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© 2003 American Society for Clinical Oncology Evaluation of Monoclonal Humanized Anti-HER2 Antibody, Trastuzumab, in Patients With Recurrent or Refractory Ovarian or Primary Peritoneal Carcinoma With Overexpression of HER2: A Phase II Trial of the Gynecologic Oncology Group
From the Division of Medical Science, Fox Chase Cancer Center, Rockledge, PA; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY; Duke University School of Medicine, Durham, NC; Department of Gynecologic Oncology, M.D. Anderson Cancer Center Orlando, Orlando, FL; and Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA. Address reprint requests to Gynecologic Oncology Group, Administrative Office, 1234 Market St, Suite 1945, Philadelphia, PA 19107; email: ma_bookman{at}fccc.edu.
Purpose: To evaluate the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal carcinoma. Patients and Methods: Eligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics. Results: A total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in eight of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included one complete and two partial responses. Median treatment duration was 8 weeks (range, 2 to 104 weeks), and median progression-free interval was 2.0 months. Conclusion: The clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.
GROWTH FACTORS and their receptors are known to play critical roles during normal and tumor cell development and regulate a diverse array of events, including cell growth, differentiation, apoptosis, migration, and invasion. Most transmembrane growth factor receptors mediate their signals through intrinsic protein tyrosine kinases that are activated after ligand binding, with or without cooperation from other receptors and cellular factors. Human epidermal growth factor receptor 2 (HER2), also called HER2/neu, p185HER2, or c-erbB2, is a type I growth factor receptor tyrosine kinase. Abnormal expression of HER2 has been observed in a number of primary tumors, which suggests that overexpression of this growth factor receptor may contribute to transformation and tumorigenesis. HER2 has been extensively studied in breast cancer, and approximately 30% of patients have tumors that overexpress this receptor,1,2 often as a result of gene amplification. In addition, there is evidence for shorter disease-free and overall survival among breast cancer patients with tumors that overexpress HER2. However, the significance of overexpression in other tumor types, including ovarian cancer, is not as clear. Several lines of evidence support a direct role for HER2 in the pathogenesis and clinical course of human cancers. First, point mutation of the rat HER2 homolog (neu proto-oncogene) promotes homodimerization and constitutive activation of the receptor, and is associated with the induction of neuroblastomas.3,4 In addition, studies using the rat neu gene to develop transgenic mice have revealed that animals expressing high levels of either a mutated neu transgene or nonmutated neu that is not constitutively activated develop breast cancer.5,6 Studies using a nonmutated human HER2 gene demonstrated cell transformation and tumor development in nude mice that was directly related to the level of HER2 gene expression.7–9 Finally, specific antibodies to the extracellular domain of the membrane-based protein encoded by the neu gene or the human HER2 gene will inhibit the growth of tumors that express the gene.10–12 These data are consistent with a direct role for the HER2 proto-oncogene in both malignant transformation and enhanced tumorigenicity and suggest a potential target for cancer therapy. A number of murine monoclonal antibodies (muMAbs) were produced against the extracellular domain of HER2. The most encouraging results were obtained using muMAb 4D5, which demonstrated direct antiproliferative effects in vitro against human breast cell lines that overexpress the HER2 receptor12 without affecting cell lines that do not overexpress this receptor.13 Additional preclinical studies with muMAb 4D5 were conducted using human breast and ovarian cancer xenografts14 that confirmed the clear antiproliferative effects against tumors that overexpress HER2 without impact on xenografts that do not overexpress HER2. The humanized version of muMAb 4D5 was engineered by inserting the complementarity-determining regions of muMAb 4D5 into the framework of a consensus human IgG1.15 Trastuzumab (Herceptin, Nomenclature Standards Committee no. 688097; Genentech Inc, South San Francisco, CA), the resulting antibody, binds the extracellular domain of HER2 with three times greater affinity than the parent muMAb 4D5. Trastuzumab is comparable to muMAb 4D5 in blocking tumor proliferation in vitro; however, unlike muMAb 4D5, it also can induce antibody-dependent cellular cytotoxicity against tumor cell lines in the presence of human peripheral-blood mononuclear cells. In view of the prolonged clearance of the humanized protein and desire to maintain continuous tumor exposure, phase II trials in metastatic breast cancer were conducted using a weekly infusion of 2 mg/kg. When tested as a single agent in patients with overexpression of HER2, objective responses were observed in 12% to 15% of patients.16,17 Toxicity was generally mild, with febrile reactions and chills in some patients, particularly during the first infusion. Importantly, there was no evidence of a host antitrastuzumab immune response. However, a small number of patients with high circulating levels of the extracellular domain of HER2 experienced accelerated antibody clearance, which was attributed to immune complex formation. On the basis of the safety and efficacy demonstrated in breast cancer, the evidence that demonstrates HER2 overexpression in a proportion of ovarian tumors, and an interest in future combinations of trastuzumab with chemotherapy, the Gynecologic Oncology Group (GOG) initiated a phase II evaluation of single-agent trastuzumab for patients with recurrent or persistent ovarian or primary peritoneal carcinoma. The GOG seeks to further the clinical development of agents that target the epidermal growth factor receptor family for the treatment of ovarian cancer and possibly other gynecologic malignancies.
