Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma: The GEMCAD 1402 Randomized Clinical Trial

Abstract

Importance: 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 (CT) and/or chemoradiotherapy (CRT) remains controversial.

Objective: To study the effect of aflibercept plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) induction CT prior to standard CRT and total mesorectal excision (TME) surgery in patients with high-risk rectal adenocarcinoma.

Design, setting, and participants: In the Grupo Español Multidisciplinar En Cancer Digestivo (GEMCAD) 1402 phase 2 randomized clinical trial, 180 patients aged 18 to 75 years, identified by centrally reviewed magnetic resonance imaging to have mrT3c-d/T4/N2 rectal adenocarcinoma, were enrolled from 20 treatment centers in Spain between January 2015 and March 2017. Patients were randomized in a 2:1 treatment to control arm ratio. The primary end point was evaluated at 2 interim and 1 final analyses. 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.

Interventions: Patients received 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) prior to standard CRT and TME surgery.

Main outcomes and measures: The primary end point was a pathologic complete response (pCR) (ypT0N0). Secondary end points included toxic effects, surgical morbidity, R0 resections, compliance, and 3-year disease-free survival.

Results: For the 115 patients who received treatment with mFOLFOX6 plus aflibercept, the median (range) age was 60 (32-75) years, 77 men (66.9%) and 38 women (33.0%). For the 65 patients who received induction CT treatment with only mFOLFOX6, the median (range) age was 65 (39-75) years, 39 men (60.0%) and 26 women (40.0%). The pCR rate in the intention-to-treat population was 22.6% (95% CI, 15.3%-31.3%) in arm A and 13.8% (95% CI, 6.5%-24.6%) in arm B (P = .15). The main differential toxic effect was grade 3/4 hypertension during the induction phase. Postoperative complications were similar in both arms (15.5% in arm A and 12.9% in arm B). A total of 106 patients (92.1%) in arm A and 63 (96.9%) in arm B received all treatment cycles.

Conclusions and relevance: The study met its primary end point. 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. The GEMCAD 1402 trial provides a rationale for phase 3 trials.

Trial registration: ClinicalTrials.gov identifier: NCT02340949.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fernández-Martos reported receiving personal fees or grants from Merck, Sanofi, Servier, and Amgen. Dr Pericay reported receiving personal fees or grants from Merck, Roche, Amgen, Sanofi, Lilly, Servier, BMS, Novartis, and Ipsen. Dr Garcia-Carbonero reported receiving personal fees or grants from Roche, Merck, MSD, Bayer, Ipsen, Novartis, Pfizer, Lilly, PharmaMar, AAA, Pfizer, and Bristol-Myers Squibb. Dr Martin-Richard reported receiving personal fees or grants from Ipsen, Amgen, and Servier. Dr Alonso reported receiving personal fees or grants from Sanofi-Genzyme, Hoffmann-La Roche, Merck Serono, Amgen, Servier, Bayer, Novartis, and Ipsen. Dr Vera reported receiving personal fees or grants from Sanofi, Merck, Bayer, Amgen, Bristol-Myers Squibb, Roche, and MSD. Dr Gallego reported receiving personal fees or grants from Sanofi. Dr Capdevila reported receiving personal fees or grants from Sanofi, Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Merck Serono, and Astra Zeneca. Dr Maurel reported receiving personal fees or grants from Amgen, Merck, Servier, Nanostring, Incyte, Biocartis, Sirtex Medical Limited, Pierre Fabre, Shire, Astra Zeneca, Bayer, Servier, and Roche. Dr Montagut reported receiving personal fees or grants from Merck-Serono, Sanofi, Amgen, Roche, Biocartis, Symphogen, and has a patent to EGFR ECD mutations licensed and with royalties paid. Dr Lopez reported receiving personal fees or grants from GEMCAD, Sanofi, Roche, Merck, Amgen, Bayer, and Servier. Dr Jain reported receiving an honorarium from Amgen, consultation fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit; owning equity in Enlight, Ophthotech, and SynDevRx; and serving on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study. No other disclosures were reported.

Figures

Figure.. CONSORT Diagram

CT indicates chemotherapy; mFOLFOX6, modified fluorouracil, leucovorin, and oxaliplatin; CRT, chemoradiotherapy; RT, radiotherapy; PD, progressive disease.