CANCER BIOTHERAPY & RADIOPHARMACEUTICALS
`Volume 14, Number 1, 1999
`Mary Ann Liebert, Inc.
`
`Perceptions of Herceptin®: A Monoclonal Antibody
`for the Treatment of Breast Cancer
`
`Robert O. Dillman, M.D.
`Medical Director, Hoag Cancer Center Newport Beach, California
`
`SUMMATION
`
`In September 1998 Trastuzumab (Herceptin9) became the second monoclonal antibody approvedfor the
`treatment ofa malignant condition, and thefirst antibody approvedfor the treatment of a solid tumor. It
`is a mouse-human chimeric antibody thatproduces anti-tumor effects by blocking the HER2-neu receptor,
`andean also interact with human immune cells to effect antibody dependent cell-mediated cytotoxicity. Pivotal
`trials in breast cancer showed that it has activity as a single agent in a subset ofpatients whose tumors greatly
`overexpress HER2, butresults were even moreimpressive when it was usedin combination with chemotherapy.
`It should also prove to be useful in the treatment ofsubsets ofpatients with other adenocarcinomas whose
`tumors overexpress HER2.
`
`INTRODUCTION
`
`In the decade of the 1980s, monoclonal antibodies
`made the transition from the bench to the bedside.1
`In the 1990s, after years of optimistic anticipation,
`these products have moved from the category of
`experimental drugs to approved pharmaceuticals, and
`from the bedside to the physician's office.
`In Novem-
`ber 1997 the US Food and Drug Administration
`approved the IDEC C2B8 anti-CD20 mouse/ human
`chimeric antibody (Rituximab, Rituxan®) for the
`treatment of B-cell lymphoma, making it the first
`monoclonal antibody product approved in the United
`States for treatment of a malignant condition.2
`Available data suggests durable objective response
`rates in 60% ofpatients with follicular lymphomas,3
`
`Address reprint requests to Robert O. Dillman, M.D., Medical
`Director Hoag Cancer Center, One Hoag Drive, Building 41,
`Newport Beach, California, 92658. Tel (949) 760-2091; FAX
`(949) 760-2091; E-mail <rdillman@hoaghospitaLorg>
`
`30% in large cell and mantle zone lymphomas,4 and
`15% in small cell indolent lymphomas.3 Durable
`response rates of 95-100% have been reported for
`combinations ofCHOP chemotherapyplus Rituximab
`in low grade and intermediate grade lymphomas.5'6
`This agent has been a tremendous success in the
`marketplace, and is being explored in all types of B-
`cell malignancies.
`It would not be surprising to see
`Rituximab become the agent of choice for the first-
`line treatment of follicular lymphoma in the near
`future.
`In September 1998 the mouse/human chimeric
`anti-HER2 receptor monoclonal antibody Trastuzu-
`mab (Herceptin®) from Genentech became the second
`monoclonal antibody to gain FDA approval for
`treatment of a malignant condition based on trials in
`patients with metastatic breast cancer.
`In the process
`Trastuzumab became the first antibody product
`approved in the United States for the treatment of a
`solid tumor.
`In patients with metastatic breast cancer,
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`who have relapsed after chemotherapy, and whose
`tumors overexpress the HER2 receptor, available data
`suggests that Trastuzumab produces durable response
`rates of 10-15%.7 In randomized trials, administration
`of Trastuzumab with paclitaxel, in patients who had
`relapsed after adjuvant doxorubicin containing
`regimens, was associated with response rates of 35%
`compared to 15% for the paclitaxel alone.7 Assays
`are available to determine patients whose tumors do
`for patient
`overexpress HER2, which is crucial
`selection since it is estimated that only 25-30% of
`newly diagnosed breast cancer patients have tumors
`that overexpress the receptor. The FDA has approved
`the HercepTest™ from DAKO as an immunohisto-
`chemical kit that can be used on fresh or stored tissue
`to measure receptor levels. Other tests that measure
`expression of the HER2neu gene by fluorescence in
`situ hybridization (FISH) have also been developed.
`Trastuzumab is also being tested in other adenocarci-
`nomas in the subsets of patients whose tumors
`overexpress HER2.
