First-Line Panitumumab Plus FOLFOX-4 Followed by Maintenance Therapy with Single-Agent Panitumumab or Panitumumab Plus 5-FU/LV in Patients with RAS Wild-Type Metastatic Colorectal Cancer: The Valentino Study

Abstract

Background The optimal duration of first-line anti-EGFR-based combinations in RAS wild-type metastatic colorectal cancer patients is to be defined. We investigated whether maintenance therapy with panitumumab was non-inferior to panitumumab plus 5-fluorouracil/leucovorin (5-FU/LV) after panitumumab plus FOLFOX-4 induction. Methods In this multicentre, open-label, randomised, non-inferiority, phase 2 trial, we enrolled patients with RAS wild-type, unresectable and previously untreated metastatic colorectal adenocarcinoma. We randomly assigned patients (1:1) to either panitumumab plus FOLFOX-4 for 8 cycles followed by panitumumab plus 5-FU/LV (arm A), or panitumumab (arm B). We used the minimisation method to stratify randomisation by previous adjuvant treatment and number of metastatic sites. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was 10-month progression-free survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·515 for the hazard ratio (HR) of arm B versus A. This study is registered with ClinicalTrials.gov, number NCT02476045, and is ongoing but no longer recruiting participants. Findings Between July 7th 2015 and October 27th 2017, 229 patients were randomly assigned to arm A (n=117) or arm B (n=112). After a median follow-up of 18·0 months (IQR 13·1- 23·3), a total number of 169 disease progression or death events occurred. Non-inferiority was not reached (upper limit of the one-sided 90% CI of the HR=1·857). 10-month progression-free survival was 59·9% (51·5%-69·8%) in arm A versus 49·0% (40·5%-59·4%) in arm B (HR=1·51; 95% CI 1·11-2·07; p=0·009). During the maintenance phase, grade ≥3 treatment- and panitumumab-related adverse events had higher incidence in arm A versus B (42% vs 20%, and 27% vs 13%, respectively). Interpretation Maintenance therapy with panitumumab failed to reach non-inferior progression-free survival than panitumumab plus 5-FU/LV in RAS wild-type metastatic colorectal cancer patients. Trial Registration Number: This study is registered with ClinicalTrials.gov, number NCT02476045 Funding: Amgen. Declaration of Interest: FP has received honoraria for speaker activities and participation in advisory boards from Sanofi, Amgen, Bayer, Merck-Serono, Roche. SL has received honoraria for speaker activities and participation in advisory boards from Amgen, Bayer, Merck-Serono, Roche, Servier, Bristol-Myers Squibb. CC has received honoraria for speaker activities and participation in advisory boards from Roche, Amgen, Bayer, Servier, and research grants from Merck Serono. LR has received honoraria for speaker activities and participation in advisory boards from AstraZeneca, Abbvie, Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Incyte, Celgene ABS has received honoraria for speaker activities and participation in advisory boards from Sanofi, Amgen, Bayer, Merck-Serono, Roche. AZ has received honoraria for speaker activities and participation in advisory boards from Sanofi, Amgen, Bayer, Merck-Serono, Roche. MDB has received honoraria for speaker activities and participation in advisory boards from Amgen, Roche, Lilly, Servier. Incyte, Celgene. FDB has received honoraria for speaker activities and participation in advisory boards from Amgen, Roche, Novartis, All other authors declared no disclosures. Ethical Approval: The present study was performed in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice standards. Institutional review board and Ethics committee approval was obtained from all participating Institutions. All the patients provided written informed consent before any study-related procedures.