Drugs of the Future 1998, 23(10): 1078-1082
`Copyright
`1998 PROUS SCIENCE
`CCC: 0377-8282/98
`
`Trastuzumab (cid:9)
`
`Prop INN
`
`H erce pti nfi
`
`Antineoplastic MAb
`
`Immunoglobulin 01 (human-mouse monoclonal rhuMab HER2 il-chain anti-human p185cerbB 2 receptor),
`disulfide with human-mouse monoclonal rhuMab HER2 light chain, dimer
`
`CAS: 180288-69-1
`
`EN: 198466
`
`Introduction
`
`Protooncogenes encoding growth factors and their
`receptors are known to play a crucial role in the patho-
`genesis of several human malignancies. The human epi-
`dermal growth factor receptor 2 (HER2; erbB2 or neu)
`was identified and the HER2 oncogene gene, also known
`as neu or c-erbB-2, was found to encode a 185 kDa trans-
`membrane glycoprotein receptor (p18SHEF12) which is par-
`tially homologous to the epidermal growth factor receptor
`and has endogenous tyrosine kinase activity
`(1-3). In 1986, researchers discovered that overexpres-
`sion of the HER2 gene was common in ductal carcinomas
`such as ovarian and breast cancer and were correlated
`with survival times and potential for relapse. In addition,
`results from several studies strongly suggest that HER2
`gene may be involved in the pathogenesis and poor prog-
`nosis of HER2-overexpressing tumors (4, 5). Studies
`demonstrated that transfection of HER2 into non-neo-
`plastic cells resulted in malignant transformation and that
`transgenic mice expressing HER2 develop mammary
`tumors (6-8).
`According to the American Cancer Society, each year
`180,000 U.S. woman are diagnosed with breast cancer
`and approximately 164,000 of these new diagnoses are
`metastatic breast cancer with overexpression of HER2 in
`tumors in 25-30% of the cases. Interference with HER2
`expression is clearly a strategy of major therapeutic impli-
`cations for treatment of aggressive cancers associated
`with overexpression of the HER2 protein (ECDHER 2).
`2 have been shown to
`Antibodies directed at p185
`inhibit tumor growth in transformed cells providing further
`evidence that this receptor is an excellent target for the
`treatment of breast cancer (9-13). The murine monoclon-
`al antibody MAb 41D5 is directed against the extracellular
`domain of p185HER2 and potently inhibits growth of
`
`cells in vitro and in xenograft models of human breast
`cancer (14-16).
`However, due to the immunogenic nature of murine
`antibodies which limits their use therapeutically, MAb 41D5
`was humanized by including the 4D5 complementarity
`determining regions onto a human IgGl framework.
`Characterization of biological activity of the several result-
`ing humanized versions led to development of only one
`recombinant humanized antip185HER2 , rhuMAb HER2
`(Herceptinfi; trastuzumab) intended for use as a therapy
`for woman with metastatic breast cancer. Trastuzumab is
`the first product engineered which targets an underlying
`genetic defect resulting in cancer.
`
`Pharmacological Actions
`
`Trastuzumab is a humanized recombinant monoclon-
`al antibody directed against the extracellular domain of
`HER2. Trastuzumab has been reported to have antiprolif-
`erative and cytostatic effects on HER2-overexpressing
`breast cancer cells in vitro and in mouse xenograft mod-
`els (17-20). The results of an assay using purified periph-
`eral blood mononuclear cells (PBMC5) and SKBR-3 cells,
`an overexpressing breast cancer cell line, have shown
`that the tumor cell target must be opsonized by
`trastuzumab for in vivo antibody-dependent, cell-mediat-
`ed cytotoxicity (ADCC) (18). In another assay, the activity
`of trastuzumab was characterized in an ADCC assay
`using PBMC and SKBR-3 cells. Results showed that
`trastuzumab mediated ADCC via Fc’yRIII-leukocytes (19).
`An 18-h in vitro assay was developed using PBMCs
`from normal and trastuzumab-treated patients and
`chromium-labeled SKBR-3 target cells in order to evalu-
`ate the cytotoxic potential of trastuzumab through evalu-
`ation of ADCC in vitro. The assay, which uniquely used 7
`effector:target ratios with or without trastuzumab, allows
`for analysis of multiple samples without the need for
`overnight storage or cyropreservation of PBMCs.
`
`L.A. Sorbera, X. Rabasseda. Prous Science, P.O. Box 540,
`08080 Barcelona. Spain.
`
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`Trastuzumab was found to be effective only in HER2-
`overexpressing cell line with no affect on cells expressing
`normal levels of HER2 protein (20).