Eligibility Criteria This was a single-agent, group-wide, phase II protocol (GOG-160) for patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma with overexpression of HER2. Eligibility criteria included histologic confirmation of recurrent or persistent epithelial ovarian cancer or primary peritoneal carcinoma; demonstration of 2+ or 3+ immunohistochemical expression of HER2 by the centralized reference laboratory before study registration; disease measurable in two dimensions; GOG performance status 0 to 1; adequate bone marrow (granulocytes  1,500/µL, platelets 75,000/µL), renal (creatinine  2.0 mg/dL), hepatic (bilirubin 1.5 times upper limit normal, and AST and alkaline phosphatase 3 times upper limit normal), and pulmonary functions (forced expiratory volume in 1 second > 60% of predicted value). Patients were excluded on the basis of prior therapy with anti-HER2/neu monoclonal antibody, hypercalcemia, seropositivity for hepatitis, pregnancy or nursing, evidence of other invasive malignancies within the preceding 5 years, the presence of unstable cardiac disease, including recent myocardial infarction, or left ventricular ejection fraction (LVEF) below the institutional lower limit of normal on the basis of gated cardiac scan or echocardiogram. When the study was activated in October 1996, accrual was initially restricted to patients who had received only one prior chemotherapy regimen. However, after United States Food and Drug Administration approval of trastuzumab for the management of metastatic breast cancer in 1997, there was a reduction in the rate of screening. It was then decided to broaden eligibility to allow multiple prior therapies, provided that the remaining criteria for antigen expression, vital organ function, and performance status were met.
HER2 Screening Criteria Expression was scored using the following standard semiquantitative scale developed for HER2: 0 indicates less than 10% of cells exhibiting any level of staining; 1+ denotes more than 10% of cells with barely perceptible light membranous rimmed staining that may not totally encircle the cell membrane; 2+ refers to more than 10% of cells with light-moderate membranous rimmed staining that totally encircles the cell membrane; and 3+ reflects more than 10% of cells with moderate-strong membranous rimmed staining that totally encircles the cell membrane. Because of the uncertain biologic significance of cytoplasmic HER2 staining, only membrane staining was evaluated for this study. Eligibility was restricted to patients with a tumor that demonstrated 2+ or 3+ overexpression by immunohistochemistry. Gene amplification or gene expression (such as fluorescence in situ hybridization [FISH]) was not specifically evaluated in this clinical trial.
Registration, Treatment, and Monitoring Registered patients received the first weekly dose of trastuzumab at 4 mg/kg in 250 mL of normal saline over 90 minutes. Subsequent weekly infusions were administered at 2 mg/kg in 250 mL of normal saline over 90 minutes, but the infusion duration could be shortened to 30 minutes as determined by patient tolerance. Routine premedication for prevention of nausea or hypersensitivity reactions was not required but could be incorporated on the basis of clinical tolerance. Vital signs were monitored for at least 1 hour after the initial infusion and, subsequently, as clinically indicated. Flexibility of 1 day was allowed in the weekly treatment program to accommodate minor schedule changes. Weekly treatment was to be omitted in the event of hematologic toxicity (granulocytes < 1,000/µL or platelets < 75,000/µL). Therapy was permanently discontinued in patients with any new cardiac symptoms or findings of cardiac dysfunction, including a documented decrease in LVEF below the institutional lower limit of normal or decrease in relative percentage by 20%. In addition to weekly assessments that coincided with scheduled treatments, routine monitoring was performed every 8 weeks and included a full history, physical examination, complete blood count, comprehensive chemistry panel, tumor measurements, serum CA-125 (if initially elevated), and chest radiograph (if initially abnormal). Determination of LVEF was performed every 12 weeks, and other tests were obtained as clinically indicated for evaluation of toxicity or disease. Toxicity was graded using version 1 of the Cancer Therapy Evaluation Program Common Toxicity Criteria.
