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Originally published as JCO Early Release 10.1200/JCO.2005.05.4221 on August 8 2006 © 2006 American Society of Clinical Oncology. Clinical Activity of Pertuzumab (rhuMAb 2C4), a HER Dimerization Inhibitor, in Advanced Ovarian Cancer: Potential Predictive Relationship With Tumor HER2 Activation Status
From the Arizona Cancer Center, Tuscon and Scottsdale, AZ; Indiana University, Indianapolis, IN; Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber/Harvard Cancer Institute, Boston, MA; University of Chicago, Chicago, IL; Sarah Cannon Research Institute, Nashville, TN; Cedars-Sinai Medical Center; UCLA Medical Center, Los Angeles, CA; USC Norris Comprehensive Cancer Center; Genentech Inc, South San Francisco, CA; Fox Chase Cancer Center; James Cancer Hospital, Ohio State University, Columbus, OH. Address reprint requests to Beth Y. Karlan, MD, Cedars-Sinai Medical Center, Women's Cancer Research Institute, 8700 Beverly Blvd, #290W, Los Angeles, CA 90048; e-mail: Beth.Karlan{at}cshs.org
Purpose: Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC. Patients and Methods: Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2).
Results: Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD Conclusion: Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.
Ovarian cancer is the fourth most common cause of cancer mortality among women in the United States.1 Novel therapies with better efficacy and less toxicity, particularly for patients with platinum-resistant disease, are needed.2 The human epidermal growth factor family of receptors (HER1/EGFR, HER2, HER3, and HER4) mediate cell growth and are dysregulated in many types of cancer.3 Receptor dimerization is essential for HER pathway activation leading to receptor phosphorylation and downstream signal transduction.3 Unlike HER1, -3 and -4, HER2 has no known ligand and assumes an open conformation, with its dimerization domain permanently exposed for interaction with other ligand-activated HER receptors.4 HER2 is the preferred partner for dimer formation,5-7 and preclinical studies have shown that HER2-containing heterodimers are the most mitogenic and have the highest transformation potential of all the HER complexes.3 The HER pathway is involved in ovarian cancer pathogenesis.8-12 Many ovarian tumor samples express all members of the HER family.8 Coexpression of HER1 and HER2 is seen more frequently in ovarian cancer than in normal ovarian epithelium,9 and overexpression of both receptors correlates with poor prognosis.10-12 Preferred dimerization with HER2 (HER1/HER2, HER2/HER3) and subsequent pathway activation via receptor phosphorylation have also been shown to drive ovarian tumor cell proliferation, even in the absence of HER2 overexpression.13,14 Pertuzumab (rhuMAb 2C4, Omnitarg; Genentech Inc, South San Francisco, CA) is the first in a new class of targeted anticancer agents termed HER dimerization inhibitors (HDIs).15 Pertuzumab is a recombinant, humanized monoclonal antibody that targets an epitope within the HER2 dimerization domain.16 Once bound, pertuzumab inhibits ligand-activated HER dimerization with HER2, independent of HER2 expression levels.16,17 Pertuzumab has demonstrated growth inhibition in ovarian, lung, breast, and prostate tumor cells without HER2 overexpression.14,17,18 In a phase I clinical study, two of 21 patients with advanced cancer had confirmed partial responses (PRs). Of these, one patient demonstrated a confirmed PR that lasted 11 months in a platinum-resistant ovarian cancer with absence of HER2 gene amplification.19 The primary objectives of this phase II, open-label, multicenter study were to determine the overall response rate and investigate the safety and tolerability of two dose levels of pertuzumab in patients with advanced, refractory or recurrent ovarian cancer. As a secondary objective, HER2 activation was investigated as a predictor of outcome.