`The sequence and interval of drug delivery for com-
`bined trastuzumab and doxorubicin therapy for breast
`cancer was determined in a study in which 14 days fol-
`lowing xenograft implants, mice were treated with dox-
`orubicin, trastuzumab or a combination of the two agents
`administered simultaneously or 1-4 days apart and com-
`pared to untreated animals. A differential equation model
`involving log tumor volume vs. time was devised and
`tumor volumes were measured from days 14-42 after
`implant. Simultaneous administration of the two agents
`was determined to be the optimal mode of delivery since
`synergistic action was not observed with separate admin-
`istration and treatment with doxorubicin prior to
`trastuzumab resulted in antagonistic action (21).
`
`Pharmacokinetics
`
`In a pharmacokinetic study, 45 metastatic breast can-
`cer patients with HER2- overexpressing carcinomas were
`administered a loading dose of 250 mg trastuzumab i.v.
`followed by 100 mg/week. Out of 41 patients, 90% dis-
`played plasma trastuzumab trough levels above the tar-
`geted level of 10 tg/mI. The mean serum half-life depen-
`dent on circulating ECDHER2 released from tumors was
`found to be 8.3 – 5.0 days (22, 23).
`Anti-p185HER2 immunoliposomes have been
`designed combining the targeting and anti proliferative
`activities of trastuzumab with advanced drug delivery and
`their pharmacokinetics and pharmacodynamics were
`reported in several studies. The antip185R2 immunoli-
`posomes were constructed with trastuzumab-Fab’ frag-
`ments conjugated to PEG (0-12 mol%) and small unil-
`amellar long-circulating liposomes and loaded with
`doxorubicin for specificity of delivery of the chemothera-
`peutic agent to HER2-overexpressing cell, safely disre-
`garding normal cells. Rapid intracellular uptake of the
`encapsulated agents occurred when target cells were
`treated with doxorubicin-loaded antip185H2 in vitro and
`circulation of intact constructs in normal rats injected i.v.
`was prolonged, illustrating the improved pharmacokinet-
`ics of this drug delivery system as compared to free dox-
`orubicin treatment. The pharmacokinetics of doxorubicin
`and Fab’ from the doxorubicin-loaded antip185H 2
`immunoliposornes were found to be biexponential with
`terminal a half-life and mean residence time of> 11 h and
`16-26 h, respectively. Tumor localization of doxorubicin
`was observed when doxorubicin-loaded antip185R2
`immunoliposomes were systemically administered to
`p1 85- 2-overexpressing tumor xenograft-bearing nude
`mice. Moreover, doxorubicin-loaded anti-pi 85HEfl2
`immunoliposome treatment in SCID mice with BT-474
`tumor xenografts resulted in significant regression of
`established tumors and partial and complete responses,
`in contrast to treatment with maximum tolerated doses of
`free doxorubicin which yielded minimal inhibition of
`
`growth with a higher observed systemic toxicity.
`Therefore, use of the anti-p185’ 2 immunoliposorne
`delivery system markedly enhanced the doxorubicin ther-
`apeutic index as well as the agent’s antiproliferative effi-
`cacy (24, 25).
`
`Clinical Studies
`
`In a phase II study, trastuzurnab (250 mg iv. over 90
`min followed by 100 mg/week x 10) was administered to
`46 patients with stage IV breast cancer and antitumor
`activity was evaluated. Out of 43 evaluable patients with
`HER2 antigen shedding of less than 0.5 ig/ml, 5 objec-
`tive responses, 1 complete response, 4 partial responses
`and 2 minor responses were observed. Another patient
`had a > 50% regression in tumor volume with regrowth
`occurring at 11 weeks. The overall response rate was
`11.6%, with responses noted in the liver, mediatinum,
`lymph nodes and chest wall lesions. Stable disease was
`observed in 14 patients lasting for a mean duration of 5.1
`months. Fever and chills were observed in 5 patients fol-
`lowing the initial infusion. Other adverse effects included
`transient pain at tumor sites, demonstrating that
`trastuzurnab was well tolerated (22, 23) (Box 1).
`Trastuzumab therapy (250 mg iv. over 90 min fol-
`lowed by 100 mg/week x 10) was determined to be well
`tolerated with minimal side effects in a phase II study
`involving 44 metastatic breast cancer patients. Partial or
`complete responses were observed in 5 patients. During
`and following initial infusions, transient fever and chills
`were observed in 5 patients. Fever was not observed with
`subsequent infusions (26).