Complete response (CR) required the disappearance of all gross evidence of disease for at least 4 weeks. Partial response (PR) required
Laboratory Studies
Statistical Design
A total of 837 patients with recurrent ovarian or primary peritoneal cancer were screened for immunohistochemical expression of HER2 by a centralized reference laboratory (Table 1  and Fig 1). Overall, only 95 tumors (11.4%) exhibited 2+ or 3+ expression, despite the early transition to a more sensitive immunohistochemistry assay that used a mixture of primary antibodies to recognize cell surface HER2 in formalin-fixed and paraffin-embedded tissue sections. The first stage of accrual was from October 7, 1996, through June 29, 1998. At interim analysis, the frequency of HER2 overexpression was less than half of the 30% expected on the basis of historical data. Only two responses were observed during the first stage (n = 27), which did not meet the original response criteria to open the second stage. However, to confirm the low frequency of HER2 overexpression and obtain additional biologic data, and with consideration for the safety and tolerability of this antibody-based treatment program, it was elected to activate the second stage of accrual from April 12, 1999, through January 28, 2000. There was no difference in the frequency of positive (2+ or 3+) staining observed during screening for the first stage of patient accrual compared with the second stage (data not shown). Ultimately, a total of 45 patients were registered in two stages. Among these 45 patients, two were found ineligible by GOG central pathology review because of inadequate pathology or wrong primary tumor, respectively; and two never received treatment and were not assessable. Of the 41 eligible and assessable patients, 27 had tumors that exhibited 2+ immunohistochemical expression of HER2 and 14 had tumors that displayed 3+ HER2 expression.
Characteristics of the 41 eligible and treated patients are listed in Table 2 . In addition to 34% of patients who received only one prior chemotherapeutic regimen and 66% who received between two and seven regimens, prior therapy included radiotherapy (10%), hormonal therapy (7%), and immunotherapy (2%).
Treatment with trastuzumab was generally well tolerated in this patient population, as illustrated by the distribution of reported toxicities (Table 3 ). The most frequently reported toxicities grade 2 included anemia, gastrointestinal, neuropathy, and fatigue, none of which are unexpected in this population on the basis of prior therapy or are likely to be directly related to trastuzumab administration. One patient experienced severe renal dysfunction, and another developed grade 3 hypercalcemia with rapid decline in performance status and was transferred to hospice after the initial dose; neither was considered to be a drug-related event. Dose delays that occurred in four patients did not seem to be secondary to drug-related toxicity. There were no treatment-related fatalities.
Pretreatment sera was available from 24 of the 41 eligible and assessable patients, and the circulating level of the extracellular domain of HER2 was analyzed by ELISA. Although 16 patients had levels below the lower threshold limit of 2.60 ng/mL for this assay, evidence of serum HER2 was documented in eight patients, with pretreatment values ranging from 3.66 to 120 ng/mL. Detectable serum HER2 (categorized as above or below the lower threshold limit of detection), however, was not associated with the level of HER2 expression in the tumor (two-sided Fisher’s exact test, P = .167). In addition, there was no apparent relationship between the serum level of the extracellular domain of HER2 and cycle 1 toxicity, but tumor expression of HER2 was associated with the observation of fever, chills, fatigue, or allergic reaction during the first infusion of trastuzumab (Table 4 ).
Serial serum specimens were obtained from 28 patients at various points during treatment, and these were analyzed for the presence of host antibodies directed against either the F(ab)'2 or Fc fragments of trastuzumab. All samples tested were nonreactive (< 2.0 log titer units). In addition, there was no clinical evidence of a host immune response directed against the antibody. During extended therapy, one patient with diabetes mellitus developed life-threatening, but reversible, membranous glomerulonephritis with severe renal dysfunction that required a period of dialysis. Even in this particular patient, there was no evidence of antibodies directed against trastuzumab, and this event was not believed to be directly related to drug administration.
