Phase II trial of the Hsp90 inhibitor tanespimycin (Tan) + trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC)

Abstract

1027 Background: Tan (17-AAG) inhibits Hsp90 activity, resulting in degradation of client proteins including the HER2 receptor. A phase 1 trial demonstrated clinical activity of T + Tan in pts with HER2+ MBC (1 PR + 4 MRs in 15 pts with median of 2 prior T-based regimens; Modi et al, JCO 2007). Tan was initially a Cremophor-based product; a suspension became available and was substituted in this phase 2 trial. Methods: Eligible pts have HER2+ MBC and either PD within 3m following adjuvant T or PD following 1-line of T-based therapy for MBC. Pts receive standard weekly doses of T followed by Tan (450 mg/m2). Early pts received a Cremophor-based Tan product with antihistamine/steroid premeds. Later pts received the suspension Tan product without premeds. Primary endpoint: ORR by RECIST, disease status assessed every 8w. Results: As of 19Dec07, 29 pts enrolled (mean age 54 yrs, range 31–71; median KPS 90). 21 pts received Cremophor product; 8 pts received suspension product (4 pts crossed-over to the suspension product). 21 pts are evaluable for efficacy. Drug-related toxicity: fatigue (39%), diarrhea (33%), dizziness (24%) and headache (19%). Grade 3 drug-related toxicity in 3 pts (headache/fatigue; ↑ LFTs; and unsteady gait/euphoria, diarrhea), all reversible; 1 pt withdrawn for toxicity. Toxicities common to cytotoxic chemotherapy noticeably absent (alopecia, myelosuppression, peripheral neuropathy). Activity: 5 pts have a confirmed PR (1) 75% decrease in liver metastases, 8 months (m) on study; (2) 45% decrease in hilar node, 15+m/active; (3) 33% decrease in right breast lesion, 7+m /active; (4) 57% decrease in lymph nodes, liver, and left breast lesions, on study 7m; (5) 37% decrease in lymph nodes, 5+m/active. All 4 active pts maintained PR when cross-over to the new formulation. Two additional pts had MR with ↓ tumor markers (6 and 5 m); 5 pts had SD for 4, 4, 4+, 7 and 8 m. Conclusions: The combination of T + Tan is active in pts with HER2+ MBC with progression on T-based therapy (response rate of 24% and clinical benefit rate of 57%). Toxicity is very manageable. The newer suspension product produces a similar safety profile with responses maintained upon cross-over. Accrual continues on the suspension product. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Kosan Biosciences Kosan Biosciences Kosan Biosciences Kosan Biosciences