`The safety and efficacy of trastuzumab monotherapy
`(4 mg/kg followed by 2 mg/kg/week iv. for 1 year and 6
`months) was examined in an open-label study involving
`222 patients with HER2-overexpressing metastatic breast
`cancer. An overall response rate of 21% was observed
`with complete, partial and minor responses in 4%, 17%
`and 7% of the patients, respectively. Stable and progres-
`sive disease were observed in 30% and 42% of the
`patients, respectively. Duration of tumor responsiveness
`to treatment was estimated (Kaplan-Meier) to be 8.4
`months with a mean survival of 13 months. Trastuzumab
`treatment was terminated in 2 patients due to adverse
`effects and a decrease in cardiac ejection fraction was
`observed in 9 patients with a prior history of cardiac
`events (27) (Box 2).
`In a phase II open-label multicenter study, metastatic
`breast cancer patients with immunohistochernically
`defined 2+ or 3+ HER2-overexpression were adminis-
`tered trastuzurnab (250 mg followed by 100 mg/week x 8)
`and cisplatin (75 Mg/M2 on days 1, 29 and 57) with 54%
`and 69% of the patients undergoing prior hormone thera-
`py or radiotherapy, respectively. After 8 weeks, respon-
`sive patients and those exhibiting stable disease were
`placed on maintenance therapy. One complete response,
`8 partial responses, 9 minor plus stable diseases and 18
`progressive diseases were observed out of the 36 evalu-
`
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`1080
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`Trastuzumab
`
`Box I: Efficacy and safety of trastuzumab in patients with metastatic breast cancer overexpressing the antigen (22, 23).
`
`Study Design (cid:9)
`
`Open clinical trial
`
`Study Population (cid:9)
`
`Patients with metastatic breast carcinoma overexpressing the 185-kd transmembrane glycoprotein receptor
`p185HER2 (n = 46)
`
`Intervention Groups Trastuzumab, 250 mg iv. (cid:9)
`
`100 mg i.v. lx/week x 10 weeks
`
`Withdrawals [causes] 3 patients [bacteremia in 1, death in 1, patient’s request in 1]
`
`Adverse Effects (cid:9)
`
`Fever on 5 occasions, pain at tumor site in 3, diarrhea in 2, nausea/vomiting in 1
`
`Significance of (cid:9)
`Results (cid:9)
`
`Response rate, 5/43 (11.6%) patients [complete remission in 1/43 (2.3%); partial remission in
`4/43 (9.3%)]
`
`Conclusions (cid:9)
`
`Trastuzumab is effective and well tolerated, which suggests that growth factors can induce regression
`of cancer
`
`Source: Prous Science CTLine database.
`
`Box 2: Efficacy and safety of trastuzumab in patients with relapsing metastatic breast cancer overexpressing HER2 (27).
`
`Study Design (cid:9)
`
`Open clinical trial
`
`Study Population (cid:9)
`
`Patients with relapsing metastatic breast cancer overexpressing HER2 (n = 222)
`
`Intervention Groups Trastuzumab, 4 mg/kg - 2 mg/kg/week x 11 months (median)
`
`Withdrawals (cid:9)
`
`2 due to adverse effects. 9 patients never received treatment
`
`Adverse Effects (cid:9)
`
`Ejection fraction decrease in 9 patients
`
`Significance of (cid:9)
`Results (cid:9)
`
`Complete remission rate, 8/222 (3.6%) patients
`Partial remission rate, 36/222 (16.2%) patients
`Response rate, 21%
`Response duration (median), 8.4 months
`Survival time (median), 13 months
`
`Conclusions (cid:9)
`
`Trastuzumab is active in HER2-overexpressing metastatic cancer and has a favorable toxicity profile
`
`Source: Prous Science CTLine database.
`
`able patients, suggesting that addition of trastuzumab to
`therapy improved the overall response rate well above
`those expected with cisplatin treatment alone. No serious
`adverse effects were observed with trastuzumab treat-
`ment except the side effects associated with cisplatin,
`including grade 3-4 toxicities in 54% of the patients (27,
`28) (Box 3).
`Preliminary results from a phase Ill study examining
`the cytotoxic potential of trastuzumab and the immune
`status of treated patients with metastatic breast cancer
`demonstrated in an in vitro ADCC assay with treated
`patient PBMCs, an enhancement of cytotoxic activity,
`suggesting that the antitumor activity of effector cells may
`also be increased in vivo (29).
`Further studies have also demonstrated the additive
`effects of trastuzumab given in conjunction with
`chemotherapy in patients with HER2-overexpressing
`metastatic breast cancer. In a randomized phase Ill trial,
`469 patients were administered initial chemotherapy with
`
`either doxorubicin-cyclophosphamide (60 mg/m 2 and 600
`Mg/M2, respectively) or paclitaxel (175 mg/m 2 x 3 h) every
`3 weeks for 6 cycles with half of the patients receiving
`trastuzumab (4 mg/kg followed by 2 mg/kg/week i.v.).
