Abstract P3-14-04: Efficacy and Safety of Neratinib (HKI-272) in Combination with Paclitaxel in Her2+ Metastatic Breast Cancer
Authors: Chow L , Gupta S , Hershman DL , Epstein R , Bondarenko I , Vo Van M-L , Freyman A , Zhao Y , Abbas R , Awada A. 
Published: April 2011

Abstract
Background: Neratinib (HKI-272), an irreversible inhibitor of the tyrosine kinase receptors Her1, -2 and -4, has shown antitumor activity in patients with Her2+ disease, with or without prior trastuzumab exposure. In preclinical models, neratinib inhibits Her receptor signaling via the phosphatidyl inositol-3-kinase (PI3K) and MAPK pathways. PI3K signaling activity may mediate resistance to trastuzumab and endocrine therapy in breast cancer. The objective of this ongoing phase 1/2 study is to evaluate the efficacy and safety of neratinib combined with paclitaxel in patients with solid tumors and Her2+ metastatic breast cancer. Material and Methods: This was an open-label, 2-part study. In part 1, patients with solid tumors received ascending daily oral dosages of neratinib (160 mg, 240 mg) plus IV paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle to determine the maximum tolerated dose [MTD]. In part 2, patients with Her2+ metastatic breast cancer in the first-to fourth-line setting received neratinib plus paclitaxel at the MTD. Tumor response (assessed using modified RECIST criteria), safety, and pharmacokinetic (PK) parameters were evaluated.
Results: Full doses of both neratinib (240 mg) and paclitaxel (80 mg/m2) were well tolerated in part 1 and evaluated in patients with Her2+ breast cancer in part 2. As of 26 April 2010, data were available for 102 patients in part 2 (median age [range], 50.5 years [20.0-76.0]; 100% were female). The objective response rate (ORR; complete plus partial responses) among 99 evaluable patients in part 2 was 71% (95% confidence interval [CI], 60.7-79.4); ORR in the first-line subset (n = 33) was 70% (95% CI, 51.3-84.4). Median progression-free survival was 55.6 weeks in the overall population and 57.0 weeks in the first-line subset. Of 38 patients treated with prior Her2-directed therapy, 26 responded (ORR, 68% [95% CI, 51.3-82.5]), including 10 of 14 patients treated with prior lapatinib (ORR, 71% [95% CI, 41.9-91.6]). Responses were observed in 31 of 39 patients with prior endocrine therapy (ORR, 79% [95% CI, 63.5-90.7]) and 49 of 62 patients with prior taxane treatment (ORR, 79% [95% CI, 66.8-88.3]). The most common treatment-emergent adverse events (TEAEs) in part 2 were diarrhea (91%), neutropenia (53%), peripheral sensory neuropathy (52%), alopecia (48%), and leukopenia (44%). Common grade ≥3 TEAEs were diarrhea (28%) and neutropenia (22%). Median time to onset of diarrhea was 3 days, and median duration was 35.5 days. Three patients discontinueddue to an AE (mouth ulceration, fatigue, ejection fraction reduction); 4 deaths were reported (AE, n = 2; disease progression, n = 2). Evaluation of PK parameters suggested no interaction between the 2 drugs; exposures were similar to those observed for each drug as monotherapy. Discussion: High clinical responses were observed in patients with Her2+ breast cancer, including the first-line subset and patient subsets with prior Her2-directed, endocrine, and taxane therapies. The combination of neratinib 240 mg and paclitaxel 80 mg/m2 was tolerable, with a toxicity profile similar to each drug given as monotherapy. A phase 3 trial is ongoing to study this combination in the first-line setting compared with trastuzumab plus paclitaxel.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-04.