Combined Weekly Topotecan and Biweekly Bevacizumab in Women With Platinum- Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer

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1 Combined Weekly Topotecan and Biweekly Bevacizumab in Women With Platinum- Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer Results of a Phase 2 Study Kathryn F. McGonigle, MD 1 ; Howard G. Muntz, MD 1 ; Jacqueline Vuky, MD 2 ; Pamela J. Paley, MD 3 ; Dan S. Veljovich, MD 3 ; Benjamin E. Greer, MD 4 ; Barbara A. Goff, MD 4 ; Heidi J. Gray, MD 4 ; and Thomas W. Malpass, MD 2 BACKGROUND: A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum-resistant ovarian, peritoneal, or fallopian tube cancer (OC). METHODS: Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m 2 on days 1, 8, and 15 of a 28-day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression-free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity. RESULTS: Patients (N ¼ 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], ) and 16.6 months (95% CI, ), with 22 (55%) patients progression-free for 6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P ¼.03); median PFS, 10.9 versus 2.8 months (P ¼.08); median OS, 22.9 versus 12.8 months (P ¼.02). CONCLUSIONS: A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted. Cancer 2011;117: VC 2011 American Cancer Society. KEYWORDS: angiogenesis inhibitors, topotecan, chemotherapy, ovarian cancer, primary peritoneal carcinoma, fallopian tube cancer. Most women with advanced ovarian cancer (OC) respond to first-line platinum and taxane chemotherapy. 1 Overall, only 20% to 40% of patients who receive current treatment options survive beyond 5 years after diagnosis of OC. 2 The majority of OC patients develop recurrent disease that becomes increasingly resistant to chemotherapy. 3 Median survival of patients with platinum-resistant OC is <12 months, and response rates to any subsequent chemotherapy are generally lower compared with patients whose disease remains platinum-sensitive. The targeted agent bevacizumab (Genentech, South San Francisco, California), a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), is approved by the US Food and Drug Administration for use Corresponding author: Kathryn F. McGonigle, MD, Women s Cancer Care of Seattle, 1560 North 115th St, Suite #101, Seattle, WA 98133; Fax: (206) ; kathryn.mcgonigle@nwhsea.org 1 Women s Cancer Care of Seattle, Seattle, Washington; 2 Section of Hematology and Medical Oncology, Virginia Mason Medical Center, Seattle, Washington; 3 Pacific Gynecology Specialists, Seattle, Washington; 4 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Washington Medical Center, Seattle, Washington This original research was presented in part at the 2008 American Society of Clinical Oncology, Chicago, Illinois (Journal of Clinical Oncology. 2008;26. Abstract 5551) and the 2009 Annual Meeting on Women s Cancer, San Antonio, Texas (Gynecologic Oncology. 2009;112:S145. Abstract 286). The authors thank Cancer Research and Biostatistics, Seattle, Washington, for statistical analysis. DOI: /cncr.25967, Received: November 24, 2010; Revised: January 5, 2011; Accepted: January 5, 2011, Published online February 24, 2011 in Wiley Online Library (wileyonlinelibrary.com) Cancer August 15,

2 in multiple metastatic or advanced malignancies, including colorectal cancer, nonsmall cell lung cancer, breast cancer, glioblastoma, and renal cell cancer. 4 Bevacizumab has also demonstrated significant antitumor activity in patients with OC when used concurrently with standard first-line platinum and taxane chemotherapy, when continued as maintenance in the treatment-naive setting, 5,6 and when used as both a single agent 7,8 and in combination with chemotherapy in recurrent OC. 9 Bevacizumab has also shown single-agent activity in endometrial 10 and cervical cancers. 11 Topotecan (GlaxoSmithKline, Philadelphia, Pennsylvania) is a topoisomerase I inhibitor approved by regulatory agencies as a monotherapy for recurrent OC as an intravenous infusion on days 1 through 5 of a 21-day course. 12 Recent studies show that weekly administration of topotecan results in moderate efficacy in recurrent ovarian cancer with fewer cases of myelosuppression compared with the 5-day regimen In addition to having a direct antitumor effect, topotecan may inhibit angiogenesis, as suggested by in vitro 18 and in vivo studies. 