ELCC 2018 News: Low Baseline Endoglin Levels May Signal Improved Survival with Nintedanib in Malignant Pleural Mesothelioma

Analysis reveals biomarkers that potentially indicate improved PFS and/or OS with nintedanib

Findings from the first analysis of putative biomarkers for improved survival following nintedanib treatment in patients with malignant pleural mesothelioma (MPM) were reported at the European Lung Cancer Congress (ELCC) 2018, held 11 to 14 April in Geneva, Switzerland.

Although this analysis uncovered no clear association between the biomarkers evaluated and the improved progression-frees survival (PFS) and overall survival (OS) that were demonstrated in patients with MPM treated with nintedanib, lower baseline levels of endoglin and VEGFR single nucleotide polymorphisms (SNPs) did show a non-significant trend toward an association with better survival.

Assoc. Professor Nick Pavlakis of the Northern Cancer Institute in St Leonards, Australia presented findings from a biomarker analysis on behalf of colleagues from the randomised phase II/III LUME-Meso study (NCT01907100) of nintedanib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin followed by nintedanib or placebo maintenance, in chemotherapy-naïve MPM patients.

Patients receiving nintedanib in addition to pemetrexed/ cisplatin and as maintenance therapy in the phase II part of LUME-Meso demonstrated prolonged PFS compared to patients receiving placebo (hazard ratio [HR] 0.54; p = 0.010), as well as a trend toward longer overall survival (OS; HR 0.77; p = 0.319).

With observation that the greatest benefit occurred in patients with epithelioid tumours, plasma angiogenic factors and genomic markers were explored for potential associations with treatment outcome in phase II epithelioid population.

The data presented at ELCC 2018 were from this biomarker analysis wherein baseline plasma levels of 58 angiogenic factors were evaluated by multiplex immunoassay (Human AngiogenesisMAP®, Myriad RBM). The investigators reviewed genes implicated in the nintedanib mechanism of action and/or the mesothelioma pathophysiology, including VEGFR1, VEGFR3, and mesothelin for known SNPs. The association of markers with the PFS and OS following nintedanib treatment was assessed by Cox regression and interaction tests with false-discovery rate (FDR) adjustment.

Low baseline endoglin levels show a non-significant trend toward both better PFS and OS

Data from the 77 patients comprising the epithelioid population were reviewed; 71 patients had available angiogenic factor data and 67 had genomic data. Investigation of the angiogenic factors revealed that only endoglin showed a possible trend for association with improvement in both PFS and OS. The greater benefit with nintedanib was observed in patients with low baseline plasma levels of endoglin.

An OS benefit was associated with major homozygous genotypes for two VEGFR3 SNPs, rs307821 G/G and rs307826 A/A, which each showed a weak association with OS.

A potential PFS benefit was associated with the VEGFR1 SNP rs9582036 A/A genotype.

The investigators noted that the FDR-adjusted interaction tests were not significant and had possibly been affected by the biomarker treatment associations, which were limited by small subgroup size, especially in the case of minor genotypes.

Conclusions: The authors concluded that these analyses were exploratory and hypothesis generating. 

Although the analysis was limited by small subgroup size, these findings represent the first biomarker results for nintedanib-treated patients with MPM, which showed potential signals for an improved PFS and OS benefit in patients with low baseline plasma endoglin levels and with major homozygous VEGFR1/3 genotypes. 

However, according to the authors, none of the biomarkers evaluated showed a clear and significant association with nintedanib efficacy. 

Disclosure: Funding from Boehringer Ingelheim was disclosed.

Reference

213O – Pavlakis N, Grosso F, Steele N, et al. Nintedanib + pemetrexed/cisplatin in malignant pleural mesothelioma (MPM): Phase II biomarker data from the LUME Meso study.