Patient Population Patients with advanced, histologically documented epithelial ovarian cancer that had recurred despite platinum-based chemotherapy were eligible. All patients gave written informed consent, and the protocol and consent form were approved by institutional review boards. Measurable disease was defined according to Response Evaluation Criteria in Solid Tumors (RECIST).20 Nonmeasurable disease patients were also eligible and defined as clinically or radiologically detectable disease (eg, ascites, mesenteric thickening) plus two consecutive elevations in pretreatment serum CA-125 measurements more than 40 IU/mL. All patients were at least 18 years old with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least 12 weeks. Other eligibility criteria included progression within 12 months with initial platinum or recurrence after re-treatment with platinum-based chemotherapeutic regimen (no limit to the number of prior therapies), and adequate cardiac, hematologic, hepatic, and renal function. Patients in cohort 1 had to be willing to undergo a tumor biopsy. Key exclusion criteria included prior treatment with any experimental anticancer agent within 4 weeks of day 1; treatment with any HER-targeted agent; history of any CNS or brain metastases; left ventricular ejection fraction (LVEF) less than 50%; and prior exposure to more than 360 mg/m2 doxorubicin or liposomal doxorubicin, more than 120 mg/m2 mitoxantrone, or more than 90 mg/m2 idarubicin.
Study Design and Treatment Schedule This open-label, multicenter study enrolled two sequential cohorts of approximately 60 patients each. Cohort 1 received a loading dose of 840 mg pertuzumab (Genentech Inc, South San Francisco, CA) on day 1 of cycle 1 and 420 mg pertuzumab on day 1 of each 3-week cycle thereafter by intravenous infusion for up to 1 year. Cohort 2 received 1,050 mg pertuzumab on day 1 of each 3-week cycle (up to 1 year). The dose and schedule selected for cohort 1 was based on pharmacodynamic data from preclinical studies18 and a phase I study that showed that 420 mg (or 6 mg/kg for a 70-kg patient) should result in steady-state serum concentrations shown to be efficacious in animal models (5 to 25 µg/mL).21 A loading dose of 840 mg was used to achieve steady-state concentrations rapidly in cohort 1. A higher pertuzumab dose was used for cohort 2 because preclinical studies suggested a dose-dependent increase in efficacy.17,18 Pertuzumab infusion was interrupted if a patient developed dyspnea or clinically significant hypotension. Therapy was discontinued for recurrent National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 grade 3 or grade 4 rash, diarrhea, or major organ toxicity; grade 4 nonhematologic toxicity; grade 3 or 4 allergic reaction; symptomatic congestive heart failure with a drop in LVEF; any other subjectively intolerable toxicity; or progressive disease.
Efficacy Determinations Efficacy-assessable patients received at least one dose of pertuzumab and underwent at least one response assessment. Three efficacy-assessable subgroups were considered: (1) all patients; (2) patients with detectable tumor HER2 phosphorylation; and (3) patients with no detectable tumor HER2 phosphorylation before therapy. Best overall response, duration of response, progression-free survival (PFS), and survival were determined for all subgroups in cohort 1 and efficacy-assessable patients in cohort 2. Disease progression was defined as progressive disease or death, whichever occurred first. Duration of PFS was defined as the time from day 1 of study to the time of documented disease progression or death. Duration of survival was defined as the time from day 1 of study to the time of death. Duration of response was defined as the time from the initial complete response or PR to the time of disease progression or death.
Total HER2 and HER2 Phosphorylation Assessment Fluorescence in situ hybridization (FISH) analysis for HER2 gene copy number was performed on frozen and formalin-fixed tumor sections using the PathVysion HER2 DNA Probe Kit (Vysis, Downers Grove, IL). FISH results were manually scored in a blinded fashion, and amplification was defined as a HER2/CEP17 ratio more than 2.0. Where possible, HER2 phosphorylation was also assessed by immunohistochemistry (IHC) using a phospho-specific anti-HER2 antibody (P-Tyr 1248; clone PN2A) on frozen tumor sections (Appendix).
