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Highlights from: The 44th Annual Meeting of the American Society of Clinical Oncology May 30-June 3, 2008; Chicago, IL
Meeting Highlights
Prepared by: Aarati Ranganathan, PhD; Marissa Shrader, PhD Reviewed by: J. Tate Thigpen, MD
Highlights from: The 44th Annual Meeting of the American Society of Clinical Oncology May 30-June 3, 2008; Chicago, IL
Results from a Phase II Trial of Pemetrexed in Persistent or Recurrent PlatinumResistant Ovarian or Primary Peritoneal Cancers Pemetrexed is a multitargeted antifolate that blocks folate-dependent enzymes involved in DNA synthesis1; its primary mechanism of action is the inhibition of thymidylate synthase, an enzyme that catalyzes the transformation of deoxyuridine monophosphate to deoxythymidine monophosphate. Early clinical data have demonstrated that antifolates have antitumor activity against a variety of tumor types,2 and pemetrexed is approved by the US Food and Drug Administration for the treatment of malignant pleural mesothelioma and non–smallcell lung cancer. During clinical development of pemetrexed, toxicities included bone marrow suppression, fatigue, diarrhea, mucositis, and rash.3 These side effects were often life threatening and occasionally lethal. After it was determined that increased baseline homocysteine and methylmalonic acid levels strongly correlated with these severe toxicities,4 all patients enrolled in clinical trials with antifolates have received folic acid and vitamin B12 supplementation. This intervention results in a clinically relevant reduction in the rate of severe and life-threatening toxicities from antifolates. In preclinical studies, ovarian cancer cell lines and sera from patients with ovarian cancer have shown high expression of the folate receptor compared with normal tissue,5,6 making ovarian cancer an attractive target for pemetrexed therapy.7 In early-phase trials, pemetrexed has been evaluated as a single agent and in combination with other cytotoxic agents such as gemcitabine and carboplatin in the treatment of recurrent/relapsed ovarian cancer.8-10 Miller and colleagues conducted a single-arm phase II trial of pemetrexed in persistent or recurrent platinum-resistant or -refractory ovarian or primary peritoneal can-
cers.11 The results of this trial were recently presented at the 2008 Annual Meeting of the American Society of Clinical Oncology held May 30 through June 3 in Chicago, IL, and are summarized herein. Patients whose disease had progressed on or within 6 months of therapy with 1 previous platinum-based chemotherapeutic regimen and had a Gynecologic Oncology Group (GOG) performance status (PS) of 0-2 were enrolled. Patients not treated with first-line paclitaxel who received second-line therapy with a paclitaxel-based regimen or patients who had received 1 additional noncytotoxic treatment regimen such as radiation therapy or biologic agents were eligible. The primary endpoint of the trial was antitumor activity of pemetrexed, and the secondary endpoint was safety. Of 51 patients enrolled, 48 received pemetrexed 900 mg/m2 intravenously on day 1 every 21 days until disease progression or unacceptable toxicity occurred. Pretreatment with dexamethasone as prophylaxis against rash and folic acid and vitamin B12 to reduce hematologic toxicities were given to all patients. Thirty patients had GOG PS 0, 15 had GOG PS 1, and 3 had GOG PS 2. A majority of the patients had serous histology (34 of 48 patients) and grade 3 disease (31 of 48 patients). Median platinum-free interval was 3 months. Nineteen patients received > 5 courses of pemetrexed therapy. Ten of 48 patients (21%) had responses (complete response, 1 patient [2%]; partial responses [PRs], 9 patients [19%]; Table 1). Median duration of response was 6.8 months. Disease stabilization for a median of 4.1 months was noted in an additional 17 patients (35%); of these, 1 patient remained on therapy at the time of analysis. Median progression-free survival (PFS) was 3+ months, and median overall survival (OS) was 11.4+ months. Grade 3/4 hematologic toxicities included leukopenia in 12 patients (25%), thrombocytopenia in 6 patients (12.5%), neutropenia in 20 patients
Table 1 Phase II Trial of Pemetrexed in Persistent or Recurrent PlatinumResistant Ovarian or Primary Peritoneal Cancers: Results Result (N = 48)
Pemetrexed 900 mg/m2
Efficacy CR, n (%)
1 (2)
PR, n (%)
9 (19)
ORR, %
21
Median DOR, months
6.8
SD, n (%)
17 (35)
Median duration of disease stabilization, months
4.1
Median PFS, months
3+
Median OS, months
11.4+
Grade 3/4 Adverse Events, n (%) Hematologic Neutropenia
20 (42)
Leukopenia
12 (25)
Thrombocytopenia
6 (12.5)
Anemia
7 (15)
Nonhematologic Constitutional
