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Background: EGFR inhibition leads to the production of reactive oxygen metabolites, causing skin inflammatory reactions. Lycopene has an extreme antioxidant activity and, due to its hydrophobic structure, accumulates specifically in the skin. Methods: To assess lycopene effectiveness in reducing skin toxicity induced by panitumumab, 28 patients received lactolycopene or placebo in a phase-II PASTO study. Patients were evaluated at the beginning of each cycle and data were analyzed as the difference in mean grade of skin toxicity, frequency and duration of > G2 skin toxicity and frequency of tetracyclines administration. Lycopene, β-carotene and malondialdehyde plasma concentrations were analyzed to measure antioxidant consumption and oxidative stress. Findings: In the placebo group, ten out of 15 patients (66·67%), developed a > G2 skin toxicity, during 36 out of 92 cumulative cycles (39·1%), versus 3 out of 13 (23·08%), during 8 out of 64 cumulative cycles (12·5%) in the lactolycopene group. The time to the appearance of > G2 skin toxicity was different in the two groups (p= 0.0007 logrank test). Mean value of skin toxicity during treatment was 2·4 and 1·4 for placebo and lactolycopene group, respectively. Tetracyclines were administered for > G2 skin toxicity according to the protocol. Mean plasma concentration of lycopene and β-carotene decreased during treatment compared to day 0 (-141·94% and -157·22% respectively) in the placebo group, with a +109·36% mean malondialdehyde concentration increase. In contrast, in the lactolycopene group, mean plasma lycopene concentration increased during treatment (+94·18%), with a mean malondialdehyde concentration decrease (-68·83%) and a mean β-carotene concentration decrease (-105·5%) smaller than in the placebo group . Interpretation: Despite the limited number of patients, results clearly show lycopene effectiveness in reducing skin toxicity in patients treated with panitumumab. In our series lactolycopene administration was able to protect tissues from oxidative stress and to replenish antioxidants consumption. Trial Registration: registered in ClinicalTrials.gov (PaSTo – Clinicaltrials.gov: NCT 03167268) Funding Statement: AMOlavitaONLUS, Indena Spa. Declaration of Interests: MM1 is the vice-president and MP the treasurer of AMOlavitaONLUS. AMOlavitaONLUS is the sole owner and it holds all the ownership rights on the international patent application entitled “Use of carotenoid derivatives to reduce the toxicity and increase the efficacy of antiEGFR antitumor treatments” (N°PCT/IB2018/050229). MM1 and MP are exclusively inventors of the patent and they have no ownership right on the patent. Indena Spa, who supplied free of charge lactolycopene for the Pasto Clinical Trial, is not the owner of the patent for lactolycopene production. All other authors declare no competing interest. Ethics Approval Statement: The protocol was approved by the ethics committees of all participating institutions. Written informed consent was obtained from all patients.

Epidermal Growth Factor Receptor (EGFR) inhibition leads to the production of reactive oxygen metabolites causing skin inflammatory reactions. Anti-EGFR therapies are frequently associated with skin toxicities which often cause treatment delay and impairment to patient quality of life. Lycopene is a compound in the carotenoid group with an extreme antioxidant action which accumulates in the skin due to its hydrophobic structure. In a pilot study, we describe lactolycopene effectiveness in reducing skin toxicity and protecting tissues from oxidative stress in patients treated with panitumumab. Despite the limited number of patients, we show an absolute reduction of skin grade 2–3 toxicity in 41% of patients and 46% of panitumumab cumulative cycles in the experimental group versus placebo; lactolycopene administration was able to abolish malondialdehyde (MDA) production, a biomarker used to measure lipid peroxidation in the organism, and replenish antioxidant consumption in the course of anti-EGFR therapy. Trial registration: Clinicaltrials.gov NCT 03,167,268 (Pasto trial).