Alvespimycin (KOS-1022) and trastuzumab (T): Activity in HER2+ metastatic breast cancer (MBC)
Sub-category: New Systemic Agents---New drugs and targets (includes antiangiogenics)
Category: Treatment
Meeting: 2007 Breast Cancer Symposium
Abstract No: 165
Author(s):S. Modi, K. Miller, L. S. Rosen, B. Schneider, L. Chap, Z. Zhong, K. Kersey, A. L. Hannah, C. Hudis
Abstract:
Background: Hsp90 inhibition by Alvespimycin (A) results in degradation of client proteins, including the HER2 receptor using a HER2-expressing cell line in vivo.
Methods: Pts receive T followed by A via IV infusion over 1 hr every week.
Objectives: define the recommended dose/toxicity of T+A. PK: after the 1st and 4th infusion. PBLs: purified to investigate changes in intracellular signaling proteins by immunoblot.
Results: 25 pts treated at 60 (n=9), 80 (n=10) and 100 mg/m2 (n=6). Median prior cytotoxic regimens: 6.5 (range 1-15); prior T-regimens for MBC pts: median 4, range 0-9).
Diagnoses: HER2+ MBC (n=22), ovarian (n=3). DLT at 100 mg/m2: 1 pt with hypoxia and ?LVEF; DLT at 80 mg/m2; 2 pts with Grade 3 keratitis (reversible and retreated upon resolution). 80 mg/m2 was expanded due to grade 2 arthralgia, myalgia, fatigue at 100 mg/m2.
Drug-related toxicity: diarrhea (61%), fatigue (48%), arthralgia (44%), headache (39%), nausea (35%), myalgias (26%), blurry vision (26%), pain in extremity (26%) and dry eye (22%); drug-related Grade 3+ toxicity (other than DLT): 1 episode of fatigue and diarrhea. PK (n=24): t1/2 19.1 hr (39%CV); Clearance 16.9 L/hr (45%CV); Vz 439L (43%CV); no change upon weekly dosing. AUCinf/Cmax (80 mg/m2): 8572 ng*hr/mL (43%CV) and 1633 ng/mL (60%CV).
HER2+ MBC activity: 1 pt (13 prior regimens; 3 x T and lapatanib) with evaluable disease showed complete resolution of lung metastases by CT/PET with significant improvement in dyspnea; 1 active pt (11 prior regimens, 5 x T; 2x lapatanib) with 10% reduction in tumor mass with change consistent with tumor necrosis, ?64% CEA and ?63% CA27.29; 5 additional pts with HER2+ MBC with SD (4, 5, 6+, 11+ and 12 months).
OvarianCA activity: 1 pt (13 prior regimens; 16+ months on-study) with evaluable disease showed near complete resolution of ascites and pleural effusion at end of Cycle 2 with ?83% CA125. Dose-dependent increase in Hsp70 in PBLs; at 80 mg/m2, Hsp70 induction was maintained prior to successive weekly doses (maximal ?Hsp70 induction at 72 hrs following the 4th infusion).
Conclusions: Consistent with earlier Hsp90 inhibitor experience, the combination of T+A is active in H-refractory HER2+ MBC, with accrual continuing at 80 mg/m2 to define a recommended phase 2 dose. |
