Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy

Baselga, José; Gelmon, Karen A.; Verma, Shailendra; Wardley, Andrew M; Conte, Pierfranco; Miles, David; Bianchi, Giulia; Cortés, Javier; McNally, Virginia; Ross, Graham; Fumoleau, P.; Gianni, Luca

doi:10.1200/jco.2009.24.2024

Cited by 578 publications

(363 citation statements)

References 21 publications

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“…The combination of trastuzumab and pertuzumab has achieved success in the clinic. A phase II trial in patients with Her2-positive metastatic breast cancer who had previously progressed on trastuzumab therapy achieved a 50% clinical benefit rate and 24.2% objective response rate (43). We show here that MM-111 inhibition of ligand-activated ErbB3 phosphorylation is superior to pertuzumab and the combination of MM-111 and trastuzumab is more effective at inhibiting tumor cell growth than pertuzumab plus trastuzumab.…”

Section: Discussionmentioning

confidence: 63%

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

McDonagh

Huhalov

Harms

et al. 2012

Molecular Cancer Therapeutics

259

207

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The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse. Mol Cancer Ther; 11(3); 582-93. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 63%

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

McDonagh

Huhalov

Harms

et al. 2012

Molecular Cancer Therapeutics

259

207

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“…8 Their mechanisms of action are complementary, providing broader blockade of the HER2-positive tumor cell proliferation and survival signaling. 9 The CLEOPATRA clinical trial showed that patients with metastatic HER2-positive breast cancer treated with combination of pertuzumab and trastuzumab plus docetaxel significantly prolonged progression-free survival, 10 and simultaneous blockade of HER2 by trastuzumab and pertuzumab may overcome trastuzumab-resistance. 11 …”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Huang

Liu

et al. 2018

mAbs

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MBS301, a glyco-engineered bispecific anti-human epidermal growth factor receptor 2 (HER2) antibody with a typical IgG1 monoclonal antibody structure, was developed through dual-cell expression and in vitro assembling process. MBS301 consists of two half antibodies engineered from trastuzumab and pertuzumab, respectively. Integrity and purity profiles of MB301 indicated that the heterodimerization of the two half antibodies was successful. The high and similar melting temperatures (Tm1,72.0°C and Tm2, 84.8°C) of MBS301 compared with those of its parental monoclonal antibodies trastuzumab and pertuzumab (in-house made T-mab and P-mab, respectively) revealed its structural compactness. With computer-modeling experiments and Biacore binding and competition kinetics studies, the binding stoichiometry between MBS301 and HER2-ECD was determined to be 1:1 and the two arms of MBS301 were shown to bind to domains II and IV of HER2-ECD antigen simultaneously. MBS301 displayed synergistic bioactivities as the combination of T-mab and P-mab in vitro in multiple cancer cell lines and in vivo in xenograft mouse model studies, and showed more effective activity than T-mab or P-mab used individually. Moreover, fucose-knockout dramatically increased MBS301’s binding affinity to low affinity FcγRIIIa allotype 158F (KD = 2.35 × 10−7M) to near the high affinity level of allotype V158 (KD = 1.17 × 10−7M). This resulted in far more effective ADCC activity of MBS301 than the combination of T-mab and P-mab in killing HER2-positive cancer cells. Hence, a novel fully afucosylated anti-HER2 bispecific antibody with improved antitumor activities was generated and shown to have the potential to be used for treating HER2-positive but trastuzumab-resistant solid tumors.

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“…Pertuzumab is currently undergoing ovarian cancer trials in combination with cytotoxic agents including gemcitabine (20) and carboplatin (21). A recent trial in breast cancer suggests that the combination of trastuzumab and pertuzumab can produce clinical benefit in 50% of trastuzumab-resistant disease (22), despite pertuzumab having very limited activity as a single agent. The modest single-agent response rate of pertuzumab was reported for breast cancer patients whose tumors did not overexpress HER2 (23).…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Faratian

Zweemer

Nagumo

et al. 2011

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated.Experimental Design: The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens.Results: The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogenregulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERa)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERa in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERa and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination.Conclusions: These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERa-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. Ó2011 AACR.

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Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy

Abstract: The combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy.

Cited by 578 publications

References 21 publications

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

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