19 The clinical activity of bevacizumab and topotecan as monotherapies, the potential for synergistic antiangiogenic effects, and their nonoverlapping toxicity profiles provide compelling rationale for combining these agents for the treatment of patients with recurrent OC. Here, we present findings from a prospective phase 2 study that evaluated the toxicity and efficacy of topotecan and bevacizumab in patients with recurrent platinum-resistant OC. MATERIALS AND METHODS Patient Population Following approval by the institutional review boards of each site, the study was opened to patient accrual at the Virginia Mason Medical Center and the Puget Sound Oncology Consortium. Eligibility criteria included advanced or recurrent epithelial ovarian, peritoneal, or fallopian tube cancer. In an attempt to decrease the potential for gastrointestinal perforation, our study population was restricted to patients who had received a maximum of 2 prior chemotherapy regimens. All patients received prior primary taxane and platinum-based chemotherapy, and no more than 1 other chemotherapy regimen. Prior exposure to topotecan was acceptable, and subjects were at least 18 years old. Patients were required to have primary or secondary platinum-resistant disease, defined as progression on platinum therapy, recurrence or persistence less than 6 months after initial platinum therapy or after retreatment with a second platinum-based therapy. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) or CA-125 levels above 100 on 2 separate occasions (1 week or more apart) was required. Furthermore, patients had an estimated survival of 12 weeks or longer; a Karnofsky performance status of 70% or greater; adequate bone marrow, renal, and liver functions by prespecified criteria; and signed informed consent. Patients were excluded for prior treatment with an antiangiogenesis agent, history of other malignancy within 3 years (except for nonmelanoma skin cancer), inadequately controlled hypertension (systolic blood pressure above 150 mm Hg and/or diastolic blood pressure above 100 mm Hg), New York Heart Association class II or greater congestive heart failure, myocardial infarction, unstable angina, stroke, transient ischemic attack, or significant vascular disease within 6 months, or a history of hypertensive crisis or hypertensive encephalopathy. Further exclusions included history of hemoptysis within 1 month, evidence of bleeding diathesis or significant coagulopathy (for patients not on anticoagulation therapy), or known central nervous system disease, except treated brain metastases. Additional exclusion criteria were history of abdominal fistula, grade 4 bowel obstruction, gastrointestinal perforation or intra-abdominal abscess within 6 months, current symptoms of GI obstruction grade 1 or greater, major surgical procedure within 28 days, or minor surgical procedure within 7 days of treatment, grade 2 or greater peripheral neuropathy, and serious nonhealing wound, active ulcer, or untreated bone fracture. Study Design and Treatment Schedule Treatment was administered in 28-day cycles, with intravenous bevacizumab 10 mg/kg given on days 1 and 15 and intravenous topotecan 4 mg/m 2 given on days 1, 8, and 15 (maximum topotecan dose of 8 mg). Treatment was continued until progressive disease (PD) as defined by RECIST, symptomatic deterioration related to obvious clinical progression, excessive toxicity according to prespecified criteria, toxicity requiring topotecan delay of more than 2 weeks, or bevacizumab delay of more than 2 months, or topotecan-related toxicities requiring more than 2 dose reductions. Dose reductions of bevacizumab were not permitted. Bevacizumab was withheld for grade 2 or greater bowel obstruction or any grade 3 or greater bevacizumab toxicity until recovery to grade 1. Criteria for the discontinuation of bevacizumab included grade 4 bevacizumab-related toxicities, diagnosis of reversible posterior leukoencephalopathy syndrome, repeat grade Cancer August 15, 2011

