ASCo--new combo regimen effective in herceptin resistant her2+ breast cancer

[Lani]

AACR: Novel Combo Therapy May Overcome Resistant Breast Cancer

By Ed Susman, Contributing Writer, MedPage Today
Published: April 26, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner


the treatment discussed in this study is not FDA approved for any purpose and is available only in a clinical trial setting.


Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
WASHINGTON -- A combination therapy comprising trastuzumab (Herceptin) and two investigational agents, pertuzumab and an anti-tubulin cytotoxic agent (DM1), was effective against breast tumors refractory to medical treatment in preclinical testing, a researcher said here.
The combination treatment is now in clinical trials, said Carter Fields, a researcher at Genentech in South San Francisco, Calif., who reported data from animal experiments here at the annual meeting of the American Association for Cancer Research.

The company is investigating the effectiveness of a conjugate drug linking trastuzumab with DM1.

Alone, the conjugate appeared to have modest efficacy against treatment-refractory breast tumors, but when combined with pertuzumab, an antibody that inhibits dimerization of the HER2 receptor protein, the combination shut off tumor growth.

"When we do these combination drug experiments, we reduce the potency of each component agent by as much as 50%, which leaves 'room for synergy', meaning that the sum of the parts equals more than the whole," Fields said.

In xenograft models of breast cancer and lung cancer, mice treated with a control vehicle substance, pertuzumab, the trastuzumab-DM1 conjugate, or a combination of all the active drugs showed that the combination virtually stopped tumors from growing relative to baseline, whereas tumor volume rose significantly in the other arms of the study.

For example, in laboratory animals implanted with MDA-MB-175-V II xenografts, tumor volume at baseline was about 200 mm3 for all the animals. After 35 days, tumor volume in the combination arm was less than at baseline while in the control animals volume reached 1,000 mm3 after 25 days, when the animals were sacrificed; in the pertuzumab monotherapy arm, the tumor volume reached 1,000 mm3 after 35 days, and in the trastuzumab-DM1 monotherapy arm the tumor volume reached about 800 mm3 after 35 days.

"The combination of both agents results in significantly (P<0.05) enhanced antitumor efficacy," Fields told MedPage Today at his poster presentation.

In another experiment with laboratory animals exposed to Calu-3 xenografts, tumor growth was again delayed the longest in patients treated with high-dose combination regimens. In mice exposed to KPL-4 xenografts, mean tumor volume rose for all mice except those on the high-dose 3mg/kg combination of trastuzumab-DM1 and pertuzumab where researchers reported about an 80% decline in tumor volume from a baseline of about 275 mm3 to around 50 mm3 after 54 days.

Fields noted that the effects of the combination lasted long after treatment stopped. The animals received only a baseline combination treatment, followed by two more pertuzumab infusions -- the final one on day 14.

Overall, Fields said the experiments showed that the trastuzumab-DM1 and pertuzumab combination:

Inhibits proliferation of the three cell lines both in vitro and in vivo, more effectively than either agent alone
Exhibits synergistic effects in vitro
Induces apoptosis to a greater extent than either agent alone
"Together, these studies support the hypothesis that T-DM1 in combination with pertuzumab for HER2-amplified cancer may offer an additional therapeutic approach for patients whose disease progresses on trastuzumab and lapatinib-based therapy," according to Fields.

Genentech funded the study.

Fields is an employee of Genentech.


Primary source: American Association for Cancer Research
Source reference:
Fields C, et al "Dual targeting of HER2: Enhanced anti-tumor efficacy of trastuzumab-DM1 combined with pertuzumab" AACR 2010; Abstract 5607.