`
`The HER2 Receptor as a Target Antigen
`
`HER2-neu is a 185 kd transmembrane receptor that
`is a member of the epidermal growth factor (EGR)
`tyrosine kinase receptor family of receptors.8 The
`receptor is involved with the autophosphorylation of
`specific tyrosine residues after they are activated by
`binding of EGF or Neu differentiation factor (NDF).9
`Overexpression ofthe erbB-2 proto-oncogene results
`in overexpression of the HER2-neu receptor on the
`cell surface and increased cell proliferation.10 Clini-
`cally, among breast cancer patients, overexpression
`of HER2 has been associated with a relatively poor
`prognosis.11
`Trastuzumab (Herceptin®)
`
`Trastuzumab is a mouse/human IgG, chimeric
`monoclonal antibody that reacts with the pi 85-
`HER2/neu receptor.12
`is produced using
`It
`recombinant DNA technology with Chinese Hamster
`Ovary (CHO) cells serving as the manufacturing
`factory. Binding of Trastuzumab to the HER2
`results in internalization (modulation,
`receptor
`downregulation) of the receptor. The presence of
`Trastuzumab results in competitive inhibition of
`binding of EGF and NDF to the receptor.13 Such
`inhibition interferes with phosphorylation and the
`
`6
`
`subsequent signal transduction that facilitates cell
`This chimeric antibody can also
`proliferation.
`produce anti-tumor effects via the immune system.
`Thanks to the human IgG, constant regions, the Fc
`portion of the chimeric antibody mediates antibody
`dependent cell mediated cytotoxicity (ADCC) in
`vitro}l4 However, it is likely that the regulatory
`effects associated with blocking the receptor are
`actually more important than the immune mechanisms
`in producing a tumor response.
`
`Summary of Clinical Trials
`
`In a preliminary study, 46 patients with metastatic
`breast cancer whose tumors overexpressed HER2-neu
`received chimeric anti-pl 85Her2/neu at a dose of 250
`mg i.v. on week one, then 100 mg i.v. weekly for 10
`weeks.15 There was one complete and four partial
`responses among 43 évaluable patients for an
`objective tumor response rate of 12%. Trastuzumab
`plus Cisplatin at a dose of 75 mg/m2 on days 1, 29,
`and 57 was given to 37 patients with metastatic breast
`cancer. The first antibody dose was 250 mg, then 100
`mg i.v. weekly for nine weeks.16 There were nine
`partial responders among the 37 patients who were
`treated for a response rate of 24% associated with a
`median duration of response of 5.3 months.
`The approval of Herceptin® was based on three
`key trials that were conducted in 222 patients with
`metastatic breast cancer whose disease had progressed
`after prior chemotherapy, and 469, patients with
`received prior
`metastatic disease who had not
`chemotherapy for metastatic disease.7 All patients
`had to have tumors that overexpressed HER2, which
`was defined as 2+ or 3+ expression on a scale of 0-3.
`In these trials an initial 4 mg/kg Trastuzumab dose
`was followed by 2 mg/kg weekly. The first dose of
`antibody was infused i.v. over 90 minutes.
`In the
`infusion related toxicity,
`absence of significant
`subsequent doses were infused i.v. over 30 minutes.
`Herceptin® as Single Agent Therapy of Breast
`Cancer
`
`In an open-label, non-randomized trial of 222 patients
`who had failed chemotherapy,
`there were four
`complete and 21 partial responses for an overall
`objective response rate of 12% by intent to treat
`analysis. This is in the same range of response rates
`that is seen for single agents such as doxorubicin and
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`Toxicities Associated with Herceptin* Treatment
`
`paclitaxel when given to patients whose disease has
`progressed despite chemotherapy.
`The median
`duration of response among the 25 patients was nine
`months, and the median survival was 13 months,
`results that are also comparable to chemotherapy.
`The patient population included 66% who had
`received prior adjuvant chemotherapy. Two or more
`chemotherapy regimens for metastatic disease had
`been received by 68% of the patients. Fifty-five
`patients (25%) had relapsed after high-dose chemo-
`therapy and autologous stem cell rescue prior to
`receiving antibody therapy.
`
`Herceptin® Plus Combination Chemotherapy in
`the Treatment of Breast Cancer
`
`The presence of anti-pl85Her2/neu enhanced the
`cytotoxic effects of chemotherapy in vitro and in
`animal studies.17 In the pivotal clinical trials, the 469
`patients who had not received prior chemotherapy-
`were randomized to receive Trastuzumab ± chemo-
`therapy. Patients who had not received an anthra-
`cycline previously were randomized to receive
`Trastuzumab alone or with doxorubicin 60 mg/m2 and
`cyclophosphamide 600 mg/m2 i.v. every three weeks
`for six cycles. Patients who had received adjuvant
`chemotherapy that included an anthracycline were
`randomized to receive Trastuzumab alone or with
`paclitaxel 175 mg/m2 i.v. over three hours every three
`weeks. Results Of these trials are summarized in
`Tables 1 and 2.