3 Topotecan and Bevacizumab in Ovarian Cancer/McGonigle et al hemorrhage, grades 2 to 4 pulmonary or central nervous system hemorrhage, or any grade of arterial thrombosis, gastrointestinal perforation, or wound dehiscence. Topotecan was withheld and reduced by 1 dose level (eg, 25%) in the event of grade 4 neutropenia lasting more than 7 days, recurrent grade 4 neutropenia, febrile neutropenia, grade 3 thrombocytopenia, recurrent grade 2 thrombocytopenia, grade 2 or greater peripheral neuropathy, grade 2 or greater renal toxicity, grade 3 or greater hepatic toxicity, or any grade 2 or greater toxicity impacting organ function. For grades 2 and 3 neutropenia lasting more than 7 days, dose reductions were allowed on a case-bycase basis. Topotecan was also withheld for an absolute neutrophil count below 1200/lL and for thrombocytopenia (below 75,000/lL). Prophylactic oral antibiotics were allowed to manage neutropenia at the discretion of the treating physician. Per protocol, when topotecan was withheld because of toxicity, the dose was delayed, and the patient received all 3 weekly treatments over a longer period of time. However, on occasion (at the request of the patient or treating physician), the patient received only 2 of the weekly treatments for a cycle before moving on to the next cycle. Filgrastim or pegfilgrastim was allowed with the next dose of chemotherapy at the discretion of the treating physician. When used, pegfilgrastim was generally given after the third dose of chemotherapy in the 2-week window between cycles. Erythropoietinstimulating agents were also allowed. Toxicity and Efficacy Determinations Patients receiving any study treatment were evaluable for adverse events. Patients were evaluated clinically and with standard laboratory tests at baseline and at regular intervals during the study. Patients discontinued from the treatment phase of the study for any reason were evaluated again approximately 30 days after discontinuing treatment. Safety assessments focused on tests designed to detect known toxicities of bevacizumab, including blood pressure monitoring, hemostasis evaluation, monitoring of proteinuria by urinary protein:creatinine ratio or dipstick at least every 6 weeks, and close monitoring of GI toxicity by the treating physician and principal investigator (K.F.M.). Toxicity related to either drug was assessed by using National Cancer Institute Common Toxicity Criteria, version 3.0. Response in patients with measurable tumors was assessed by modified Response Evaluation Criteria In Solid Tumors (RECIST), which required that a complete response (CR) also be characterized by a normalization of CA-125 levels. In patients with nonmeasurable disease, CA-125 levels were used to determine response according to Rustin criteria. 20 Progression-free survival (PFS) and overall survival (OS) were defined as the number of months after commencing study treatment until PD or death, respectively. Statistical Design and Analysis This phase 2 trial was designed with PFS as the primary endpoint; secondary objectives were OS, objective response rate (ORR), and toxicity. The planned enrollment of 40 patients was determined assuming a median PFS of 9 months (based on a median PFS of 7.2 months for low-dose, metronomic cyclophosphamide plus bevacizumab in a phase 2 study 9 ) and an analysis calculating the sample size at which the narrowing of its 95% confidence interval (CI) became greater than 0.20 for every 2 patients added. PFS and OS were estimated by using the Kaplan- Meier method. For calculating the 95% CI of median PFS and OS, a normal approximation was used that assumed event times were exponentially distributed. Standard statistical methods (chi-square, log-rank tests) were used in post hoc analyses that compared efficacy parameters in patients who received 1 versus 2 prior treatment regimens and in patients with primary versus secondary platinum resistance. All confidence intervals were 2-sided, with an alpha level of.05. The log-rank and chi-squared tests are 1-sided nondirectional tests. An alpha level of.05 was used to define statistical significance for these tests. RESULTS Patients Forty patients were enrolled from August 2006 through November The present analysis was performed on data collected through January 31, At this date, 2 patients remained on study, and all patients were evaluable for toxicity and efficacy. Demographic information is included in Table 1. All patients had been previously treated with platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). One patient had received topotecan, as part of consolidation therapy on a clinical research protocol. Twenty-one (53%) patients had received 1 prior chemotherapy regimen and were considered primary platinum-resistant. Of the 19 patients who received 2 prior regimens, 7 were primary platinum-resistant and received second-line nonplatinum therapy before enrollment on this study. Thus, 28 patients overall were Cancer August 15,