7 (15)
Infection
5 (10)
Neurologic
5 (10)
Abbreviations: CR = complete response; DOR = duration of response; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease
(42%), and anemia in 7 patients (15%). Most common grade 3/4 nonhematologic adverse events were constitutional (15%), infection (10%), and neurologic (10%). Clinical Relevance In this phase II trial of pemetrexed alone in women with previously treated platinum-refrac-
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Clinical Ovarian Cancer • December 2008
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Meeting Highlights tory or -resistant ovarian or primary peritoneal cancers, pemetrexed demonstrated encouraging antitumor activity with manageable hematologic toxicity. The efficacy and safety of different doses of pemetrexed (500 mg/m2 vs. 900 mg/m2) have also been assessed in pretreated patients.10 In a recent report of the results from the phase II trial randomizing patients with platinumresistant epithelial ovarian cancer to high-dose (n = 51) or low-dose (n = 51) pemetrexed, no significant difference in efficacy was noted between the treatment arms (overall response rate, 10% vs. 9%; median PFS, 2.8 months in both arms; median OS, 10.3 months vs. 11.9 months). As expected, overall toxicity was increased with high-dose pemetrexed; 6 deaths occurred in the high-dose arm (2 possibly related to treatment) and 1 in the low-dose arm, and serious adverse events were more frequent in the high-dose arm compared with the lowdose arm (14 patients [27.5%] vs. 8 patients [16%]). Based on the promising results of early-phase trials in epithelial ovarian cancer, further evaluation of pemetrexed, especially in combination with other agents, is warranted in different clinical settings. Phase III Trial Comparing Conventional-Dose Versus Dose-Dense Weekly Paclitaxel/Carboplatin in Advanced Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancers: JGOG 3016 The first-line standard of care for patients with advanced ovarian cancers includes platinum/taxane doublet chemotherapy administered every 3 weeks for a maximum of 6 cycles.12 Ovarian cancer is very chemosensitive; hence, increasing the total delivered dose of chemotherapy has the potential to enhance clinical benefit in patients with ovarian cancer.13 High-dose regimens of platinum agent–based chemotherapy have been investigated in several studies, including randomized phase III trials, but have not shown improvement in survival compared with conventional-dose regimens in advanced ovarian cancer.14 Administration of a dose-dense weekly paclitaxel combination regimen is another strategy that has been attempted to increase the total dose of chemotherapy delivered.15,16 Because the individual doses of paclitaxel are lower in this case versus the 3-weekly regimen, there is also a potential for reducing treatment-related toxicities with the strategy.15
92
Table 2 Results of JGOG 3016 Conventional Regimen
Dose-Dense Weekly Regimen
Efficacy
n = 319
n = 312
CR*
16%
Result
Hazard Ratio
P Value
20%
_
_ _
PR*
38%
36%
_
ORR*
53%
56%
_
SD*
31%
29%
.72 _
Median PFS, months
17.2
28
0.714
.0015
0.735
.0496
2-Year OS rate
_
78%
84%
Grade 3/4 AEs
n = 314
n = 312
Neutropenia
80%
92%
_
.15
Thrombocytopenia
38%
44%
_
.19 .0001
Anemia
44%
69%
_
Motor neuropathy
14%
12%
_
.55
23%
_
.20
Sensory neuropathy
27%
Conventional regimen: paclitaxel 180 mg/m2 and carboplatin area under the curve (AUC) 6 on day 1 every 21 days for 6-9 cycles. Dose-dense weekly regimen: paclitaxel 80 mg/m2 on days 1, 8, and 15 and carboplatin AUC 6 on day 1 every 21 days for 6-9 cycles. *N evaluable for response: conventional regimen, 135 patients; dose-dense weekly regimen, 147 patients. Abbreviations: AEs = adverse events; CR = complete response; JGOG = Japanese Gynecologic Oncology Group; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease
In early-phase single-arm trials with dosedense paclitaxel/carboplatin in pretreated advanced ovarian cancer, treatment was well tolerated and effective, with response rates (RRs) ranging from 48% to 88%.15-19 Median PFS ranged between 5 months and 21 months and median OS between 8 months and 43 months.15,17,18 A recent phase II trial reported the efficacy and safety of the dosedense weekly paclitaxel/carboplatin combination as initial therapy in elderly patients with advanced ovarian cancer.20 Of the 26 patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0/1 who received treatment, 13 were evaluable for response; 5 patients (38%) showed PRs. Median estimated PFS and OS were 13.6 months and 32 months, respectively. Dr. Isonishi and colleagues from the Japanese Gynecologic Oncology Group (JGOG) conducted a randomized phase III NOVEL trial (JGOG 3016) to compare the efficacy and safety of conventional-dose paclitaxel/carboplatin with a dose-dense weekly regimen in previously untreated women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers.21 A total of 637 patients with International Federation of Gynecology and Obstetrics (FIGO) stage II-IV disease and ECOG PS 0-3 were randomized to receive paClinical Ovarian Cancer • December 2008