`Adverse side effects such as grade 3-4 myocardial dys-
`function were observed in 18% of the patients receiving
`doxorubicin-cyclophosphamide plus trastuzumab as
`compared to only 3%, 0% and 2% in those treated with
`doxorubicin-cyclophosphamide alone, paclitaxel alone or
`paclitaxel plus trastuzumab, respectively. Addition of
`trastuzumab to chemotherapy did not increase the inci-
`dence of side effects. The overall response rate was sig-
`nificantly improved in patients receiving both chemother-
`apy and trastuzumab (62% vs. 36.2% with chemotherapy
`alone) as well as the time to disease progression (8.6 vs.
`5.5 months with chemotherapy alone). These results sug-
`gest that the combination of paclitaxel and trastuzumab is
`the better regimen when risk and benefit factors are taken
`into account (30) (Box 4).
`
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`(cid:9)
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`Drugs Fut 1998, 23(10) (cid:9)
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`1081
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`Box 3: Response rate in patients with HER2-overexpressing metastatic breast cancer to trastuzumab plus c/splat/n (28).
`
`Study Design (cid:9)
`
`Open clinical trial
`
`Study Population (cid:9)
`
`Patients with HER2-overexpressing metastatic breast cancer (n = 36)
`
`Intervention Groups Trastuzumab, 250 mg -* 100 mg/week x 8 weeks
`Cisplatin, 75 mg/m 2 on days 1, 29 and 57
`
`Significance of (cid:9)
`Results (cid:9)
`
`Complete remission rate, 1/36 (2.8%) patients
`Partial remission rate, 7/36 (19.4%) patients
`
`Conclusions (cid:9)
`
`Trastuzurnab plus cisplatin improves response rates in patients with metastatic breast cancer expressing
`the HER2/neu growth factor receptor
`
`Source: Prous Science CTLine database.
`
`Box 4: Synergism between trastuzumab and chemotherapy in metastatic breast cancer patients (30).
`
`Study Design (cid:9)
`
`Randomized clinical trial
`
`Study Population (cid:9)
`
`Patients with metastatic breast cancer (n = 469)
`
`Intervention Groups (AC) Doxorubicin, 60 mg/ml + cyclophosphamide, 600 mg/m 2 1x/3 weeks x 6 cycles
`(AC+H) Doxorubicin, 60 mg/ml + cyclophosphamide, 600 Mg/M2 1x/3 weeks x 6 cycles + trastuzumab,
`4 mg/kg 2 mg/kg iv. lx/week
`(T) Paclitaxel, 175 mg/m 2 1x/3 weeks x 6 cycles
`(T+H) Paclitaxel, 175 Mg/M2 1x/3 weeks x 6 cycles + frastuzumab, 4 mg/kg - 2 mg/kg iv. ix/week
`
`Adverse Effects (cid:9)
`
`AC, 71%
`AC+H, 68%
`T, 59%
`T+H, 70%
`
`Significance of (cid:9)
`Results (cid:9)
`
`Response rate, AC (42.1%) < AC+H (64.9%)
`Response rate, T (25%) < T+H (57.3%)
`Time to progression, AC (6.5 months) < AC+H (9 months)
`Time to progression, T (4.2 months) <T+H (7.1 months)
`
`Conclusions (cid:9)
`
`Trastuzumab markedly increases the clinical benefit of chemotherapy in metastatic breast cancer patients
`overexpressing HER2
`
`Source: Prous Science CTLine database.
`
`Genentech’s trastuzumab has been available to the
`U.S. oncology medical community since October 5, 1998.
`Trastuzumab was approved by the FDA for the treatment
`of metastatic breast cancer in patients with tumors over-
`expressing the HER2 protein. Used as first-line therapy, it
`is given in combination with paclitaxel; as second- or
`third-line therapy, trastuzumab is used alone. The product
`is supplied as a lyophilized, sterile powder for i.v. infusion
`containing 440 mg trastuzumab/vial (31).
`The FDA has also approved the immunohistochemi-
`cal test DAKO’s HercepTest for marketing, designed
`specifically to identify breast cancer patients whose
`tumors overexpress the HER2 protein and who may
`therefore benefit from treatment with trastuzumab (32).
`
`Manufacturer
`
`Genentech, Inc. (US); licensed to Roche outside the
`U. S.
`
`References
`
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`
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`
`31. Genentech begins shipping Herceptin to U.S. oncologists.
`Daily Essentials October 30, 1998.
`
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`
`32. HER2 diagnostic test approved in U.S.: Will help identify can-
`didates for Herceptin therapy. Daily Essentials October 8, 1998.
`
`IMMUNOGEN 2053, pg. 5
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`IPR2014-00676
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`(cid:9)
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