LBA-005VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity.

Background: Addition of (ziv)-aflibercept (A) to FOLFIRI in second-line therapy for metastatic colorectal cancer (CRC) has been shown to be beneficial in phase III VELOUR trial (NCT00561470). A follow-up study (NCT01754272) was undertaken to acquire tumor samples for biomarker analyses and identify subgroups of patients with differential treatment effects. The primary results assessing efficacy according to well-established CRC subgroups defined by RAS, BRAF status and sidedness are reported here. Methods: Tissue specimens were collected for 666 patients from 1226 ITT pts. Suitable specimens were assayed for somatic mutation using NGS targeting extended RAS and BRAF genes. NGS assays with no missing values were obtained for 482 pts. Affymetrix gene chip technology was used for whole-transcriptome profiling; sidedness was extracted from available pathological reports. Differences between subgroups were assessed by interaction analysis. Results: The treatment effects on overall survival (OS) for the 482 pts is still significant HR = 0.80 (CI 0.65-0.99), and similar to the ITT (n = 1226) results (HR = 0.82, CI 0.71-0.93). Two established ways of defining mutations (traditional KRAS exon 2 and extended RAS using NGS) show a trend for a differential effect across mutation groups.(see table for OS). Interestingly, BRAF mutants (which are all RAS wild type) show a trend for better outcome Same is seen for PFS and RR. Sidedness did not affect efficacy (HR: 0.83 (0.63- 1.1) for left and HR: 0.83 (0.54-1.3) for right. Conclusions: None of the mutations subgroup results shows significant interaction, although the ratios of treatment HR favor RAS wild types. Similar trends were observed in published trials with bevacizumab or ramucirumab. Sanofi supported this ISS. Clinical trial information: NCT01754272LBA – 005 TableMutationStatusNMed OS FOLFIRI+ PlaceboMed OS FOLFIRI + AHR 95% CIInteraction (ratio of HR, 95% CI, p-value)KRASex2wt28111.614.90.74 (0.56-0.99)1.21 (0.79 - 1.86)mut20110.612.60.90 (0.65-1.24)p = 0.38ExtRaswt21811.716.00.70 (0.50-0.97)1.39 (0.90 - 2.13)mut26411.212.60.93 (0.70-1.23)p = 0.13BRAFwt44612.413.00.84 (0.67-1.05)0.49 (0.22 - 1.09)mut365.510.30.42 (0.16-1.09)p = 0.08 Open table in a new tab