Biomarker Analysis Identifies Prognostic Markers for Aflibercept Efficacy in CRC

Sabine Tejpar, MD, PhD

Ziv-aflibercept (Zaltrap) prolonged overall survival (OS) compared to placebo across subgroups of patients with metastatic colorectal cancer (mCRC) with wild-type and mutated RAS, KRAS, and BRAF genes; in addition, this efficacy was unaffected by right-sided versus left-sided location of the primary tumor, according to findings presented at the 2017 ESMO World Congress on Gastrointestinal Cancer (WGI).

Comparable benefit with aflibercept was observed regardless of the location of the primary tumor, even though right-sided location has previously been identified as a prognostic factor for poorer outcomes in colorectal cancer. For OS as well as progression-free survival (PFS), efficacy of aflibercept was similar for left-sided tumors (OS hazard ratio [HR], 0.86; PFS HR, 0.74; interaction P-value = 0.96) and for right-sided tumors (OS HR, 0.85; PFS HR, 0.70; interaction P-value = 0.69). These data are a result of a non-interventional follow-up study of the VELOUR trial (NCT01754272).

Molecular profiling revealed that patients who were classified as RAS wild-type and those with RAS mutations comprised 40% of the intent to treat (ITT) population of VELOUR.

An analysis of OS data from VELOUR across relevant patient genetic characteristics showed patients with RAS wild-type tumors had an improved OS of 16.0 months versus 10.6 with placebo (HR, 0.70). OS was also improved compared to placebo in patients with mutated RAS (HR, 0.93).

The comparison of OS favored aflibercept over placebo in patients with wild-type KRAS (HR, 0.74), and with mutated KRAS tumors (HR, 0.90).

The BRAF subgroup of VELOUR showed the poorest OS in the placebo group compared to the aflibercept group.. Patients with BRAF mutations had median OS of 10.3 versus 5.5 months with placebo (HR, 0.42). Patients with BRAF wild-type tumors had median OS 13.0 versus 12.4 months with aflibercept versus placebo (HR, 0.84).

“Aflibercept may have special beneficial effect in BRAF-mutated patients,” said Sabine Tejpar, MD, PhD, Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium, who presented findings on behalf of the VELOUR Translational Research Consortium (VTRC), which was assembled by the Catholic University of Leuven and Almac Diagnostics.

The VTRC investigators performed molecular profiling of formaldehyde fixed paraffin embedded (FFPE) specimens of tumor samples and serial plasma samples obtained from patients participating in the phase III VELOUR study. VELOUR compared second-line treatment with aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) to placebo in patients with mCRC who were refractory to a first-line oxaliplatin-based chemotherapy regimen (NCT00561470). The trial demonstrated that aflibercept significantly improved median survival over placebo from 12.06 months to 13.50 months, (HR, 0.817; 95% CI, 0.714-0.935; P = .0032).

“While the VELOUR study confirmed the benefits of using aflibercept in combination with FOLFIRI, the availability of biomarkers accurately predicting patients’ responses to this combination would further improve clinical utility of this drug,” said Tejpar.

Testing for wild-type and mutations of RAS, KRAS, BRAF, as well as right- versus left-sided location of the primary tumor was carried out in samples obtained from the biomarker population, which comprised 484 patients with available samples out of the 1226 patients in the ITT study population. OS in the biomarker population was comparable to the OS demonstrated in the ITT population.

“There are no formal tests to compare the biomarker and ITT populations, so the populations were assessed by comparing the shape of the curves, hazard ratios, and patients’ characteristics,” said Tejpar.

OS in the full biomarker population was 12.9 months with aflibercept versus 11.4 months with placebo.

“No significant interaction was observed in the RAS-defined subgroups, although hazard ratios in RAS wild-type patients appear to be specifically strong,’ said Tejpar.

Notably, BRAF wild-type was detected in 267 patients with left-sided tumors versus 96 patients with right-sided tumors, and mutant BRAF was detected in 13 versus 11 patients with left- and right-sidedness, respectively.

Aflibercept is a monoclonal antibody that targets the vascular endothelial growth factors VEGF-A and VEGF-B, and placenta growth factor (PGF). These growth factor proteins function in pathways important for new blood vessel growth that support tumorigenesis.

“These data provide more granular evidence for treatment options within the guidelines,” commented Tejpar. “Our assessment is ongoing, and the discovery of predictive biomarkers that associate with aflibercept efficacy will aid patient selection and treatment decisions.”

Wirapati P, Pomella C, Vandenbosch B, et al. VELOUR trial biomarkers update: impact of RAS, BRAF, and sidedness on aflibercept activity. [ESMO WGI Abstract LBA-005]. Ann Oncol. 2017;28(suppl_3).