Tolerability and Safety Assessment
Statistical Analysis
HER2 Expression and Activation in an Unselected Series of Ovarian Carcinomas HER2 expression and activation in ovarian carcinomas was assessed in an anonymized series of 20 banked tumor samples, separate from the clinical trial. By immunoprecipitation and Western blotting, HER2 protein expression was demonstrated in all 20 tumors (Fig 1). This was confirmed quantitatively by HER2 ELISA. Two of the samples displayed HER2 gene amplification by FISH, whereas the others were FISH-negative (data not shown). By ELISA, HER2 phosphorylation was detected in nine of 20 tumors (45%). The two FISH-positive tumors had very high levels of HER2 protein overexpression, as well as high amounts of phosphorylated protein compared with the other FISH-negative tumors. IHC for phosphorylated HER2 (pHER2) using the HER2 P-Tyr 1248 monoclonal antibody (mAb) clone PN2A was positive in the two FISH-positive tumors, but was insufficiently sensitive to detect the lower levels of pHER2 present in the other seven ELISA-positive tumors (data not shown). These data support the use of ELISA for assaying HER2 activation in the fresh tumor biopsies.
Patients One hundred twenty-nine patients were enrolled (65 in cohort 1, 64 in cohort 2). One hundred twenty-three patients were treated with pertuzumab (61 in cohort 1, 62 in cohort 2). Patient characteristics (Table 1) were similar between cohorts. All patients had received a platinum-based therapy and had progressed, and it was approximated that 87% patients had progressed less than 6 months from their last platinum-containing regimen (as determined by start/stop of prior regimens) before entry to the study. A median of two cycles of pertuzumab was administered. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for response by either RECIST or CA-125.
Efficacy by Dose of Pertuzumab The best overall response for all patients is listed in Table 2. Two of 55 patients (3.6%) in cohort 1 and three of 62 patients (4.8%) in cohort 2 demonstrated objective PRs, for an overall RR of 4.3% (95% CI, 1.7% to 9.4%), which is below the targeted response rate of 30%. The median duration of response was 18.6 weeks (95% CI, 13.1 to 29.1). In addition, eight patients (6.8%) had stable disease (SD) lasting at least 6 months—four in each cohort. Ten patients also had CA-125 decrease of at least 50% with at least an SD at the first response evaluation (these patients were measurable by RECIST, and so CA-125 was not used and confirmed for response); two were in the PR group, four were in the SD of at least 6 months group, and four had SD of 6 months or less. Overall rate of clinical activity of the 17 of 117 patients (PR, SD > 6 months, CA-125 decrease) was therefore 14.5%, although this was not a prespecified end point.
Two patients enrolled in cohort 2 had SD for 1 year and were subsequently enrolled into a rollover study to allow continued treatment with single agent pertuzumab. Since enrolling in the extension study one patient has been treated for an additional eight cycles (total 76 weeks) and continues to be treated, and the other patient progressed after four additional cycles (total 64 weeks). Figure 2A shows a Kaplan-Meier curve of PFS for efficacy-assessable patients in cohorts 1 and 2. Median PFS for the overall population was 6.6 weeks (95% CI, 6.0 to 10.9) and was similar between cohorts 1 and 2 (7.6 weeks [95% CI, 6.0 to 11.4] versus 6.1 weeks [95% CI, 5.9 to 11.4], respectively). Figure 3A shows a Kaplan-Meier curve of overall survival for efficacy-assessable patients in cohorts 1 and 2. Median survival for the overall population was 52.7 weeks (95% CI, 38.9 to 66.7). Median survival was 46.7 weeks (95% CI, 30.4 to 66.6) for patients in cohort 1, but has not yet been reached in cohort 2. Of the five patients in cohort 2 with a PR, only one has died (at 26 weeks, with follow-up from the remaining from 56 to 93 weeks). Of the eight patients who had SD lasting at least 6 months, none have died (with follow-up from 51 to 105 weeks). Finally, of the 60 patients who had PD, 40 have died with a median survival of 33.1 weeks (the 20 censored having follow-up of 49 to 96 weeks).