Serum levels of trastuzumab were monitored through serial peak and trough levels obtained from 25 patients (Fig 2
All assessable patients had disease that was measurable in two dimensions, and tumor response was evaluated according to standard GOG criteria. Trastuzumab was administered a median of 8 weeks (range, 2 to 104 weeks). The overall objective response rate was 7.3% (one CR and two PRs), and an additional 16 patients (39%) met the criteria for stable disease (Table 5 ). Of the 22 patients with disease progression, 20 patients had documentation of increasing disease and two patients died of disease before tumor assessment. It is difficult to extrapolate these findings to the general population of patients with recurrent ovarian cancer because of potential selection bias for antibody-based therapy and the requirement for overexpression of HER2. Several patients with responding or stable disease received therapy for more than 1 year, confirming the overall tolerability of the treatment regimen, as well as variability in the natural history of this disease. However, median progression-free survival was only 2.0 months in this population of patients with recurrent disease (Fig 3). There was no relationship between tumor expression of HER2 and clinical response, progression-free survival, or overall survival (data not shown). Furthermore, there was no relationship between the serum level of the extracellular domain of HER2 and patient outcome (data not shown).
Patients who achieved at least stable disease at the initial 8-week assessment were eligible for treatment with higher doses (4mg/kg) in the event of subsequent disease progression. Nineteen patients were potentially eligible for dose escalation at progression. This option, to date, has been selected by 12 patients without evidence of a secondary response but with variable periods of secondary disease stabilization. The median number of additional cycles administered after dose escalation was 8.5 (range, three to 45 cycles).
Although ovarian cancer can be initially managed with cytoreductive surgery and platinum-based chemotherapy, recurrences are common and most tumors will eventually become resistant to standard cytotoxic chemotherapy. This has prompted investigation of a variety of biologic strategies, including monoclonal antibodies, immunoconjugates, and cytokines. On the basis of encouraging data in patients with breast cancer, there has been considerable interest in targeting HER2 in ovarian cancer. Low-level expression of HER2 can be detected in normal ovarian surface epithelium by immunohistochemistry, but the role of HER2 in normal ovarian function remains unclear. Among 40 patients with early-stage ovarian cancer, low-level expression of HER2 was documented in 70% of patients, whereas focal high-level expression was restricted to only 20% of patients18 without a detectable impact on prognosis. In advanced disease, overexpression of HER2 has been associated with decreased median survival,19 but this has not been a uniform finding.20 The true prognostic significance of HER2 overexpression in patients with advanced-stage disease remains unclear and is being examined retrospectively among patients who participated in GOG phase III trials (M. Birrer, personal communication, GOG 9404). Of interest is preliminary analysis that demonstrates no correlation of HER2 expression with clinical outcome and a low frequency of gene amplification in patients with HER2 overexpression, suggesting that the biologic role of HER2 in ovarian cancer may differ from that previously demonstrated in breast cancer.
On the basis of earlier data, it was assumed that approximately 30% of patients with ovarian cancer would have tumors with This study used an immunohistochemistry procedure to select patients for receptor-targeted therapy that express a moderate (2+) to high (3+) level of HER2 protein on the cell surface of their tumor cells. To promote uniformity of interpretation, all immunohistochemical assays were performed through a centralized reference laboratory using a standardized procedure and scoring criteria that selectively evaluated the presence and intensity of membranous staining. There is now general agreement that the membranous staining pattern correlates with functional receptor expression and prognosis.21 Cytoplasmic staining does not seem to have clinical significance22 and may partially represent cross-reactivity with other cellular proteins. The selective evaluation of membranous staining may have contributed, at least in part, to the reduced frequency of HER2 overexpression detected in the current trial. Multiple antibodies and kits are available for immunohistochemical detection of HER2, each with differing sensitivity and specificity.23 Our trial used monoclonal anti-HER2 antibodies (4D5 and CB-11), which have a high degree of specificity for this antigen and which may have also contributed to a lower rate of HER2 overexpression. For example, one widely used United States Food and Drug Administration-approved test kit (HercepTest Dako Corporation, Carpinteria, CA) uses a polyclonal sera with broader reactivity (specific as well as nonspecific) that could effectively increase the percentage of positive cases that are detected compared with that observed using monoclonal reagents.24 FISH is a powerful and specific technique that directly measures the number of DNA gene copies rather than expression of the protein product. However, some tumors will demonstrate overexpression of the protein product without associated gene amplification, and those specimens would have been scored as negative using FISH. Although not used in the current trial, FISH may ultimately provide better information regarding prognosis.
