemical analysis of acetylated tubulin in formalin-fixed paraffin-embedded.

Figure 4. Immunohistochemistry Analysis of Acetylated Tubulin in Pre- and Post-Treatment Biopsies from Responder and Non-Responder Patients

Immunohistochemistry was performed using an anti-acetylated tubulin antibody (brown staining) in tumor biopsy samples from responder patients (#12 and #27, panel A) and a non-responder patient (#31, panel B) taken before and after treatment. Hematoxylin was used as a nuclear stain (blue). Scale bar = 20 μM. In panel B, the solid arrow indicates normal metaphase in the pre-treatment specimen, and the dashed arrows indicate abnormal mitotic figures in the post-treatment sample.

Figure 5. PFS stratified by basal FTase alpha expression (A: top figure) and PFS stratified by basal FTase beta expression (B: bottom figure)