Efficacy by pHER2 Status Because many of the tumors did not meet the minimal requirement to be assayed by ELISA (  99-mg sample with 30% tumor content), only 34 of the 65 tumor biopsies obtained from patients in cohort 1 were adequate for evaluation by ELISA. All assessable samples had detectable levels of HER2 protein (median, 6.7 ng/mg; range, 1.4 to 21.7 ng/mg). No tumor biopsies were found to have HER2 overexpression levels comparable with those seen in the two FISH-positive banked tumor samples from the unselected series (906 and 565 ng/mg protein). FISH assays of the fresh tumor biopsies and/or archival tumor samples from patients in either cohort did not demonstrate HER2 gene amplification in any of the assessable patient tumors. Of the 34 fresh tumor specimens that were adequate for evaluation, 10 (29.4%) were found to have detectable levels of phosphorylated HER2 (pHER2+). Of the 34 assessable biopsies, 28 patients were also assessable for clinical efficacy; eight (28.6%) of 28 patients had pretreatment tumor samples that were pHER2+, whereas 20 (71.4%) of 28 were pHER2–.
The best overall response according to pHER2 status for efficacy assessable patients in cohort 1 is listed in Table 3. PR was observed in one (12.5%) of eight patients with pHER2+ tumors, but in none of the patients with pHER2– tumors. A higher proportion of patients with pHER2+ tumors had SD at the first response evaluation compared with patients with pHER2– tumors (75% v 25%, respectively). Overall rate of clinical activity (PR, SD
The Kaplan-Meier curve of PFS for efficacy-assessable patients in cohort 1 (Fig 2B) shows that median PFS for patients with pHER2+ tumors was 20.9 weeks (95% CI, 11.1 to 24.6) compared with 5.8 weeks (95% CI, 5.3 to 10.6) for patients with pHER2– tumors (P = .14) and 9.1 weeks (95% CI, 6.1 to 12.1) for patients with pHER2-unknown tumors. The Kaplan-Meier curve of overall survival for efficacy-assessable pHER2+ patients was 74.6 weeks (95% CI, 28.4 to not yet reached), 37.0 weeks (95% CI, 18.6 to not yet reached) for pHER2– patients, and 48.4 weeks (95% CI, 21.6 to 82.1) for pHER2-unknown tumors. The log-rank test showed a trend toward improved survival for pHER2+ versus pHER2– tumors (P = .365).
Safety
There were 44 serious adverse events (SAEs) reported and six (4.9%) were considered treatment-related (one case each of diarrhea, abdominal pain, LVEF decrease, atrial fibrillation, pericardial effusion, and pneumonia). Death not resulting from progressive disease occurred in one patient who experienced respiratory arrest before receiving pertuzumab, and another who died 9 months after her last dose of pertuzumab. Due to reports of cardiotoxicity associated with HER2 inhibition, cardiac function has been monitored carefully in all pertuzumab clinical trials. One patient (1.6%) in cohort 1 and four (6.5%) in cohort 2 had a decrease in LVEF to less than 50%. All patients were asymptomatic, and only one decrease was confirmed by a central facility. To place this cardiac safety data in context, of 167 assessable patients with cardiac monitoring across three phase II studies of single-agent pertuzumab in the United States (non–small-cell lung cancer [NSCLC], prostate cancer, and the current study), nine (5.4%) have had a decrease in LVEF to less than 50%. All patients were asymptomatic, and only two (1.2%) were confirmed by a central facility.