4 Table 1. Patient Characteristics Characteristic Patients (N540) Median age, y (range) 58.6 (30-83) Median time from initial diagnosis, mo (range) 14.3 ( ) Median time from last platinum, mo (range) 2.3 (0-6.0) Caucasian race, no. (%) 40 (100) Disease site, no. (%) a Ovary 35 (88) Primary peritoneal cavity 4 (10) Fallopian tube 1 (3) Disease stage, no. (%) a IA 1 (3) IIA 1 (3) IIIA 2 (5) IIIB 2 (5) IIIC 28 (70) IV 6 (15) Disease histology Serous carcinoma 32 (80) Adenocarcinoma (NOS) 4 (10) Clear cell carcinoma 4 (10) Platinum resistance Primary 28 (70) Secondary 12 (30) No. of prior treatment regimens 1 21 (53) 2 19 (47) Primary treatment regimens b Carboplatin or cisplatin1taxane6third agent 40 (100) Secondary treatment regimens Carboplatin or cisplatin1taxane 7 (37) Liposomal doxorubicin 5 (26)) Carboplatin1gemcitabine 4 (21) Paclitaxel 1 (5) Ispinesib (SB ) c 1 (5) Carboplatin 1 (5) NOS indicates not otherwise specified. a Percentages may not equal 100% secondary to rounding. b One patient received intraperitoneal topotecan as part of consolidation treatment on a research protocol for primary therapy. c Ispinesib (SB ) is an agent being investigated by GlaxoSmithKline (Philadelphia, Pennsylvania) as a kinesin spindle protein inhibitor. primary platinum-resistant. One patient had elevated CA-125 without measurable disease, and the remaining 39 patients had measurable disease based on RECIST. Treatment Exposure Median duration on study was 33 weeks (range, weeks), and patients received a median of 8 cycles of therapy (range, <1-32 cycles). Thirty-one patients went off study as a result of PD: 21 by RECIST on CT scan, 7 because of general symptomatic deterioration, and 3 because of bowel obstruction. One patient received only 1 weekly dose of study treatment and then went off study because of rapidly progressing disease. Three patients went off study because of toxicity: 1 for grade 3 proteinuria and recurrent thrombocytopenia and 2 for grade 4 cardiotoxicity. Four patients voluntarily withdrew from the study after achieving partial response (PR) as best response. Safety and Tolerability The majority of adverse events were mild or moderate (Table 2). The most common grade 3 or 4 toxicities were neutropenia (18%), hypertension (20%), GI toxicity (18%), pain (13%), metabolic toxicity (16%), bowel obstruction (10%), and cardiotoxicity (8%). Grade 4 events included cardiotoxicity (myocardial ischemia, 5%), bowel obstruction (3%), anemia (3%), neutropenia (3%), pain (3%), and hyponatremia (3%). The grade 4 cardiac events were assessed as not related to the patients underlying cancer or study treatment. Two patients who had medical risk factors for, but no history of, coronary artery disease (CAD) developed myocardial ischemia after 8 and 24 cycles of treatment, respectively. The majority of grade 3 and 4 nonhematologic toxicities were assessed to be related to PD or underlying disease, including patients with bowel obstruction, pain, and pulmonary/noninfectious toxicity, as well as a case of gonadal vein thrombosis. Grade 3 fatigue, GI, and infectious and metabolic toxicities were possibly related to study treatment versus underlying disease. Twelve (30%) patients with grade 2 or 3 hypertension (grade 1 events were not recorded) and 3 cases of grade 2 or 3 proteinuria were likely related to bevacizumab. Early hypertension (within 3 months) was observed in half of the patients with this toxicity (n ¼ 6). There were no cases of bowel perforation, febrile neutropenia, or treatment-related death. Overall, dose delays 7 days or longer occurred in 27 (68%) patients, and delays related to toxicity occurred in 22 (55%) patients. Twelve (30%) patients had dose delays for reasons related to scheduling conflicts; 7 of these also had 1 or more dose delays due to toxicity. Six (15%) patients required 3 or more dose delays (range, 3-7 delays) because of toxicity, and 5 (13%) patients had dose delays for more than 14 days. Neutropenia and/or thrombocytopenia prompted delays in 19 (48%) patients, and nonhematologic toxicities (eg, respiratory infection, fatigue, hypertension) were the cause in 11 (28%) patients, 8 of whom also experienced delays due to hematologic toxicity. The dose of topotecan was reduced by 25% in 4 patients because of hematologic toxicity. Three patients 3734 Cancer August 15, 2011

