Results of a large, multi-national phase III trial in second-line treatment of metastatic colorectal cancer (mCRC) are presented for the first time at the ESMO 13th World Congress on Gastrointestinal Cancer (June 22-25, 2011, Barcelona, Spain).

The abstract outlining results of the EFC10262-VELOUR trial has been considered as one of the top abstracts by the Congress Scientific Committee from more than 500 abstracts submitted to the Congress.

Dr Eric Van Cutsem of the University Hospitals Leuven, Belgium presented the results of this trial, which looked at intravenous afliberceptin in combination with irinotecan/5-FU (FOLFIRI) to treat patients with mCRC. Alfibercept is a soluble fusion protein of the extracellular domains of human VEGFR-1 and VEGFR-2 linked to a human IgG1 Fc portion.

It binds all VEGF-A isoforms, VEGF-B, and PlGF with high affinity and has a half-life of 17 days. Thus, it mimics the activity of bevacizumab, a monoclonal antibody against all isoforms of VEGF-A, with additional binding of other, potentially pro-angiogenic factors.

Preclinical and clinical evidence supported the evaluation of the combination of aflibercept with FOLFIRI, an effective chemotherapy regimen for the treatment of patients with mCRC.

The primary endpoint of the VELOUR study was overall survival (OS). Patients with mCRC, performance status (PS) 0-2, and adequate organ function after failure of one oxaliplatin-based therapy were treated with FOLFIRI and randomized 1:1 to either aflibercept or placebo every 2 weeks, with stratification by ECOG PS (0 vs 1 vs 2) and prior bevacizumab (yes vs no). The study had 90% power to detect a 20% lower hazard rate for death in the aflibercept arm after 863 events.

From November 2007 to March 2010, 1226 patients (median age 61 year, male 58.6%, PS 0-1 97.9%, more than 1 metastatic organ 56.4% and prior bevacizumab 30.4%) were randomized to receive FOLFIRI and aflibercept (n = 614) or placebo (n = 612). Baseline characteristics were similar in both arms.

Relative dose intensity was > 0.80 for aflibercept, placebo and FOLFIRI. At data cut-off median follow-up was 22.28 mo

nths, and 863 patients had died. Median OS was 13.50 months for aflibercept and 12.06 months for placebo (p = 0.0032). Secondary endpoints also favored aflibercept: progression-free survival (PFS) was 6.90 vs 4.67 months (p = 0.00007) and overall response rate 19.8% vs 11.1% (p=0.0001).

Grade 3-4 adverse events with > 2% higher incidence in aflibercept vs placebo were diarrhea, asthenia/fatigue, stomatitis/ulceration, infections, hypertension, abdominal pains, neutropenia/neutropenic complications and proteinuria.

Adverse events leading to treatment discontinuation occurred in 26.6% and 12.1% of patients in aflibercept vs placebo; for aflibercept, most common causes were asthenia/fatigue, infections, diarrhea, hypertension and venous thromboembolic events.

The authors concluded that intravenous aflibercept in combination with FOLFIRI significantly improves OS and PFS in patients with mCRC, previously treated with an oxaliplatin containing regimen. A similar effect was seen with aflibercept whether or not patients had received prior bevacizumab therapy.

The safety profile was acceptable and consistent with other anti-VEGF adverse events, even if aflibercept seems to increase chemotherapy-specific complications, such as diarrhea, neutropenia and stomatitis.

The cohort of patients with prior bevacizumab therapy demonstrated an attenuated benefit for aflibercept. While these results appear to be intriguing at first glance, they have to be compared to the findings of E3200, a phase III trial which compared FOLFOX with or without bevacizumab in second-line therapy after failure of IFL.

The results of E3200 and VELOUR are remarkably similar, adding to the idea of VEGF inhibition in second-line colorectal cancer. The key issue is, though, if VEGF inhibition should be carried over from first to second-line therapy, meaning beyond progression.

This question will be answered by a European phase III trial which investigates the use of bevacizumab beyond progression added to sequential chemotherapy backbone in advanced colorectal cancer.

Source: ESMO