Neratinib (HKI-272), an irreversible pan erbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer.

Abstract

Abstract Abstract #37 Background: Neratinib (HKI-272) irreversibly inhibits the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase 1 study, neratinib was tolerable and demonstrated antitumor activity in patients (pts) with solid tumors, including 8 of 25 evaluable pts with erbB2-positive advanced breast cancer. In this open-label, 2-arm phase 2 study, pts with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib.
 Methods: ErbB2 gene amplification in tumor tissue, by FISH was a requirement for study entry. Pts were assigned to arm A if they had prior treatment with trastuzumab and to arm B if they had no prior treatment with trastuzumab or other erbB2-targeted drug. All pts received oral doses of 240 mg of neratinib daily. The primary endpoint was progression-free (PFS) survival rate at 16 weeks (wks).
 Results: Enrollment of 136 pts (arm A: 66 pts; arm B: 70 pts; median age 50 years [range 31-83 years]) was completed in November 2007. Common neratinib-related adverse events (AEs), any grade, were diarrhea (89%), nausea (29%), vomiting (23%), fatigue (16%), and anorexia (15%). Diarrhea was the only ≥grade 3 AE that occurred in ≥5% of pts, 26/136 (19%) total pts, 27% in arm A and 11% in arm B. Dose reductions occurred in 27% total pts, 36% in arm A and 19% in arm B, most commonly because of diarrhea. The main reasons for discontinuation of the study were disease progression (arm A: 74%, arm B: 43%), and AEs (arm A: 8%, arm B: 4%).
 124 pts (arm A: 61 pts, arm B: 63 pts) were evaluable for efficacy based on independent assessment and 131 pts (arm A: 65 pts, arm B: 66 pts) were evaluable based on investigator assessment. The objective response rates (complete or partial response) were 26% (95% CI 16%, 39%) in arm A, 51% (95% CI: 38%, 64%) in arm B for independent assessment and 34% (95% CI: 23%, 47%) in arm A, 62% (95% CI: 49%, 74%) in arm B for investigator assessment. The 16-wk PFS rates were 61% in arm A, 75% in arm B (independent); 57% in arm A, and 78% in arm B (investigator). The median PFS for independent [and investigator assessment] was 23 [22] wks in arm A and 40 [35] wks in arm B.
 Discussion: Neratinib demonstrates robust antitumor activity in pts with erbB2-positive advanced breast cancer, with objective response rates of 26% in pts who had prior treatment with trastuzumab and 51% in pts who had no prior treatment with trastuzumab. Additional updated efficacy and safety data will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 37.