5 Topotecan and Bevacizumab in Ovarian Cancer/McGonigle et al Table 2. Grade 2 to 4 Toxicities Patients (N540) All Grade 2 Grade 3 Grade 4 Adverse Event No. (%) No. (%) No. (%) No. (%) Hematologic Neutropenia 22 (55) 15 (38) 6 (15) 1 (3) Anemia 19 (48) 17 (43) 1 (3) 1 (3) Leukopenia 16 (40) 14 (35) 2 (5) 0 (0) Thrombocytopenia 13 (33) 11 (28) 2 (5) 0 (0) Nonhematologic Fatigue 20 (50) 18 (45) 2 (5) 0 (0) Pain 18 (45) 13 (33) 4 (10) 1 (3) GI toxicity, excluding bowel obstruction a 18 (45) 11 (28) 7 (18) 0 (0) Bowel obstruction 4 (10) 0 (0) 3 (8) 1 (3) Infection b 16 (40) 14 (35) 2 (5) 0 (0) Neurologic c 6 (15) 5 (13) 1 (3) 0 (0) Hypertension 12 (30) 4 (10) 8 (20) 0 (0) Metabolic d 12 (30) 6 (15) 5 (13) 1 (3) Constitutional symptoms e 8 (20) 8 (20) 0 (0) 0 (0) Pulmonary (noninfectious) f 6 (15) 4 (10) 2 (5) 0 (0) Musculoskeletal 5 (13) 5 (13) 0 (0) 0 (0) Other g 5 (13) 5 (13) 0 (0) 0 (0) Cardiac, nonhypertension h 4 (10) 1 (3) 1 (3) 2 (5) Proteinuria 3 (8) 2 (5) 1 (3) 0 (0) Venous thrombosis i 1 (3) 0 (0) 1 (3) 0 (0) Bleeding 1 (3) 0 (0) 1 (3) 0 (0) Percentages may not equal 100% secondary to rounding; some patients had multiple toxicities. GI, gastrointestinal. a Includes constipation, dehydration, anorexia, nausea with vomiting, worsening of underlying gastroparesis, gastroesophageal reflux, diarrhea, and symptomatic gallstones requiring surgery. b Includes pneumonia, bronchitis/sinusitis, other upper respiratory, otitis media, urinary tract, cellulitis, thrush. c Includes depression, anxiety, headache. d Includes hyponatremia, hypokalemia, hyperglycemia, hypercholesterolemia, elevation in liver function tests, hypophosphatemia. e Includes weight loss, insomnia, chills, rigors. f Includes dyspnea, shortness of breath, pleuritic pain, hoarseness, cough. g Includes pruritus, rash, allergic rhinitis, dry skin. h Includes myocardial infarction (grade 4), hypotension related to dehydration (grade 3), and vasovagal (grade 2). i Gonadal vein thrombosis requiring anticoagulation. discontinued study treatment as a result of toxicity: 2 with grade 4 cardiac disease and 1 with grade 3 proteinuria and hematologic toxicity. Sixteen (40%) patients received erythropoietin-stimulating agents, and 8 (20%) patients received either filgrastim or pegfilgrastim or both at least once during the study treatment. Efficacy Median PFS (Fig. 1A) and OS (Fig. 1B) were 7.8 months and 16.6 months, respectively (Table 3). Twenty-two of the 40 (55%) patients had PFS of 6 months or longer. Best responses were PR in 10 (25%) patients, stable disease (SD) in 14 (35%), and PD in 16 (40%) (Table 3). All patients with PR and 86% of patients with SD had PFS longer than 6 months. One patient who had previously received topotecan as part of consolidation therapy achieved SD but then progressed at 7.1 months. Two patients remained on study treatment 1 with SD, the other with PR after 21.1 and 30.3 months, respectively. The patient with PR remains on study at the time of submission of this article(january 4, 2011) after 43 cycles and 41.3 months on treatment. The median PFS for the 13 other patients with SD was 8.6 months (range, months), and all of these patients eventually progressed. Only 2 of the patients with PR developed PD on study treatment at 8.9 and 16.3 months, respectively. Seven patients with PR withdrew from the study, 3 because of toxicity and 4 by choice, after a median duration on study of 12.1 months (range, months). Post hoc analysis showed that patients in this cohort who received 2 prior regimens had improved outcomes compared with patients who had received 1 prior regimen Cancer August 15,

6 Figure 1. (A) Progression-free survival and (B) overall survival rates are shown for patients with platinum-resistant OC treated with weekly topotecan and biweekly bevacizumab, all patients (N ¼ 40). Table 3. Efficacy Outcomes Platinum Resistance a Parameter All Patients N540 1 Prior CT n521 2 Prior CT n519 Primary n528 Secondary n512 Best response No. (%) No. (%) No. (%) No. (%) No. (%) OR (all PR) 10 (25) 5 (23.8) 5 (26.3) 7 (25.0) 3 (25.0) SD 14 (27.5) 4 (19.0) 10 (52.6) 7 (25.0) 7 (58.3) PD 16 (47.5) 12 (57.1) 4 (21.1) 14 (50.0) 2 (16.7) Disease control (PR/SD) 24 (60.0) 9 (42.9) 15 (78.9) 14 (50.0) 10 (83.3) P.03 b.08 b Survival Mo (95% CI) Mo (95% CI) Mo (95% CI) Mo (95% CI) Mo (95% CI) Median PFS 7.8 ( ) 2.8 ( ) 10.9 ( ) 5.5 ( ) 9.4 ( ) P.08 c 0.33 c Median OS 16.6 ( ) 12.8 ( ) 22.9 ( ) 14.2 ( ) NR P.02 c.08 c CT indicates chemotherapy; CR, complete response; NR, not reached; OR, objective response; PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval; PFS, progression-free survival; OS, overall survival. a Primary platinum-resistance is defined as progression <6 months after first exposure to platinum; secondary platinum resistance is defined as progression >6 months after first exposure to platinum, then progression <6 months after re-treatment with platinum. b Exact Pearson chi-square test (post hoc analysis, PR/SD vs PD). c Log-rank test (post hoc analysis) Cancer August 15, 2011