clitaxel 180 mg/m2 and carboplatin area under the curve (AUC) 6 on day 1 (conventional regimen, n = 320) or paclitaxel 80 mg/m2 on days 1, 8, and 15 and carboplatin AUC 6 on day 1 (dose-dense weekly regimen, n = 317) every 21 days for 6 cycles. Responding patients received an additional 3 cycles of chemotherapy. Patients were stratified based on residual disease (≤ 1 cm vs. > 1 cm), FIGO stage (II vs. III vs. IV), and histology (clear-cell/mucinous vs. serous/others). Interval or secondary debulking surgery was allowed. The primary endpoint of the trial was PFS, and secondary endpoints included OS and toxicity. Baseline patient characteristics were well balanced between the treatment arms. Median age of all eligible patients (conventional regimen, n = 319; dose-dense weekly regimen, n = 312) was 57 years. Ninety percent of the patients in both arms had an ECOG PS of 0/1, 89% had undergone primary debulking surgery, and approximately 10% had undergone interval debulking. Stage II disease was noted in 17% and 20% of patients in the conventional-dose and dose-dense arms, respectively; stage III disease in 67% and 65%, respectively; and stage IV disease in 16% and 15%, respectively. Over half of the patients in both arms (conventional-dose, 55%; dose-dense weekly, 54%) had
Meeting Highlights Table 3 Randomized Phase II Trial Comparing Carboplatin-Based Chemotherapy with or Without Pertuzumab in Women with Relapsed Platinum-Sensitive Disease: Efficacy Efficacy Measure
Chemotherapy Chemotherapy + Pertuzumab Alone
HR/OR
P Value
Response Rate Overall confirmed
47 of 74 (63.5%)
39 of 75 (52%)
RECIST
40 of 74 (61%)
37 of 75 (59%)
CA 125
13 of 74 (24%)
7 of 75 (14%)
7.85 Months _
7.2 Months _
HER3 q 0.65; all evaluable patients, N = 59
_
_
HER3 < 0.65; patients with DFI 6-12 months, n = 27
_
_
HER3 q 0.65; patients with DFI 6-12 months, n = 22
_
_
HER3 < 0.65; patients with DFI > 12 months, n = 31
_
_
HER3 q 0.65; patients with DFI > 12 months, n = 37
_
_
1.61 80% CI, .1549 1.05-2.47 _ _ _
_
Median PFS Overall HER3 < 0.65; all evaluable patients, N = 58
1.00
.9799
0.813
.5086
1.377
.3295
0.554
.157
1.272
.6078
1.043
.9197
0.934
.8650
Abbreviations: CA = cancer antigen; DFI = disease-free interval; HR = hazard ratio; OR = odds ratio; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors
residual disease > 1 cm. Nearly 85% of patients in both arms had serous/other histologies. Median PFS was significantly improved in patients receiving dose-dense weekly paclitaxel/carboplatin (28 months vs. 17.2 months with conventional-dose paclitaxel/carboplatin, hazard ratio [HR], 0.714; P = .0015; Table 2). Moreover, the relative risk of disease progression was reduced with the dose-dense weekly regimen among all subgroups analyzed except in patients with clear-cell/mucinous histology. At the time of analysis, OS data were not mature; however, the 2-year OS rate was significantly higher in the dose-dense arm (84% vs. 78% in the conventional-dose arm, HR, 0.735; P = .0496). Among patients evaluable for clinical response, no significant difference in the overall RR was noted between the treatment arms (conventional dose, 53% of 135 patients vs. dose-dense weekly, 56% of 147 patients; P = .72). Complete responses were experienced in 16% and 20% of the patients receiving conventional and dose-dense regimens, respectively, and PRs in 38% and 36%, respectively. Additionally, 31% and 29% of the patients in the conventional and dose-dense arms, respectively, showed disease stabilization. Adverse events were assessed among all patients in the dose-dense arm and among 314 patients in the conventional-dose arm. More patients in
the dose-dense arm compared with the conventional dose arm discontinued protocol therapy because of adverse events (113 of 312 [36%] vs. 69 of 319 [22%]). Grade 3/4 hematologic toxicities, including neutropenia, thrombocytopenia, and anemia, were increased with dose-dense weekly paclitaxel/carboplatin compared with conventional-dose paclitaxel/carboplatin; grade 3/4 anemia was significantly higher (137 of 314 patients [44%] vs. 214 of 312 patients [69%]; P < .0001). The frequency of grade 3/4 neuropathy was similar in the treatment groups. Clinical Relevance The phase III JGOG 3016 trial evaluating conventional-dose paclitaxel/carboplatin versus dose-dense weekly paclitaxel/carboplatin in chemotherapy-naive women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers met its primary endpoint and significantly prolonged median PFS among patients receiving the dose-dense regimen (P = .0015). Benefit in PFS was observed among all subgroups analyzed except patients with clear-cell/mucinous histology. Although OS data are not yet mature, significant increase in the 2-year OS rate with the dose-dense regimen was noted (P = .0496). Hematologic toxicities were higher in the dose-dense weekly arm; however, the incidence of grade 3/4 neuropathy was not Clinical Ovarian Cancer • December 2008