Our initial analysis of banked ovarian tumor samples demonstrated that HER2 activation was detectable in a subset of tumors, including tumors with nonamplified HER2 genes and lower levels of HER2 protein expression, as well as tumors with HER2 gene amplification and highly overexpressed HER2 protein. We hypothesized that targeting HER2 pathway activation with pertuzumab would inhibit the growth of these tumors. This study demonstrates that single-agent pertuzumab has clinical activity in heavily-pretreated patients with advanced ovarian cancer. A low number of responses were seen, and the primary end point of response rate was not met; however, a larger proportion of patients achieved CA-125 responses and prolonged SD. In retrospect, a 30% response rate is a high bar for activity from a biologic agent. Despite differences in eligibility criteria, median survival after pertuzumab was comparable to the median survival of platinum-resistant patients reported by Gordon et al23 in a phase III trial with liposomal doxorubicin and topotecan (35.6 weeks and 41.3 weeks, respectively). Recent data suggest that tumor response rate may not be the optimal end point for assessing the clinical benefit of biologic agents like pertuzumab. Erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase,24 produced a 7.4% RR in second-line metastatic NSCLC patients with wild-type EGFR. Though few tumor regressions were observed, erlotinib demonstrated significant improvement in PFS and overall survival in NSCLC.24 A key aspect of therapy with targeted agents is accurate selection of patients most likely to benefit from treatment. Our data and other studies suggest that ovarian cancer has a low incidence of HER2 gene amplification and protein overexpression.25 In a study of ovarian cancer patients treated with trastuzumab, the overall incidence of both HER2 2+ and 3+ expression was only 11.4% of tumors (95 of 837 tumors screened by IHC), and only 4.1% were HER2 3+.26 Conversely in this study, none of the patients' tumors had HER2 amplification; however 29.4% had evidence of activated HER2 (pHER2+). The prevalence of pHER2+ observed in the study of banked ovarian samples was 45%. This is well within the range of a useful diagnostic tool for patient selection. HER2 amplification was not required for any clinical activity associated with pertuzumab in this study, reflecting results obtained in the preclinical setting.17 These results lend further support for the use of markers of HER2 activation and not overexpression as the appropriate diagnostic for selection in ovarian cancer. Consistent with the mechanism of action of pertuzumab, the efficacy results for cohort 1 suggest that patients with HER2 phosphorylation showed better outcome following pertuzumab therapy, compared to patients with pHER2– tumors. However, it remains unknown whether the presence of pHER2 specifically predicts outcome to pertuzumab or is simply a good prognostic marker in ovarian cancer. Randomized trials are needed to confirm the utility of pHER2 as a diagnostic marker. Additionally, the assessment of HER2 phosphorylation status in formalin-fixed pathology specimens presents technical challenges for routine diagnostic testing. Because fresh-frozen tissue is required for the pHER2 assay, alternative predictive markers of HER2 activation are being investigated as potential diagnostic tests moving forward. Data from microarray expression profiling of the present tumor series indicate that higher coexpression of HER2, EGFR, HER3 and certain HER ligands may correlate with pHER2 status.27 Other HER targeting agents have been studied in ovarian cancer. Erlotinib produced a 6% RR in EGFR+ advanced ovarian cancer patients.28 Trastuzumab produced a response rate of 7.3% in HER2 2+ and 3+ patients.26 Treatment with gefitinib in 26 assessable recurrent ovarian cancer patients resulted in four patients with SD for at least 6 months with one of them (3.8%) having a PR.29 In the current study, pertuzumab had a comparable low response rate although, of note, patients were not preselected. Given that pertuzumab blocks all HER2-mediated signaling, in contrast to targeted blockade of EGFR1 or HER2 overexpression, pertuzumab may result in higher rates of clinical activity in an appropriately selected population. It will be interesting to observe the clinical activity of the dual EGFR and HER2 inhibitor lapatinib, currently under investigation in unselected ovarian cancer patients progressing within 12 months of a platinum regimen, with 6-month PFS as the primary end point. In addition to further exploring HER2 activation as a marker for patient selection, future development of pertuzumab will evaluate the drug in combination with other chemotherapies and targeted agents. Multiple trials have shown that the clinical effect of chemotherapy is maximized when combined with targeted drugs (ie, trastuzumab in breast cancer; bevacizumab in breast cancer, colorectal cancer, and NSCLC; cetuximab in colorectal cancer30-37). Furthermore, preliminary preclinical data suggest that combining pertuzumab with other agents leads to additive activity.38 Given these data and its tolerable safety profile, combination studies with pertuzumab are warranted and are ongoing.
