The most frequent adverse event due to the anti-EGFR(aEGFR) antibody is skin toxicity. Preclinical studies have shown Vitamin K1(VK1) reactivates the EGFR signaling pathway blocked by aEGFR drugs, suggesting that a VK1 cream may reduce aEGFR drugs-induced skin toxicity. We conducted a multi-centre, self-controlled, double-blinded randomized phase III trial to evaluate the efficacy of topical application of a prophylactic 0.1%VK1 cream in Cetuximab(Cmab) therapy.
Patients were eligible if they were ≧20 years of age, had an ECOG PS of 0-2, an unresectable metastatic colorectal cancer with a wild-type KRAS exon 2, and no prior aEGFR treatment. Each patient applied a VK1-containing moisturizing cream to either the left or right side of face and a moisturizing cream alone to the other side. The side of the face on which the VK1 cream was applied was determined by the permuted block method. Cream application was continued until day 29, the appearance of Gr ≧ 2 skin toxicity or occurrence of Gr ≧ 3 adverse event. Prophylactic use of antibiotics or corticosteroids was not allowed. The primary endpoint was the incidence of Gr ≧ 2 skin toxicity CTCAE v4.0) within 4 weeks. Secondary endpoints included the incidence of Gr ≧ 2 skin toxicity MASCC scale) and safety of the VK1 cream.
From Dec. 2013 to Mar. 2015, 33 patients were enrolled, out of which 28 were eligible for efficacy analysis. The patients' background was median age, 66 (48–87); male/female, 21/7; PS 0/1/2, 8/16/4; number of prior regimens 0/1/2/ ≧ 3, 8/6/9/5. Cmab was administered in combination with CPT-11 or FOLFIRI (16), with FOLFOX (2), or as monotherapy (10). Protocol treatment was discontinued for 13 patients: in 10 for the appearance of Gr 2/3 acneiform eruptions, 1 for disease progression, and 2 due to the refusal of the patients. The compliance rate of cream application was 98.2%. The incidence of Gr ≧ 2 skin toxicity on the face within 4 weeks was 36% (10/28) with both the VK1 cream and the control (P = 1.00, McNemar test). There was no significant difference in the incidence of Gr ≧ 2 skin toxicity on the face between the two arms, according to the MASCC scale.
Topical application of the VK1 cream was not effective in reducing the incidence of Cmab-related skin reactions.
Clinical trial identification
K. Yamazaki: corporate-sponsored research: Bristol; other substantive relationships: lecture fee from Merck and Bristol. M. Izawa: employee of Bristol-Myers Squibb. T. Yamanaka: other substantive relationships: honoraria; Taiho, Chugai, Takeda, Merck-Serono, Bristol-Meyers). All other authors have declared no conflicts of interest.