A phase I/II study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2019-11, Vol.22 (6), p.1206-1214
• Main Authors: Kim, Tae-Yong, Han, Hye Sook, Lee, Keun-Wook, Zang, Dae Young, Rha, Sun Young, Park, Young Iee, Kim, Jin-Soo, Lee, Kyung-Hun, Park, Se Hoon, Song, Eun-Kee, Jung, Soo-A, Lee, NaMi, Kim, Yeul Hong, Cho, Jae Yong, Bang, Yung-Jue
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Appetite loss; Cancer Research; Chemotherapy; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Drug therapy; Enzyme inhibitors; Epidermal growth factor receptors; ErbB-2 protein; Female; Fever; Gastric cancer; Gastroenterology; Humans; Immunotherapy; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Neutropenia; Oncology; Original Article; Paclitaxel; Paclitaxel - administration & dosage; Prospective Studies; Protein-tyrosine kinase; Pruritus; Quinazolines - administration & dosage; Receptor, ErbB-2 - metabolism; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Stomatitis; Surgical Oncology; Survival; Survival Rate; Targeted cancer therapy; Toxicity; Trastuzumab; Trastuzumab - administration & dosage
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-019-00958-4

Background Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC). Methods Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m 2 infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks. Results In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8–21.9) and 29.5 weeks (95% CI 17.9–59.2), respectively. Conclusions The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.