7 Topotecan and Bevacizumab in Ovarian Cancer/McGonigle et al Figure 2. (A) Progression-free survival and (B) overall survival rates in patients with platinum-resistant OC treated with weekly topotecan and biweekly bevacizumab, by number of prior regimens (N ¼ 40). (see Table 3, Fig. 2A and 2B): PR/SD (disease control rate) was 78.9% versus 42.9% (P ¼.03);medianPFSwas 10.9monthsversus2.8months(P ¼.08);medianOSwas 22.9monthsversus12.8months(P ¼.02); and PFS at 6 months was 73.7% versus 38.1% (P ¼.08). Similar trends were observed with improved outcomes for patients with secondary platinum-resistant compared with primary platinum-resistant disease, but these differences were much less robust and not statistically significant (Table 3). There were no differences in clinical outcomes (PR or SD vs PD) in patients developing early hypertension compared with patients without this toxicity. DISCUSSION Weekly topotecan and biweekly bevacizumab in combination demonstrated acceptable toxicity along with considerable activity in patients with platinum-resistant OC. Similar to the results seen in studies of topotecan and bevacizumab as single agents, 6,14-17 the combination of these treatments showed a high proportion of long-term PR or SD: 4 of 40 (10%) patients remained on study treatment for longer than 21 months, and 9 of 40 (22.5%) remained on study treatment for longer than 12 months (data not shown). Although differences in patient populations and design confound the interpretation of between-study comparisons, the ORR of 25% and median PFS and OS of 7.8 months and 16.6 months, respectively, with combined topotecan and bevacizumab are similar to outcomes obtained in prospective studies of single-agent weekly topotecan, 15,17 single-agent bevacizumab, 7,8 and chemotherapy plus bevacizumab 9 in patient populations with generally lower proportions of platinum-resistant OC (Table 4). In particular, the results of a previous phase 2 study combining low-dose metronomic cyclophosphamide with bevacizumab in 70 patients with recurrent OC (ORR, 24%; median PFS, 7.2 months; median OS, 16.9 months) are remarkably similar to those reported here (see Cancer August 15,

8 Table 4. Efficacy Results of Selected Phase 2 Studies in Recurrent Ovarian Cancer Platinum-Resistant Patients Prior Regimens ORR Median TTP or PFS Median OS 6-Month PFS Treatment No. (%) No. % Mo. Mo. % Single-agent weekly topotecan (44.4) y 22.3 NR Single-agent weekly topotecan (0) y 21.2 NR Single-agent bevacizumab 7 62 (58.1) Single-agent bevacizumab 8 44 (100) Bevacizumabþmetronomic CTX 9 70 (40.0) Bevacizumabþweekly topotecan a 40 (100.0) ORR indicates objective response rate; TTP, time to progression; PFS, progression-free survival; OS, overall survival; CTX, cyclophosphamide; NR, not reported. a Current study. Table 4). 9 However, only 40% of the patients treated with cyclophosphamide and bevacizumab had platinumresistant disease compared with 100% in the current study. Outcomes were improved in patients with platinum-sensitive disease the median PFS was 7.9 versus 4.4 months, and median OS was 24.2 versus 11.4 months for platinum-sensitive and platinum-resistant disease, respectively (personal communication with A. Garcia; September, 2010). Thus, the results with topotecan and bevacizumab appear to be favorable when restricted to outcomes reported for patients with platinum-resistant disease. Our data also compare favorably with studies of chemotherapy in platinum-resistant OC, which generally demonstrate a median PFS in the 3-month to 5-month range, and median OS between 11 months and 14 months Preliminary results for bevacizumab combined with liposomal doxorubicin in recurrent OC have also been reported for 2 small phase 2 studies, 24,25 with ORRs of 13% (2 of 15) and 36% (8 of 22). Overall, the similarity of results across prospective single-arm studies suggests the need for randomized studies to delineate the relative benefits of chemotherapy, bevacizumab, and