Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial

Abstract

Importance: Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined.

Objective: To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen.

Design, setting, and participants: This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018.

Interventions: Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites.

Main outcomes and measures: The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A.

Results: Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B.

Conclusions and relevance: In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects.

Trial registration: ClinicalTrials.gov identifier: NCT02476045.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Peitrantonio reported receiving honoraria for speaker activities and participation in advisory boards from Sanofi SA, Amgen, Inc, Bayer AG, Merck-Serono, Roche, and Servier Laboratories. Dr Lombardi reported receiving honoraria for speaker activities and participation in advisory boards from Amgen, Inc, Bayer AG, Merck-Serono, Roche, Servier Laboratories, and Bristol-Myers Squibb. Dr Cremolini reported receiving honoraria for speaker activities and participation in advisory boards from Roche, Amgen, Inc, Bayer AG, and Servier Laboratories and research grants from Merck-Serono. Dr Rimassa reported receiving honoraria for speaker activities and participation in advisory boards from AstraZeneca, AbbVie, Eli Lilly and Company, Bayer AG, Sirtex Medical Limited, Italfarmaco SpA, Sanofi SA, ArQule, Inc, Baxter International, Inc, Ipsen, Exelixis, Inc, Amgen, Inc, Incyte Corp, and Celgene Corporation. Dr Sartore-Bianchi reported receiving honoraria for speaker activities and participation in advisory boards from Sanofi SA, Amgen, Inc, Bayer AG, Merck-Serono, and Roche. Dr Zaniboni reported receiving honoraria for speaker activities and participation in advisory boards from Sanofi SA, Amgen, Inc, Bayer AG, Merck-Serono, and Roche. Dr Di Bartolomeo reported receiving honoraria for speaker activities and participation in advisory boards from Amgen, Inc, Roche, Eli Lilly and Company, Servier Laboratories. Incyte Corp, and Celgene Corporation. Dr de Braud reported receiving honoraria for speaker activities and participation in advisory boards from Amgen, Inc, Roche, and Novartis International AG. No other disclosures were reported.

Figures

Figure 1.. Consort Diagram of the Study

FOLFOX4 indicates panitumumab, 6 mg/kg (1-hour infusion for the first administration, 30-minute infusion thereafter), oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks. FU indicates fluorouracil; LV, leucovorin.

Figure 2.. Kaplan-Meier Curves for Progression-Free Survival (PFS) and Overall Survival According to Treatment Arm

Data are shown in the intention-to-treat population at the date of first data cutoff (July 30, 2018). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) vs 49.0% (95% CI, 40.5%-59.4%) in arm A vs arm B. The hazard ratio (HR) of arm B vs arm A was 1.51 (95% CI, 1.11-2.07; P = .009). Overall survival at the median follow-up of 18 months was 66.4% (95% CI, 57.1%-77.2%) vs 62.4% (52.3%-74.4%) in arm A vs arm B (HR, 1.13; 95% CI, 0.71-1.81; P = .60). FU indicates fluorouracil; LV, leucovorin.

Figure 3.. Forest Plots of Progression-Free Survival by Patient Subgroups Within the Intention-to-Treat Population

ECOG indicates Eastern Cooperative Oncology Group; FU, fluorouracil; HR, hazard ratio; LV, leucovorin. Dashed line indicates predefined noninferiority boundary (HR, 1.515).