Abstract PR6: Phase 1b/2 trial of HER3 inhibitor U3-1287 in combination with erlotinib in advanced NSCLC patients (pts): HERALD study

Background: EGFR is frequently overexpressed in NSCLC, and while many advanced NSCLC tumors initially respond to EGFR tyrosine kinase inhibitors (TKIs), development of therapeutic resistance often follows. HER3 is a key dimerization partner of HER family members, including EGFR, and activates oncogenic signaling pathways. HER3 overexpression occurs in many solid tumors and is associated with poor prognosis in lung cancer pts. Data indicate that HER3 expression may play a role in EGFR TKI resistance, suggesting that simultaneous inhibition of HER3 and EGFR may be beneficial. U3-1287 is a fully human anti-HER3 monoclonal antibody with synergistic anticancer activity in combination with anti-EGFR inhibitors in preclinical models. The phase 1b/2 HERALD trial was initiated to investigate the combination of U3-1287 with erlotinib in the treatment of advanced NSCLC pts after failure of at least 1 prior chemotherapy. Results as of August 12, 2011 are reported here. Methods: Eligible pts had stage IIIB/IV NSCLC that progressed on ≥1 prior chemotherapy treatments and were EGFR treatment-naive. In the open-label, phase 1b portion, pts received erlotinib 150 mg/day orally and U3-1287 18 mg/kg intravenously every 3 weeks (Q3W). In the event that 18 mg/kg was not tolerated based on DLT assessment, sequential cohorts were to receive de-escalating doses of U3-1287. As no DLTs were reported, the recommended phase 2 dose is 18 mg/kg Q3W for U3-1287 in combination with 150 mg/day erlotinib. The phase 2 portion of the study is a randomized, placebo-controlled, double-blind study assessing the efficacy and safety of U3-1287 combined with erlotinib relative to erlotinib alone. It is a 3-arm study of 150 mg/day erlotinib with U3-1287 high-dose (18 mg/kg Q3W), U3-1287 low-dose (18 mg/kg loading dose followed by 9 mg/kg Q3W), or placebo. Study end points include adverse event (AE) incidence, pharmacokinetics, human antihuman antibody (HAHA) formation, tumor response, and progression-free survival (PFS). Results: The phase 1b portion of the trial enrolled 7 pts (4 male), with a median age of 68 years (range, 48–78). There were no reported DLTs. Erlotinib-related AEs reported in ≥2 pts were rash (6 pts), diarrhea (4), dry skin (3), decreased appetite (3), stomatitis (3), dehydration, dermatitis acneiform, dysgeusia, mucosal inflammation, nausea, and skin exfoliation (2 each). The only U3-1287–related AE reported in ≥2 pts was decreased appetite (2 pts). AEs grade ≥3 occurred in 2 pts: one grade 3 case each of pain, fatigue, headache, dehydration, diarrhea, and blood creatinine increase; none were related to U3-1287. Three pts had 3 serious AEs: grade 3 pain (unrelated to study treatment), grade 3 dehydration (erlotinib-related), and grade 1 decreased appetite (erlotinib- and U3-1287-related). All seven pts tested negative for HAHA formation after drug administration. As of Aug 12, 3 pts have ended study treatment due to disease progression. Four pts had best responses of stable disease lasting 86, 87, 90, and 117 days. As of Aug 12, in the phase 2 portion, 11 pts (4 male) have been screened; first study treatment was June 21. Pts had a median age of 70 years (range, 49–83). There have been 2 serious AEs in 1 pt, both unrelated to study treatment: grade 2 cardiac disorder requiring hospitalization and death due to multi-organ failure. Treatment-related AEs reported were diarrhea (3 pts), rash (3), cardiac disorder, decreased appetite, nausea, and vomiting (1 each); all were grade 1 or 2. Conclusions: Results across the phase 1b and 2 portions indicate that U3-1287 in combination with erlotinib is generally well tolerated. This abstract is also presented as Poster B38.