Some tumors have been found to shed the extracellular domain of HER2 into the circulation, where it may interfere with tumor targeting. Other truncated proteins are concentrated in the perinuclear cytoplasm and can directly interfere with signal transduction after antibody binding.25 Presence of these abnormal proteins could explain some of the variability observed in other studies. Although not every patient in the current study had a pretreatment serum sample available for testing, the serum level of HER2 was generally low (Table 4
Of 837 screened samples, 95 patients were identified with 2+ or 3+ expression of HER2. Only 45 of those potentially eligible patients were ultimately enrolled onto the phase II study, which may reflect a change in patient eligibility or performance status over time because of the requirement for advanced screening of antigen expression. Only three of the 41 assessable patients achieved an objective response (Table 5 Of primary clinical importance is a small number of patients who achieved an objective response (CR or PR) or prolonged stable disease after antibody-based treatment. The overall response rate of 7.3% is lower than the 12% to 15% response rates reported for the single-agent phase II trials in breast cancer.16,17 In view of the small number of patients enrolled onto the current study (all of whom had moderate- [2+] or high- [3+] level HER2 expression) and the observation of only three objective responses, it was not possible to identify specific clinical or laboratory features that predicted for tumor response. In an effort to broaden the potential impact of antibody-targeted therapy, there has been ongoing interest in combinations of trastuzumab with cytotoxic chemotherapy as supported by preclinical models with cisplatin, doxorubicin, and paclitaxel.26–30 Although supra-additive effects have been observed in preclinical models, these effects are generally dependent on receptor-mediated signal transduction and high-level HER2 expression. As such, potential tumor-specific effects in the setting of low-level expression are uncertain. A phase II trial using a combination of trastuzumab and cisplatin31 in patients with previously treated breast cancer and overexpression of HER2 achieved a response rate of 24%, exceeding historical controls for cisplatin and trastuzumab as single agents. This was followed by a nonblinded phase III trial for patients with metastatic breast cancer and HER2 overexpression (2+ or 3+) that compared chemotherapy (either a combination of doxorubicin and cyclophosphamide or single-agent paclitaxel) with or without trastuzumab.32 In this trial of 469 registered patients, response rate, time to progression, and median survival were significantly improved for the group receiving trastuzumab. This result prompted the evaluation of new combinations in other disease sites, including lung cancer, esophageal adenocarcinoma, and ovarian cancer. In ovarian cancer, the best opportunity for observing a potentially important clinical benefit would be through integration with front-line platinum-based therapy. However, on the basis of the low frequency of HER2 overexpression, and low response rates to single-agent trastuzumab, this does not seem practical. Instead, it would seem more appropriate to continue efforts to target other related signal transduction molecules (such as the epidermal growth factor receptor), which may increase the proportion of patients that might benefit from a combined therapy approach.
The following Gynecologic Oncology Group institutions participated in this study: Duke University Medical Center, Durham, NC; University of Minnesota Medical School, Minneapolis, MN; Emory University Clinic, Atlanta, GA; University of California at Los Angeles, Los Angeles, CA; University of Washington, Seattle, WA; Milton S. Hershey Medical Center, Hershey, PA; Tufts-New England Medical Center, Boston, MA; Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL; Community Clinical Oncology Program, The Cleveland Clinic Foundation, Cleveland, OH; State University of New York at Stony Brook, Stony Brook, NY; Washington University School of Medicine, St. Louis, MO; Columbus Cancer Council, University of Massachusetts Medical Center, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; University of Virginia, Charlottesville, VA; University of Chicago, Chicago, IL; Tacoma General Hospital, Tacoma, WA; Tampa Bay Cancer Consortium, Tampa Bay, FL.
We gratefully acknowledge support from Genentech Incorporated (South San Francisco, CA) for performance of laboratory assays reported in this article. The study drug was provided by Genentech through a Cooperative Research and Development Agreement in collaboration with the Cancer Therapy Evaluation Program of the National Cancer Institute. We also thank Michael Birrer, MD, PhD, for sharing preliminary data on gene expression, and Beth Karlan, MD, for her expert assistance as study co-chair.
Supported by National Cancer Institute (Bethesda, MD) grant no. CA 27469 to the Gynecologic Oncology Group Administrative Office and grant no. CA 37517 to the Gynecologic Oncology Group Statistical Office.
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32. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792, 2001 Submitted November 27, 2001; accepted September 13, 2002. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
