ELCC 2015 News: VEGF SNPs Identified as Prognostic Markers for Bevacizumab Response in Patients with Advanced Non-Squamous NSCLC

Final results of the ANGIOMET Spanish Lung Cancer Group trial

European Lung Cancer Conference 2015: Abstract 37PD

Response rate and survival in the ANGIOMET study
© Bartomeu Massuti Sureda

Patients with advanced non-squamous non-small-cell lung cancer (NS-NSCLC) achieved median overall survival (OS) longer than one year in ANGIOMET, a prospective clinical trial of bevacizumab plus carboplatin and paclitaxel, leading the investigators to look for and identify biomarkers for this response.

Prof. Bartomeo Massuti Sureda, Department of Medical Oncology, Hospital General Universitario de Alicante, Alicante, Spain, presented the final efficacy results and identification of predictive biomarkers from the ANGIOMET trial on behalf of the Spanish Lung Cancer Group at the European Lung Cancer Conference, held 15 – 18 April 2015 in Geneva, Switzerland.

The ANGIOMET (analysis of the correlations between angiogenic markers and outcome in patients with advanced NS-NSCLC treated with carboplatin, paclitaxel, and bevacizumab) trial treated patients with advanced stage IIIB/IV NS-NSCLC (ECOG performance status 0-2) with first-line carboplatin/paclitaxel plus bevacizumab for six cycles, which were followed by maintenance with bevacizumab.

The trial enrolled 202 patients with median age of 61 years (range: 37 to 80 years). The majority (67.2%) of patients were male and 97.8% had stage IV disease, which was mostly (88.2%) adenocarcinoma. All patients (100%) were Caucasian and 15.8% of patients were never-smokers. The per protocol population comprised 199 patients who received a median five cycles of carboplatin/paclitaxel plus bevacizumab.

Clinical benefit is demonstrated with carboplatin/paclitaxel plus bevacizumab treatment in patients with advanced non-squamous NSCLC

The trial’s primary endpoint, progression-free survival (PFS) was met; patients achieved median PFS of 6.91 months (range: 6.16-7.65).

Overall survival (OS) and response rate (RR) were secondary endpoints; patients experienced OS of median 14.57 months (range: 11.83 to 17.31 months). In the intent-to-treat population of 171 patients, 1% of patients achieved complete response, 49% had partial response, stable disease was seen in 36% of patients and progressive disease occurred in 10.6% of patients. Response in 4% of patients was not evaluated.

Ancillary study identifies specific single nucleotide polymorphisms in angiogenic factors as predictive markers for outcome

European Lung Cancer Conference 2015: Abstract 37PD

Ten SNPs analysed in the ANGIOMET study and their correlation with progression-free survival
© Bartomeu Massuti Sureda

Prof. Massuti Sureda discussed results from the ancillary study that was designed to investigate the relationship between the response to this treatment, patient outcomes, and angiogenic mediators.

The ancillary study focused on molecules in the VEGF pathway where several ligands and receptors have been characterised as important in tumour angiogenesis and therapeutic efficacy. The investigators hypothesized that single nucleotide polymorphisms (SNPs) could modify levels of angiogenic factors in the tumour or blood and may associate with prognosis and outcomes with bevacizumab.

Blood samples were collected from patients prior to and after treatment, and DNA was obtained from the leukocyte fraction. Polymerase chain reaction (PCR) assay was used to genotype SNPs of angiogenic genes and plasma levels of VEGFA and VEGFR2 were determined by ELISA.
Upon analysis, shorter PFS (p = 0.01) and OS (p = 0.01) were found to associate with VEGFR1 SNP rs9582036. VEGFA SNP rs3025039 associated with poorer OS when compared to other genotypes (p = 0.009).

However, lower levels of circulating VEGF were prognostic of better outcome; a significant association with longer PFS (p = 0.04) and a trend toward improved OS (p = 0.10) was identified.

Prof. Giorgio Scagliotti from the University of Torino in Italy, who discussed the results, said that the study hypothesis was if SNPs could modify levels of angiogenic factors in tumour or serum/plasma and if they have a prognostic/predictive  impact. However, the search for reliable biomarkers predicting the efficacy of anti-angionetic therapies remains an open issue.  Potential surrogate markers for the evaluation of anti-VEGF agents could be invasive (tissue biopsy, interstitial fluid pressure measurement, measurement of tissue oxygenation, skin wound healing), minimally invasive (circulating endothelial cells, circulating progenitor cells, protein levels in plasma, VEGF polymorphisms), non-invasive such as imaging (CT imaging, PET imaging, MRI) and clinical (hypertension, gender, urine protein, e.g. MMP, VEGF).

Conclusion

The investigators found no significant association between response rates and either the SNPs analysed or levels of VEGF and VEGFR2 in patient blood samples. However, patients having lower VEGF levels in their baseline blood samples experienced improved survival outcomes.

Furthermore, it was determined that the presence of certain VEGFR1 and VEGFA SNPs in the blood of patients with advanced NS-NSCLC associated with decreased efficacy of the bevacizumab, carboplatin and paclitaxel regimen that was demonstrated by shorter PFS and OS.

Reference

37PD. SNPs in angiogenic factors as predictive markers for outcome in patients (p) with advanced non-squamous NSCLC (NS-NSCLC) treated with carboplatin, paclitaxel (CP) and bevacizumab (Bev). Final results of ANGIOMET Spanish Lung Cancer Group Trial

The study was sponsored by the Spanish Lung Cancer Group.