Tumor Lysates Fresh tumor samples were flash-frozen in liquid nitrogen within 30 minutes of removal from the patients. Hematoxylin and eosin–stained frozen sections were examined by a pathologist (D.A.E.) for histologic confirmation and assessment of tumor content. Samples with a tumor cell content of 30% or greater were included in the present analysis. Frozen tumors were homogenized on ice in RPMI-1640-1640 (Gibco, Carlsbad, CA) containing 50 mmol/L Tris-HCl pH 7.6,150 mmol/L NaCl, 1% Triton X-100, 1:10 Protease Inhibitor Cocktail (Roche Applied Sciences, Indianapolis, IN), 1:100 Phosphatase Inhibitor Cocktail I (Sigma-Aldrich, St Louis, MO), 1:100 Phosphatase Inhibitor Cocktail II (Sigma-Aldrich), 50 mmol/L sodium fluoride and 2 mmol/L sodium orthovanadate. The homogenates were then lysed for 1 hour at 4°C then centrifuged at maximum speed in a tabletop microfuge for 10 minutes at 4°C to remove cellular debris. The supernatants were precleared by incubating for 30 minutes with 50 µL Ultralink Protein A/G (Pierce, Rockford, IL), which was then removed by centrifugation. Supernatants were immediately analyzed by ELISA or immunoprecipitation.
Total HER2 ELISA
IHC
pHER2 ELISA The pHER2 ELISA Standard Material was prepared by collecting lysates from three 245- x 245-mm cell culture trays containing SKBR3 cells (American Type Culture Collection #HTB-30, Manassas, VA), which were 80% to 90% confluent. Cell lysates were clarified by centrifugation and the supernatants were collected. The supernatant was used as the standard material. The standard material was assigned a concentration of 1,056 U/mL so that the lowest calibrator in the assay reporting range would be 1 U/mL.
Immunoprecipitation and Western Analysis
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We acknowledge Stephen Kelsey and Gracie Lieberman for their contribution to this study.
published online ahead of print at www.jco.org on August 7, 2006. Supported by Genentech Inc, South San Francisco, CA. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005, and the 34th Annual Meeting of the Western Association of Gynecologic Oncologists, Santa Fe, NM, June 15-18, 2005. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005 2. Armstrong DK: Relapsed ovarian cancer: Challenges and management strategies for a chronic disease. Oncologist 5:20-28, 2002 (suppl)[CrossRef] 3. tk;3Yarden Y, Sliwkowski MX: Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2:127-137, 2001[CrossRef][Medline] 4. Garrett TP, McKern NM, Lou M, et al: The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 11:495-505, 2003[CrossRef][Medline] 5. Tzahar E, Waterman H, Chen X, et al: A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276-5287, 1996[Abstract] 6. Graus-Porta D, Beerli RR, Daly JM, et al: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. Embo J 16:1647-1655, 1997[CrossRef][Medline] 7. Sundaresan S, Roberts PE, King KL, et al: Biological response to ErbB ligands in nontransformed cell lines correlates with a specific pattern of receptor expression. Endocrinology 139:4756-4764, 1998 8. Campiglio M, Ali S, Knyazev PG, et al: Characteristics of EGFR family-mediated HRG signals in human ovarian cancer. J Cell Biochem 73:522-532, 1999[CrossRef][Medline] 9. Bast RC Jr, Pusztai L, Kerns BJ, et al: Coexpression of the HER-2 gene product, p185HER-2, and epidermal growth factor receptor, p170EGF-R, on epithelial ovarian cancers and normal tissues. Hybridoma 17:313-321, 1998[Medline] 10. Bartlett JM, Langdon SP, Simpson BJ, et al: The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer 73:301-306, 1996[Medline] 11. Berchuck A, Kamel A, Whitaker R, et al: Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50:4087-4091, 1990 12. