Background: HER3 is a key dimerization partner for HER-family members that activates oncogenic signaling pathways. Patritumab is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding Japanese Phase I study in patients with advanced solid tumors, the tolerability of U3-1287 was confirmed up to the dose of 18 mg/kg without dose-limiting toxicities (DLTs). This study aimed to assess the safety, pharmacokinetics, and recommended dose of U3-1287 in combination with erlotinib for Japanese patients with advanced NSCLC. The incidence of anti-U3-1287 antibodies (HAHA), tumor response, and level of serum soluble HER3 (sHER3) were also evaluated.

Methods: This study enrolled stage IIIB/IV NSCLC patients who had progressed after at least one prior chemotherapy. This study consisted of 2 parts; dose escalation (Part 1) and dose expansion (Part 2). Patients in Part 1 received patritumab 9 mg/kg or 18 mg/kg every 3 weeks (q3w) i.v., in addition to erlotinib 150 mg/day daily p.o. DLTs were assessed in Part 1. In Part 2, patients received the recommended dose of patritumab in combination with erlotinib determined in Part 1.

Results: Twenty-four patients, 6 in Part 1 and 18 in Part 2, were enrolled. Thirteen patients had activating epidermal growth factor receptor (EGFR) mutation (12 out of 13 patients received prior gefitinib therapy), 9 had wild type EGFR, and 2 had unknown status. The most common (≥ 50% overall) adverse events were diarrhea (95.8%), stomatitis (91.7%), paronychia (83.3%), dermatitis acneiform (70.8%), dry skin (62.5%), decreased weight (54.2%), and decreased appetite (50.0%), which were generally mild and manageable. Serious adverse events (SAEs) were reported in 4 patients; hepatic dysfunction, bacterial infection, pneumonia, cancer pain, and rash acneiform. All SAEs except for cancer pain were considered to be related to both patritumab and erlotinib treatment. No DLTs were observed. One patient with activating EGFR mutations achieved partial response and 13 patients including 10 patients with activating EGFR mutations had stable disease. The median progression-free survivals were 46.0 days at 9 mg/kg (n =3), 91.0 days at 18 mg/kg (n = 21), 44.0 days for the wild type EGFR (n= 9) and 107.0 days for the activating EGFR mutations (n = 13). One patient had positive HAHA immunoassay results and the samples were also evaluated using the cell-based bioassay. However, no neutralizing antibodies were detected. The level of sHER3 increased after patritumab administration in all subjects. These changes did not correlate with the dose level of patritumab.

Conclusions: The tolerability of patritumab with erlotinib has been confirmed up to the dose of 18 mg/kg of U3-1287 in Japanese patients with advanced NSCLC.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A67.

Citation Format: Noboru Yamamoto, Atsushi Horiike, Makoto Nishio, Haruyasu Murakami, Nobuyuki Yamamoto, Hiroyasu Kaneda, Kazuhiko Nakagawa, Tomohide Tamura. Phase I study of HER3 targeted antibody patritumab (U3-1287) in combination with erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A67.