combination therapy in recurrent OC (see Table 4). In the current study, patients who received 2 prior regimens had improved outcomes compared with those who received only 1 prior regimen (see Table 3). To determine whether this benefit was related to the status of platinum resistance, another post hoc analysis was performed to compare outcomes between patients with primary platinum-resistant disease and those with secondary platinum-resistant disease. The benefit appeared to be only partly related to these characteristics, suggesting that a subset of patients with relatively indolent disease and primary platinum-resistance may gain benefit from combined topotecan and bevacizumab. The toxicity of this combination regimen generally reflected the known safety profiles of both agents. With the possible exception of hypertension, there was no evidence of synergistic toxicity. Consistent with the findings of previous studies of weekly topotecan, grade 2 thrombocytopenia, neutropenia, and anemia were common, whereas grade 3 and 4 hematologic toxicities were uncommon and generally manageable with dose delays or dose reductions. Although dose delays occurred frequently, topotecan dose reductions were required in only 4 patients, and only 3 patients discontinued study treatment as a result of toxicity. Excluding hypertension and proteinuria, the majority of grade 3 and 4 nonhematologic toxicities were assessed to be related to underlying disease rather than to treatment. The absence of gastrointestinal perforation in the current study together with the low rate of GI toxicity observed in the first-line phase 3 Gynecologic Oncology Group (GOG) 0218 trial (grade 3 GI perforation, hemorrhage, or fistula in 2.3% to 2.6% of bevacizumab-treated patients) 5 support the conclusion that heavily pretreated patients appear to be at a higher risk of gastrointestinal perforation while receiving bevacizumab Although effectively managed with supportive medication, the incidence (20%) of grade 3 hypertension observed with this combination regimen was higher than the 9% to 10% rate observed with single-agent bevacizumab in recurrent OC 7,8 ; however, it was similar to that (15.7%) reported for low-dose metronomic cyclophosphamide plus bevacizumab. 9 It has been suggested that higher rates of hypertension occur when cytotoxic agents with potential antiangiogenic activity are combined with bevacizumab. 30 A number of reports have also suggested a possible correlation between the development of hypertension and improved clinical outcome with bevacizumab 31,32 ; however, a rigorous analysis of data from phase 3738 Cancer August 15, 2011

9 Topotecan and Bevacizumab in Ovarian Cancer/McGonigle et al 3 trials in multiple solid tumors identified that early hypertension was not predictive of PFS or OS benefit with bevacizumab in most trials. 33 The significance of our observation that response did not differ according to the occurrence of hypertension is limited by the small number of patients under evaluation. In conclusion, the combination of weekly topotecan and biweekly bevacizumab provides very good efficacy with acceptable toxicity in patients with platinum-resistant OC, although randomized trials are needed to determine the relative clinical benefit of single-agent versus combined regimens in this treatment setting. Our results further suggest that patients who progress quickly on platinum therapy may not be the best candidates for this therapeutic combination and that patients whose disease is more indolent appear to gain substantial clinical benefit. Further investigation of this regimen in platinum-resistant OC is warranted. CONFLICT OF INTEREST DISCLOSURES Support for third-party writing and editorial assistance for this article was provided by Genentech. This investigator-initiated study was supported by Genentech and GlaxoSmithKline (NCT ). K. F. McGonigle has served in an advisory role to Genentech and GlaxoSmithKline and has received honoraria for speaking engagements from GlaxoSmithKline. H.G. Muntz has received honoraria for speaking engagements from GlaxoSmithKline. REFERENCES 1. Bookman MA. Developmental chemotherapy and management of recurrent ovarian cancer. J Clin Oncol. 2003;21: 149s-167s. 2. Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95:S161-S Modesitt SC, Jazaeri AA. Recurrent epithelial ovarian cancer: Pharmacotherapy and novel therapeutics. Expert Opin Pharmacother. 