Safety and Efficacy of Neratinib (HKI-272) in Combination with Paclitaxel in ErbB2+ Metastatic Breast Cancer. (2009)

Abstract Background: Neratinib (HKI-272), an irreversible pan-ErbB inhibitor of the tyrosine kinase receptors ErbB1, -2 and -4, has shown antitumor activity in patients with ErbB2+ disease, with or without prior trastuzumab exposure. In preclinical models, neratinib inhibits ErbB receptor complex downstream signaling via the phosphatidyl inositol-3-kinase (PI3K) pathway. PI3K signaling activity may mediate resistance to trastuzumab and endocrine therapy in breast cancer (BC). The objective of this ongoing phase 1/2 study is to evaluate the safety and efficacy of neratinib in combination with paclitaxel in patients with solid tumors and ErbB2+ metastatic BC.Material and Methods: This open-label, 2-part study enrolled patients with solid tumors (part 1; determine the maximum tolerated dose [MTD]) and ErbB2+ advanced/metastatic BC in the first- to fourth-line setting (part 2; objective response rate [ORR] at the MTD). In part 1, patients received ascending multiple 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. In part 2, patients received neratinib plus paclitaxel at the MTD. Tumor response was assessed using modified RECIST criteria. Safety and pharmacokinetic (PK) parameters were also 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 ErbB2+ BC in part 2. As of 1 May 2009, data were available for 102 patients in part 2 (median age [range], 50.5 [20.0-76.0] years; 100% were female). Treatment-emergent adverse events (TEAEs) reported in ≥10% of patients included diarrhea (89%), neutropenia (42%), rash (26%), nausea (26%), and vomiting (20%). Common grade ≥3 TEAEs included diarrhea (25%), leukopenia (20%), and neutropenia (17%). Diarrhea was generally observed early (median onset, 3 days after the first dose of neratinib; median duration, 17 days). One patient withdrew because of toxicity (renal failure, dehydration). Evaluation of preliminary PK parameters suggested no interaction between the 2 drugs; exposures were similar to those observed for each drug as monotherapy. The ORR in part 2 (complete plus partial responses) among 97 evaluable patients was 62.9% (80% confidence interval [CI], 55.9-69.4). Median progression-free survival is estimated at 40 weeks (76% of patients censored). Of 37 patients treated with prior Her2-directed therapy, 21 responded (ORR, 56.8% [80% CI, 44.9-68.0]), including 9 of 13 patients treated with prior lapatinib (ORR, 69.2% [80% CI, 47.7-85.8]). Responses were observed in 27 of 37 patients with prior endocrine therapy in any line (ORR, 73.0% [80% CI, 61.5-82.5]), and 43 of 60 patients with prior taxane treatment (ORR, 71.7% [80% CI, 62.9-79.3]).Discussion: The combination of neratinib 240 mg and paclitaxel 80 mg/m2 was tolerable, with a similar toxicity profile to each drug given as monotherapy. Although the sample size of the trial was limited, differential clinical activity was observed in ErbB2+ metastatic BC with respect to prior treatment, supporting further investigation of patient subsets in future trials. A phase 3 trial is planned to study this combination in the first-line setting compared with trastuzumab plus paclitaxel. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5081.