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

Filippo Pietrantonio, Federica Morano, Salvatore Corallo, Rosalba Miceli, Sara Lonardi, Alessandra Raimondi, Chiara Cremolini, Lorenza Rimassa, Francesca Bergamo, Andrea Sartore-Bianchi, Marco Tampellini, Patrizia Racca, Matteo Clavarezza, Rosa Berenato, Marta Caporale, Maria Antista, Monica Niger, Valeria Smiroldo, Roberto Murialdo, Alberto Zaniboni & 10 others Vincenzo Adamo, Gianluca Tomasello, Monica Giordano, Fausto Petrelli, Raffaella Longarini, Saverio Cinieri, Alfredo Falcone, Vittorina Zagonel, Maria Di Bartolomeo, Filippo De Braud

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalJAMA oncology
DOIs
Publication statusPublished - Jan 1 2019

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Leucovorin
Fluorouracil
Colorectal Neoplasms
Randomized Controlled Trials
Therapeutics
Disease-Free Survival
oxaliplatin
Poisons
panitumumab
Maintenance
Random Allocation
Disease Progression
Adenocarcinoma
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Pietrantonio, Filippo; Morano, Federica; Corallo, Salvatore; Miceli, Rosalba; Lonardi, Sara; Raimondi, Alessandra; Cremolini, Chiara; Rimassa, Lorenza; Bergamo, Francesca; Sartore-Bianchi, Andrea; Tampellini, Marco; Racca, Patrizia; Clavarezza, Matteo; Berenato, Rosa; Caporale, Marta; Antista, Maria; Niger, Monica; Smiroldo, Valeria; Murialdo, Roberto; Zaniboni, Alberto; Adamo, Vincenzo; Tomasello, Gianluca; Giordano, Monica; Petrelli, Fausto; Longarini, Raffaella; Cinieri, Saverio; Falcone, Alfredo; Zagonel, Vittorina; Di Bartolomeo, Maria; De Braud, Filippo.

In: JAMA oncology, 01.01.2019.

Research output: Contribution to journalArticle

Pietrantonio, F, Morano, F, Corallo, S, Miceli, R, Lonardi, S, Raimondi, A, Cremolini, C, Rimassa, L, Bergamo, F, Sartore-Bianchi, A, Tampellini, M, Racca, P, Clavarezza, M, Berenato, R, Caporale, M, Antista, M, Niger, M, Smiroldo, V, Murialdo, R, Zaniboni, A, Adamo, V, Tomasello, G, Giordano, M, Petrelli, F, Longarini, R, Cinieri, S, Falcone, A, Zagonel, V, Di Bartolomeo, M & De Braud, F 2019, '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', JAMA oncology. https://doi.org/10.1001/jamaoncol.2019.1467
Pietrantonio, Filippo ; Morano, Federica ; Corallo, Salvatore ; Miceli, Rosalba ; Lonardi, Sara ; Raimondi, Alessandra ; Cremolini, Chiara ; Rimassa, Lorenza ; Bergamo, Francesca ; Sartore-Bianchi, Andrea ; Tampellini, Marco ; Racca, Patrizia ; Clavarezza, Matteo ; Berenato, Rosa ; Caporale, Marta ; Antista, Maria ; Niger, Monica ; Smiroldo, Valeria ; Murialdo, Roberto ; Zaniboni, Alberto ; Adamo, Vincenzo ; Tomasello, Gianluca ; Giordano, Monica ; Petrelli, Fausto ; Longarini, Raffaella ; Cinieri, Saverio ; Falcone, Alfredo ; Zagonel, Vittorina ; Di Bartolomeo, Maria ; De Braud, Filippo. / 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. In: JAMA oncology. 2019.
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title = "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.",
author = "Filippo Pietrantonio and Federica Morano and Salvatore Corallo and Rosalba Miceli and Sara Lonardi and Alessandra Raimondi and Chiara Cremolini and Lorenza Rimassa and Francesca Bergamo and Andrea Sartore-Bianchi and Marco Tampellini and Patrizia Racca and Matteo Clavarezza and Rosa Berenato and Marta Caporale and Maria Antista and Monica Niger and Valeria Smiroldo and Roberto Murialdo and Alberto Zaniboni and Vincenzo Adamo and Gianluca Tomasello and Monica Giordano and Fausto Petrelli and Raffaella Longarini and Saverio Cinieri and Alfredo Falcone and Vittorina Zagonel and {Di Bartolomeo}, Maria and {De Braud}, Filippo",
year = "2019",
month = "1",
day = "1",
doi = "10.1001/jamaoncol.2019.1467",
language = "English",
journal = "JAMA oncology",
issn = "2374-2437",
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TY - JOUR

T1 - Maintenance Therapy with Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients with RAS Wild-Type Metastatic Colorectal Cancer

T2 - A Phase 2 Randomized Clinical Trial

AU - Pietrantonio, Filippo

AU - Morano, Federica

AU - Corallo, Salvatore

AU - Miceli, Rosalba

AU - Lonardi, Sara

AU - Raimondi, Alessandra

AU - Cremolini, Chiara

AU - Rimassa, Lorenza

AU - Bergamo, Francesca

AU - Sartore-Bianchi, Andrea

AU - Tampellini, Marco

AU - Racca, Patrizia

AU - Clavarezza, Matteo

AU - Berenato, Rosa

AU - Caporale, Marta

AU - Antista, Maria

AU - Niger, Monica

AU - Smiroldo, Valeria

AU - Murialdo, Roberto

AU - Zaniboni, Alberto

AU - Adamo, Vincenzo

AU - Tomasello, Gianluca

AU - Giordano, Monica

AU - Petrelli, Fausto

AU - Longarini, Raffaella

AU - Cinieri, Saverio

AU - Falcone, Alfredo

AU - Zagonel, Vittorina

AU - Di Bartolomeo, Maria

AU - De Braud, Filippo

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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