title: Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer.
abstract: Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5%, H1 = 17%, α = 0.05, β = 0.2). From 19 enrolled patients, 17 (89%) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41%) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95% of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5%) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p < 0.05). At surgery, patients with important pathological regression (grade 3 Dworak) had higher plasma TGF-α (p = 0.03) but lower plasma EGF (p = 0.003) compared to those with grade 0-2 Dworak. Our study suggests that concomitant panitumumab and preoperative radiotherapy in KRAS wild-type LARC is feasible and results in some tumor regression. However, pCR rate remained modest. Given that the primary endpoint of our study was not reached, we remain unable to recommend the use of panitumumab as a radiosensitizer in KRAS wild-type LARC outside a research setting.
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle d'imagerie médicale, radiothérapie et oncologie (IREC/MIRO), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Feby Ingriani
authors.initials: FI
authors.lastname: Mardjuadi
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Coche
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Anne
authors.initials: A
authors.lastname: Jouret-Mourin
authors.forename: Pierre
authors.initials: P
authors.lastname: Scalliet
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Goeminne
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Daisne
authors.forename: Thierry
authors.initials: T
authors.lastname: Delaunoit
authors.forename: Peter
authors.initials: P
authors.lastname: Vuylsteke
authors.forename: Yves
authors.initials: Y
authors.lastname: Humblet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meert
authors.forename: Marc
authors.initials: M
authors.lastname: van den Eynde
authors.forename: Anne
authors.initials: A
authors.lastname: Moxhon
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Canon
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011878:Radiotherapy / Q000379:methods; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D008024:Ligands; D011838:Radiation-Sensitizing Agents; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)