`
`The acute toxicities observed in the clinical trials of
`Trastuzumab are summarized in Table 3. The types
`and frequencies of toxicities observed are similar to
`those that have been described with many monoclonal
`antibodies, particularly those that react with antigens
`on circulating cells.18
`Based on studies ofradiolabeled antibodies that
`react with surface antigens on circulating cells and
`radiolabeling of cells that had been coated with
`antibody and then returned to the circulation, it
`appears that such cells are rapidly removed in the
`reticuloendothelial system followed by release of
`cytokines such as tumor necrosis factor alpha.19 The
`combination of cells in the lungs and release of
`cytokines may explain the side effects such as skin
`rash, shortness ofbreath, bronchospasm, hypotension,
`chills or rigors, sweats, fever, headache, arthralgias
`and myalgias that are typically seen. EGF-related
`receptors are expressed on some circulating cells such
`as activated lymphocytes. Because these receptors
`modulate (internalize, endocytose) after MoAb
`binding, cells that are in tissues become saturated with
`antibody which results in down-regulation of the
`antigen. When these cells enter the circulation, they
`will not be removed in the RE system because there
`is little antibody on the surface. Therefore, unless one
`is measuring cell counts at short intervals shortly after
`initiation of an infusion, one will not see a measurable
`effect on the circulating cell populatipn that is being
`Association of HER2 expression and tumor response rates in clinical
`Table 1.
`trials of
`Trastuzumab in patients with metastatic breast cancer.
`MoAb alone
`MoAb + TXL
`TXL alone
`[n=92]
`[n=222]
`[n=96]
`4%
`21%
`16%
`17%
`44%
`14%
`
`2+ Her 2
`3+ Her 2
`
`MoAb = monoclonal antibody Trastuzumab
`TXL=pacIitaxel
`AC= doxorubicin + cyclophosphamide
`
`MoAb + AC
`[n=143]
`40%
`53%
`
`AC alone
`[n=138]
`43%
`
`Table 2. Association of HER2 expression and median progression free survival in clinical trials
`of Trastuzumab in patients with metastatic breast cancer.
`MoAb alone
`MoAb + TXL
`TXL alone
`4.4 months
`3.2 months
`NA
`2.2 months
`7.1 months
`NA
`
`2+
`3+
`
`Her 2
`Her 2
`
`_
`
`MoAb + AC
`7.6 months
`7.3 months
`
`AC alone
`7.1 months
`4.9 months
`
`MoAb= monoclonal antibody Trastuzumab
`TXL=paclitaxel
`AC= doxorubicin + cyclophosphamide
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`Table 3. Acute toxicities and side effects observed in clinical trials of Trastuzumab
`MoAb alone MoAb + TXL
`MoAb + AC
`TXL alone
`AC alone
`36%
`49%
`23%
`34%
`56%
`32%
`41%
`4%
`35%
`11%
`51%>
`33%
`77%
`9%
`76%
`26%
`22%
`41%
`43%
`9%
`18%
`38%
`18%
`27%
`17%
`20%
`47%
`27%
`47%
`31%>
`
`Fever
`Chills
`Nausea
`Cough
`Rash
`Infection
`
`Table 4. Frequency of severe and/or life-threatening cardiotoxicity in breast cancer patients
`treated with Trastuzumab.
`MoAb alone MoAb + TXL
`5%
`4%
`
`AC alone
`3%
`
`Cardiac III/IV
`
`TXL alone
`1%
`
`MoAb- AC
`19%
`
`targeted. One would predict that toxicity would be
`most prevalent following the first infusion of MoAb,
`and then no longer occur as long as serum levels of
`MoAb are maintained at the time of subsequent
`treatments.
