HER2 Support Group Forums - View Single Post - Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progressed

schoonder · 03-12-2010, 08:23 PM

"Let's hope that the pertuzumab & T-DM1 combination can deliver even better responses."

At the upcoming AACR meeting Genentech will discuss early data on this subject matter.

Abstract Number: 5607

Presentation Title: Dual targeting of HER2: Enhanced antitumor efficacy of trastuzumab-DM1 combined with pertuzumab

Presentation Time: Wednesday, Apr 21, 2010, 8:00 AM -11:00 AM

Location: Exhibit Hall A-C, Poster Section 30

Poster Section: 30

Poster Board Number: 28

Author Block: Carter T. Fields, Lisa M. Crocker, Mark X. Sliwkowski, Gail D. Lewis Phillips. Genentech, Inc., South San Francisco, CA

Abstract Body: The EGFR family of transmembrane receptors consists of HER1 (ErbB1/EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These receptors are often dysregulated in human solid tumors. For example, amplification and overexpression of HER2 occur in approximately 20 percent of human breast cancers and are predictive of poor clinical outcome. A principal means by which these receptors exert their growth-stimulatory effect is through homo- and hetero-dimerization which can occur in either a ligand-dependent or -independent manner and subsequently promotes receptor tyrosine kinase activity, leading to autophosphorylation and activation of downstream signal transduction pathways.
The humanized HER2 antibody, trastuzumab (Herceptin®), is approved for use in adjuvant and metastatic HER2-positive breast cancer and has shown significant clinical benefit. Trastuzumab-DM1 (T-DM1, TMAb-mcc-DM1, trastuzumab emtansine) is an antibody-cytotoxic drug conjugate composed of the maytansine derivative DM1 directly coupled, through a thioether SMCC linker, to trastuzumab. We previously reported the potent in vitro and in vivo efficacy of T-DM1 in trastuzumab-sensitive and -refractory breast tumor models. Both trastuzumab and T-DM1 bind domain IV of the HER2 extracellular domain (ECD) and inhibit HER2 function in a ligand-independent manner. T-DM1 provides additional efficacy through selective delivery of the cytotoxic agent DM1 to HER2-overexpressing cancer cells. Pertuzumab is a humanized HER2 antibody that binds domain II of the HER2 ECD and thereby inhibits ligand-induced activation of HER2 by blocking dimerization of HER2 with other HER family members. Pertuzumab in combination with trastuzumab has shown impressive preclinical as well as clinical activity in HER2-positive breast cancer.
The purpose of our studies was to evaluate the in vitro and in vivo efficacy of T-DM1 combined with pertuzumab. Our in vitro results show that combination treatment resulted in synergistic inhibition of cell proliferation in human breast and lung cancer cells that over-express HER2. Drug combination effects were analyzed by the Chou and Talalay method for determining combination index values. Similarly, we observed enhanced in vivo efficacy when administering T-DM1 in combination with pertuzumab, as compared with either agent alone, in breast and lung cancer xenograft models. Treatment of cells with T-DM1 combined with pertuzumab also resulted in a synergistic increase in apoptosis as measured by increased activity of the apoptotic enzymes, caspases 3 and 7, and increased levels of the apoptotic population in cell cycle experiments. 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.

03-12-2010, 08:23 PM	#3
schoonder Senior Member Join Date: Jul 2008 Posts: 186	Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre "Let's hope that the pertuzumab & T-DM1 combination can deliver even better responses." At the upcoming AACR meeting Genentech will discuss early data on this subject matter. Abstract Number: 5607 Presentation Title: Dual targeting of HER2: Enhanced antitumor efficacy of trastuzumab-DM1 combined with pertuzumab Presentation Time: Wednesday, Apr 21, 2010, 8:00 AM -11:00 AM Location: Exhibit Hall A-C, Poster Section 30 Poster Section: 30 Poster Board Number: 28 Author Block: Carter T. Fields, Lisa M. Crocker, Mark X. Sliwkowski, Gail D. Lewis Phillips. Genentech, Inc., South San Francisco, CA Abstract Body: The EGFR family of transmembrane receptors consists of HER1 (ErbB1/EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These receptors are often dysregulated in human solid tumors. For example, amplification and overexpression of HER2 occur in approximately 20 percent of human breast cancers and are predictive of poor clinical outcome. A principal means by which these receptors exert their growth-stimulatory effect is through homo- and hetero-dimerization which can occur in either a ligand-dependent or -independent manner and subsequently promotes receptor tyrosine kinase activity, leading to autophosphorylation and activation of downstream signal transduction pathways. The humanized HER2 antibody, trastuzumab (Herceptin®), is approved for use in adjuvant and metastatic HER2-positive breast cancer and has shown significant clinical benefit. Trastuzumab-DM1 (T-DM1, TMAb-mcc-DM1, trastuzumab emtansine) is an antibody-cytotoxic drug conjugate composed of the maytansine derivative DM1 directly coupled, through a thioether SMCC linker, to trastuzumab. We previously reported the potent in vitro and in vivo efficacy of T-DM1 in trastuzumab-sensitive and -refractory breast tumor models. Both trastuzumab and T-DM1 bind domain IV of the HER2 extracellular domain (ECD) and inhibit HER2 function in a ligand-independent manner. T-DM1 provides additional efficacy through selective delivery of the cytotoxic agent DM1 to HER2-overexpressing cancer cells. Pertuzumab is a humanized HER2 antibody that binds domain II of the HER2 ECD and thereby inhibits ligand-induced activation of HER2 by blocking dimerization of HER2 with other HER family members. Pertuzumab in combination with trastuzumab has shown impressive preclinical as well as clinical activity in HER2-positive breast cancer. The purpose of our studies was to evaluate the in vitro and in vivo efficacy of T-DM1 combined with pertuzumab. Our in vitro results show that combination treatment resulted in synergistic inhibition of cell proliferation in human breast and lung cancer cells that over-express HER2. Drug combination effects were analyzed by the Chou and Talalay method for determining combination index values. Similarly, we observed enhanced in vivo efficacy when administering T-DM1 in combination with pertuzumab, as compared with either agent alone, in breast and lung cancer xenograft models. Treatment of cells with T-DM1 combined with pertuzumab also resulted in a synergistic increase in apoptosis as measured by increased activity of the apoptotic enzymes, caspases 3 and 7, and increased levels of the apoptotic population in cell cycle experiments. 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.