Differences in multikinase inhibitors (MKI) toxicity profile according to gender. A pooled analysis of three phase II trials with lenvatinib, pazopanib and sorafenib in patients (pts) with advanced gastroenteropancreatic (GEP) neuroendocrine tumours (NETs)

Background There is a dearth of understanding of gender influence in targeted therapies toxicity. Increasing evidence suggests a possible different toxicity profile according to gender, but mostly retrospective studies in common tumors. Currently, data from prospective studies are minimal. In the present study, we will review MKI toxicity profiles according to gender in pts with NETs in three clinical trials. Methods Multicenter open-label phase II studies TALENT, PAZONET and GETNE0801 included pts with advanced GEP NETs treated with lenvatinib, pazopanib, and sorafenib-bevacizumab respectively. All studies were performed by the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All pts were included in the review, considering all toxicity grades with an incidence higher than 5% for the univariate analysis. Bevacizumab specific toxicities were excluded in patients from GETNE0801 trial. Additionally, all grade 3-4 toxicities were analyzed separately. Results 199 pts (46.23% female) with 1349 adverse events (AEs) (12.23% G3-4) divided into 125 categories were included. In female patients, nausea/vomiting, skin disorders (excluding palmar-plantar erythrodysesthesia), liver alterations (including transaminase and bilirubin), headache, pyrexia, hair disorders and dizziness were significantly more common (Table). The only toxicity with a higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p0.02). The only G3-4 toxicity significantly more frequent in women was liver toxicity (20.65% vs. 7.55%, OR 3.18, p0.009). Table: 1387P . Toxicity (all grades) Women (%) Men (%) Difference (%) Odds Ratio (95% CI) p Nausea/Vomiting 63.04 44.86 18 2.09 0.01 Skin disorders 60.87 45.79 15 1.84 0.03 Liver toxicity 57.61 30.84 26 3.04 0.0002 Headache 28.26 12.15 16 2.84 0.005 Pyrexia 17.39 5.61 11 3.44 0.01 Hair disorders 20.65 8.41 12 2.83 0.01 Dizziness 17.39 6.54 10 3.00 0.02 Dysphonia 16.30 37.38 21 0.32 0.001 Conclusions In our study, we observed significant differences in toxicity AEs by gender, especially in women with seven increased toxicities. A different approach in toxicity management should be adopted based on gender in pts with GEP NETs treated with MKI. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini, ; Travel / Accommodation / Expenses: Ipsen, Novartis, AAA, Roche, AstraZeneca, Eisai. E. Grande: Speaker Bureau / Expert testimony: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi, Adacap, Novartis, EUSA Pharma, Pierre Fabre, Lexicon, Celgene; Research grant / Funding (institution): MSD, Roche. T. Ibrahim: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Ipsen, PharmaMar, Novartis. J.W. Valle: Advisory / Consultancy: Abbott, Agios, AstraZeneca, Baxalta, Bioven, Celgene, Delcath, Genoscience Pharma, Incyte, Ipsen, Keocyt, Lilly, Merck, MidaTech, Mundipharma, Novartis, NuCana, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED Pharmaceuticals; Speaker Bureau / Expert testimony: Abbott, Celgene, Ipsen, Novartis, Pfizer, Sirtex; Travel / Accommodation / Expenses: Celgene, Ipsen, Novartis, NuCana. V. Alonso: Advisory / Consultancy: Amgen, Roche, Merck, Servier, Sanofi, Ipsen, Bayer, Novartis. R. Manneh Kopp: Speaker Bureau / Expert testimony: Pfizer, Ipsen, BMS, Roche, MSD, Sanofi, Novartis; Research grant / Funding (institution): MSD, Roche, BMS. R. Salazar: Advisory / Consultancy: VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer, Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Farma, Lylli, MSD; Speaker Bureau / Expert testimony: Pfizer, Amgen, Novartis, Merck, MSD, AZD, Celgene,. J. Capdevila: Honoraria (self): Novartis, Pfier, Ipsen, Exelixis, Bayer, Eisai, AAA, Amgen, Sanofi, Merck; Research grant / Funding (institution): Eisai, Novartis, Ipsen, AstraZeneca, Pfier, AAA. All other authors have declared no conflicts of interest.