`The major long-term toxicity associated with
`Trastuzumab is cardiac dysfunction, probably because
`HER2 is expressed on cardiac muscle cells that are
`involved in tissue repair.20 The frequencies of severe
`cardiac dysfunction observed in the three pivotal
`studies are shown in Table 4. The data suggests that
`cardiotoxicity may be a concern in patients who have
`previously received an anthracycline, even if they are
`receiving antibody alone. Paclitaxel alone was
`associated with a very low level cardiotoxicity, and
`the frequency oftoxicity was the same for Trastuzu-
`mab alone or Trastuzumab plus paclitaxel. However,
`toxicity was much greater in patients who received
`doxorubicin and cyclophosphamide in combination
`with Trastuzumab. This may relate to synergistic
`effects between the chemotherapeutic agents, particu-
`larly doxorubicin, and the MoAb, and may also relate
`to increased drug delivery of doxorubicin to cardiac
`muscle by loose binding between doxorubicin and the
`MoAb.2122 Herceptin® should not be given in combi-
`nation with an anthracycline or any other agent that
`is known to damage the myocardium.
`
`SUMMARY AND CONCLUSIONS
`
`Is Herceptin® a magic bullet for breast cancer?
`Clearly it is only effective for a minority of such
`patients. However, breast cancer is the most frequent
`
`8
`
`cancer in American women and the number two cause
`of cancer death in women behind lung cancer.
`Unfortunately, it is estimated that only 25-30% of
`patients with metastatic breast cancer have tumors
`that overexpress HER2.9 With a 15% response rate,
`that means that only 4-5% of all patients with meta-
`static breast cancer, that are suitable for clinical trials,
`might be expected to respond to Trastuzumab after
`experiencing progressive disease after chemotherapy.
`On the other hand, it is estimated that there are about
`160,000 women living with metastatic breast cancer.
`Thus, there may be 40,000-50,000 women who would
`be appropriate candidates for such therapy, and
`perhaps 10,000 who might benefit from treatment
`with Trastuzumab alone. However, the differences
`in response rates for the combination ofchemotherapy
`with Trastuzumab compared to chemotherapy alone
`ranged from 17-30%, suggesting that the number of
`patients who could benefit from treatment with this
`agent might be twice as high, or 20,000 patients a
`year.
`How does this compare to Rituxan® as single
`agent treatment. The entire B-cell lymphoma market
`for Rituximab is about 60,000 total cases of non-
`lymphoma. This includes 25,000
`localized B cell
`patients with follicular lymphoma who have a re-
`sponse rate of 50%, which would result in 12,500
`patients per year that should benefit from this treat-
`ment. There are another 25,000 patients with interme-
`diate grade lymphoma who have a response rate of
`30% following Rituximab therapy, for another 7,500
`patients who may benefit. Thus, among patients with
`follicular and intermediate B-cell lymphomas, there
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`are about 20,000 cases per year who would be
`expected to benefit from Rituximab as a single agent.
`There are many clinical situations in which
`Trastuzumab is being tested. Based on recent reports,
`a logical strategy to test in the adjuvant therapy of
`node positive, HER2-neu positive breast cancer would
`be to give AC followed by Trastuzumab plus pac-
`It would also be reasonable to administer
`litaxel.
`Trastuzumab after high-dose chemotherapy and stem
`cell rescue inpatients whose tumors overexpressed
`HER2. More importantly, HER2-neu is over-
`expressed in many other tumors including cancers of
`the lung, pancreas, prostate and ovary.23"25 Patients
`with such tumors that overexpress HER2-neu are
`appropriate candidates for treatment with Tras-
`tuzumab, ideally in the context of a clinical trial.
`Many other questions remain.
`Is there a rationale for
`indefinite therapy or retreatment in previous respond-
`ed? How will Trastuzumab work in combination with
`other pan-adenocarcinoma antibodies such as 17-1A
`(Edrecolomab, PANOREX®) that may be approved
`in the future?26"28 Is the current dose and schedule
`really optimal? How does the antibody interact with
`other chemotherapy agents in terms of toxicity and
`efficacy?
`The higher response rates and longer duration of
`disease control for chemotherapy + Trastuzumab vs.
`chemotherapy alone suggest that the best use of this
`reagent probably is in combination with chemother-
`apy, rather than as a single agent treatment for breast
`cancer, but not in combination with anthracycline.
`In the first few months since its approval, it is sus-
`pected that the greatest clinical use ofHerceptin® has
`been as a desperation treatment in patients who have
`been exhaustively treated with combination chemo-
`therapy. The results in these patients will be disap-
`pointing, because they are more heavily treated than
`those who were in the clinical trials. As physicians
`have the opportunity to combine Herceptin® with
`paclitaxel and docetaxel earlier in the course of
`treatment, patient and physician satisfaction should
`be much greater. While Herceptin® may not be truly
`a "magic bullet," it is also clear that it is not a
`"blank," and it is worth loading into the revolver!
`
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