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 13. Xu F, Yu Y, Le XF, et al: The outcome of heregulin-induced activation of ovarian cancer cells depends on the relative levels of HER-2 and HER-3 expression. Clin Cancer Res 5:3653-3660, 1999 14. Totpal K, Balter I, Akita RW: Targeting ErbB2/HER2's role as a coreceptor with rhuMAb2C4 inhibits Erb/HER ligand-dependent signaling and proliferation of ovarian tumor cell lines. Proc Am Assoc Cancer Res 44:151, 2003 (abstr 776) 15. Adams CW, Allison DE, Flagella K, et al: Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother 55:717-727, 2006[CrossRef][Medline] 16. Franklin MC, Carey KD, Vajdos FF, et al: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317-328, 2004[CrossRef][Medline] 17. Agus DB, Akita RW, Fox WD, et al: Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127-137, 2002[CrossRef][Medline] 18. Malik S, Totpal K, Balter I: Dose-response studies of recombinant humanized monoclonal antibody 2C4 in tumor xenograft models. Proc Am Assoc Cancer Res 44:150, 2003 (abstr 773) 19. Agus DB, Gordon MS, Taylor C, et al: Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534-2543, 2005 20. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 21. Allison DE, Malik M, Qureshi F, et al: Pharmacokinetics of HER2-targeted rhuMAb 2C4 (pertuzumab) in patients with advanced solid malignancies: Phase Ia results. Proc Am Soc Clin Oncol 22:197, 2003 (abstr 790) 22. Rustin GJ: Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol 21:187-193, 2003[CrossRef][Medline] 23. Gordon AN, Fleagle JT, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: A randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312-3322, 2001 24. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:200-202, 2005 25. Camilleri-Broet S, Guastalla JP, Couturier J: HER2 overexpression and amplification in advanced ovarian cancer (OC): preliminary results from a large GINECO study. J Clin Oncol 23:469s, 2005 (suppl; abstr 5059) 26. Bookman MA, Darcy KM, Clarke-Pearson D, et al: 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. J Clin Oncol 21:283-290, 2003 27. Amler LC, Krueger K, Januario T, et al: Identification of a predictive expression pattern for phosphorylated her2 as a potential diagnostic marker for pertuzumab (Omnitarg) activity in ovarian cancer. Proc Am Assoc Cancer Res 24:18, 2006 (abstr 3001) 28. Gordon AN, Finkler N, Edwards RP, et al: Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: Results from a phase II multicenter study. Intl J Gynecol Oncol 15:785-792, 2005[CrossRef] 29. Schilder RJ, Kohn E, Sill MW, et al: Phase II trial of gefitinib in patients with recurrent ovarian or primary peritoneal cancer: Gynecology Oncology Group 170C. Proc Am Soc Clin Oncol 22:451, 2003 (abstr 1814) 30. Peacock NW, Bearden J, Schnell F, et al: Phase II trial of gemcitabine plus trastuzumab in minimally pretreated HER2 overexpressing metastatic breast cancer. J Clin Oncol 23:54s, 2005 (suppl; abstr 704) 31. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 32. Hochster HS, Welles L, Hart L, et al: Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first-line treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 Studies. J Clin Oncol 23:249s, 2005 (suppl; abstr 3515) 33. Fernando N, Yu D, Morse M, et al: A phase II study of oxaliplatin, capecitabine and bevacizumab in the treatment of metastatic colorectal cancer. J Clin Oncol 23:260s, 2005 (suppl; abstr 3556) 34. Grothe W, Arnold D, Peinert S, et al: Cetuximab with oxaliplatin and capecitabine (CAPOX) in patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy. J Clin Oncol 23:288s, 2005 (suppl; abstr 3669) 35. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599. J Clin Oncol 23:2s, 2005 (suppl; abstr LBA4) 36. Scott J, Dakhil S, Cosgriff T, et al: Cetuximab + FOLFOX 6 as first line therapy for metastatic colorectal cancer. J Clin Oncol 23:297s, 2005 (suppl; abstr 3705) 37. Saltz LB, Lenz H, Hochster H, et al: Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. J Clin Oncol 23:248s, 2005 (suppl; abstr 3508)[CrossRef] 38. Friess T, Juchem R, Scheuer W, et al: Additive antitumor activity by combined treatment with recombinant humanized monoclonal antibody 2C4 and standard chemotherapeutic agents in NSCLC xenografts is independent of HER2 overexpression. Proc Am Soc Clin Oncol 22:238, 2003 (abstr 953) Submitted December 20, 2005; accepted May 1, 2006. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
