Adding Aflibercept to Modified FOLFOX6 Improves Response in High-Risk Rectal Cancer

Results from a phase 2 study suggest that adding aflibercept to modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) induction chemotherapy helps increase pathologic complete response (pCR) rates in patients with high-risk rectal cancer (JAMA Oncol. 2019;5[11]:1566-1573).

“Preclinical studies suggest that a vascular endothelial growth factor (VEGF) blockade may play a role in the preoperative treatment of rectal adenocarcinoma; however, how to combine anti-VEGF drugs with neoadjuvant chemotherapy…and/or chemoradiotherapy…remains controversial,” explained Carlos Fernández-Martos, MD, Fundación Instituto Valenciano de Oncología, Spain, and colleagues.

Dr Fernández-Martos et al conducted the Grupo Español Multidisciplinar En Cancer Digestivo (GEMCAD) 1402 study to evaluate the efficacy of combining aflibercept with modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) induction chemotherapy before administering standard chemoradiotherapy and performing surgery in patients with high-risk rectal cancer.

A total of 180 patients with mrT3c-d/T4/N2 rectal cancer were enrolled in the study between January 2015 and March 2017. These patients were randomized in a 2:1 ratio to receive neoadjuvant mFOLFOX6 with (arm A; n = 115) or without (arm B; n = 65) aflibercept 4 mg/kg (every 2 weeks, 6 cycles, and 3 months) before standard chemoradiotherapy and total mesorectal excision.

The primary end point of the GEMCAD trial was pCR, which was evaluated at 2 interim and 1 final analyses. The secondary end points included toxicity, surgical morbidity, R0 resections, compliance, and disease-free survival rates at 3 years.

“The study was designed to perform hypothesis testing at α = .2 and β = .2. A 2-sided P value of <.1984 in the final analysis of the intention-to-treat population was the threshold for considering the experimental treatment to be more effective than the control,” Dr Fernández-Martos and co-investigators said.

Patients in arm A had a median age of 60 years, and those in arm B had a median age of 65 years. In the intention-to-treat population, pCR rates were 22.6% (95% CI, 15.3%-31.3%) and 13.8% (95% CI, 6.5%-24.6%) for arms A and B, respectively (P = .15).

Of note, the primary toxicity differentiating both treatment arms during the induction phase was grade 3/4 hypertension; however, postsurgery complications were similar (15.5% and 12.9% in arms A and B, respectively). All treatment cycles were administered to 106 (92.1%) patients in arm A and 63 (96.9%) in arm B.

“The findings suggest that adding aflibercept to an induction regimen using mFOLFOX6 plays a role in increasing the pCR rate in patients with high-risk rectal adenocarcinoma, without substantially increasing surgical complications,” Dr Fernández-Martos and colleagues concluded, adding that this study provides a rationale for future phase 3 trials.—Hina Porcelli