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JAMA Oncol. 2019 Jul 3. doi: 10.1001/jamaoncol.2019.1467. [Epub ahead of print]

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.

Author information

1
Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.
2
Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
3
Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
4
Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy.
5
Unit of Medical Oncology, Azienda Ospedaliero-Universitaria (AOU) Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
6
Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
7
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
8
Department of Oncology, AOU San Luigi di Orbassano, University of Torino, Orbassano, Italy.
9
Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, Torino, Italy.
10
Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy.
11
Medical Oncology Unit A.O. Papardo and Department of Human Pathology, University of Messina, Messina, Italy.
12
Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
13
Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy.
14
Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale (ASST) Ospedale di Cremona, Cremona, Italy.
15
Medical Oncology Unit, Azienda Socio Sanitaria Territoriale Lariana, Como, Italy.
16
Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Italy.
17
Medical Oncology Unit, Azienda Ospedaliera San Gerardo, Monza, Italy.
18
Medical Oncology Unit, Ospedale Antonio Perrino, Brindisi, Italy.

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.

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