2007;8: Genentech. Avastin (bevacizumab) prescribing Information. South San Francisco, CA: Genentech; Burger RA, Brady MF, Bookman MA, et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study [abstract]. J Clin Oncol. 2010;28(15s): 946s. Abstract LBA1. 6. Perren T, Swart AM, Pfisterer J, et al. ICON7: A phase III randomised Gynaecologic Cancer InterGroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC) [abstract]. Ann Oncol. 2010;21(suppl 8):vii2-vii3. Abstract LBA4. 7. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2007;25: Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25: Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol. 2008;26: Aghajanian C, Sill MW, Darcy K, et al. A phase II evaluation of bevacizumab in the treatment of recurrent or persistent endometrial cancer: A Gynecologic Oncology Group (GOG) Study [abstract]. J Clin Oncol. 2009;27(18s):284s. Abstract Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: A Gynecologic Oncology Group Study. J Clin Oncol. 2009;27: GlaxoSmithKline. Hycamtin (topotecan hydrochloride) prescribing information. Research Triangle Park, NC: Glaxo SmithKline; Homesley HD, Hall DJ, Martin DA, et al. A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol. 2001;83: Bhoola SM, Coleman RL, Herzog T, et al. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer. Gynecol Oncol. 2004;95: Safra T, Menczer J, Bernstein R, et al. Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. Gynecol Oncol. 2007;105: Abushahin F, Singh DK, Lurain JR, Grendys EC, Rademaker AW, Schink JC. Weekly topotecan for recurrent platinum resistant ovarian cancer. Gynecol Oncol. 2008;108: Morris R, Alvarez RD, Andrews S, et al. Topotecan weekly bolus chemotherapy for relapsed platinum-sensitive ovarian and peritoneal cancers. Gynecol Oncol. 2008;109: Clements MK, Jones CB, Cumming M, Daoud SS. Antiangiogenic potential of camptothecin and topotecan. Cancer Chemother Pharmacol. 1999;44: O Leary JJ, Shapiro RL, Ren CJ, Chuang N, Cohen HW, Potmesil M. Antiangiogenic effects of camptothecin analogues 9- amino-20(s)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. Clin Cancer Res. 1999;5: Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol. 2003;21(10 suppl): 187s-193s. 21. Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25: O Byrne KJ, Bliss P, Graham JD, et al. A phase III study of Doxil/Caelyx versus paclitaxel in platinum-treated, taxanenaive relapsed ovarian cancer [abstract]. Proc Am Soc Clin Oncol. 2002;21:203a. Abstract Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: A randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19: Cancer August 15,

10 24. Verschraegen C, Muller C, Rutledge T, et al. Preliminary efficacy and safety of pegylated liposomal doxorubicin and bevacizumab in patients with platinum resistant or intolerant ovarian cancer: Initial results of a phase 2 trial. Presented at: International Gynecologic Cancer Society 12th Biennial Meeting, Bangkok, Thailand, October 25-28, Kikuchi Y Sr, Kouta H, Kikuchi R, et al. Effects of weekly bevacizumab and pegylated liposomal doxorubicin in heavily pretreated patients with recurrent or progressed ovarian cancer [abstract]. J Clin Oncol. 2009;27:15s. Abstract Richardson DL, Backes FJ, Hurt JD, et al. Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? Gynecol Oncol. 2010;118: Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: A meta-analysis. Lancet Oncol. 2009;10: Seamon LG, Richardson DL, Hurt JD, et al. Bevacizumab and weekly topotecan as salvage chemotherapy for ovarian cancer [abstract]. Gynecol Oncol. 2009;112:S57. Abstract Sfakianos GP, Numnum TM, Halverson CB, Panjeti D, Kendrick JE IV, Straughn JM Jr. The risk of gastrointestinal perforation and/or fistula in patients with recurrent ovarian cancer receiving bevacizumab compared to standard chemotherapy: A retrospective cohort study. Gynecol Oncol. 2009;114: Stone RL, Sood AK, Coleman RL. Collateral damage: toxic effects of targeted antiangiogenic therapies in ovarian cancer. Lancet Oncol. 2010;11: Bono P, Elfving H, Utriainen T, et al. Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann Oncol. 2009;20: Ryanne Wu R, Lindenberg PA, Slack R, Noone A, Marshall JL, He AR. Evaluation of hypertension as a marker of bevacizumab efficacy. J Gastrointest Cancer. 2009;40: Hurwitz H, Douglas PS, Middleton JP, et al. Analysis of early hypertension (HTN) and clinical outcome with bevacizumab (BV) [abstract]. J Clin Oncol. 2010;28(15s):242s. Abstract Cancer August 15, 2011