increased. The administration of a dose-dense weekly paclitaxel/carboplatin regimen as firstline therapy in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancers should be considered in eligible patients. Randomized Phase II Trial Assessing the Addition of Pertuzumab to CarboplatinBased Second-Line Therapy in Platinum-Sensitive Women with Ovarian, Fallopian Tube, or Primary Peritoneal Cancers The HER family of tyrosine kinases (TKs) are aberrantly expressed in ovarian cancer and have been correlated with poor prognosis.22,23 The HER2/neu TK is the preferred dimerization partner for the other HER family members24; hence, it is an attractive target for receptor-directed antitumor therapy. The humanized monoclonal antibody (MoAb) pertuzumab binds to the HER2 dimerization domain and prevents its interaction with the other HERs, thereby blocking signaling through multiple HER-mediated pathways.25 Pertuzumab alone has been assessed in several early-phase trials in advanced cancers, including ovarian carcinoma.26,27 In a phase I study including 3 patients with ovarian cancer, 1 patient with platinum-resistant disease had a PR lasting 11 months. There was no HER2 amplification in this patient, and cancer antigen (CA) 125 level was unchanged from baseline.26 In a phase II trial, 5 of 117 patients (4%) had PRs, and 8 patients (7%) had disease stabilization for ≥ 6 months. Ten patients showed ≥ 50% decline in CA 125 levels from baseline. Median PFS was 1.5 months among all patients, 4.8 months among phosphorylated HER2 (pHER2)+ patients (8 of 28 evaluable), and 1.3 months among pHER2– patients (20 of 28). Median OS was 12.1 months, 17.2 months, and 8.5 months, respectively (pHER2+ vs. pHER2–; P = .365). Kaye and colleagues conducted a randomized phase II trial to compare the efficacy and safety of combining pertuzumab with secondline carboplatin-based doublet chemotherapy in patients with platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancers.28 Women with an ECOG PS of 0/1 who had relapsed ≥ 6 months from first-line platinum-based chemotherapy were randomized to receive carboplatin-based chemotherapy with (n = 74) or without (n = 75) pertuzumab 420 mg every 3 weeks (loading dose 820 mg) for a maximum of 52 cycles. Chemotherapy
93
Meeting Highlights consisted of carboplatin AUC 5 plus paclitaxel 175 mg/m2 on day 1 or carboplatin AUC 4 on day 1 plus gemcitabine 100 mg/m2 on days 1 and 8 every 3 weeks for a maximum of 6 cycles. The primary endpoint of the trial was PFS. Median age of patients in the chemotherapy plus pertuzumab arm was 59 years, and in the chemotherapy-alone arm, it was 54 years. The median disease-free interval (DFI) was 14.3 months and 13.5 months, respectively. Approximately 60% of the patients in both arms had DFI > 12 months. Overall confirmed responses were noted in 47 of 74 (63.5%) patients receiving chemotherapy plus pertuzumab and 39 of 75 (52%) patients receiving chemotherapy alone (odds ratio, 1.61; 80% CI, 1.05-2.47; P = .1549; Table 3). Response rate by Response Evaluation Criteria in Solid Tumors was 61% with and 59% without pertuzumab. CA 125 response was observed in 24% and 14% of patients, respectively. In the overall patient population, median PFS was similar between the treatment groups (7.85 months with pertuzumab vs. 7.2 months without pertuzumab, HR, 1.00; 80% CI, 0.78-1.28; P = .9799). Blocking signaling from the HER2-HER3 pathways is associated with increased expression of the HER3 mRNA. When median PFS was analyzed based on HER3 expression levels in this study, no significant differences in the median PFS were noted based on treatment among patients with low (< 0.65) or high (≥ 0.65) HER3 mRNA expressions (chemotherapy + pertuzumab vs. chemotherapy alone: low subgroup HR, 0.813; P = .5086; high subgroup HR, 1.377; P = .3295). However, among patients whose DFI was between 6 and 12 months, median PFS showed a nonsignificant trend toward improvement based on treatment in patients with low HER3 mRNA expression levels (chemotherapy + pertuzumab vs. chemotherapy alone: HR, 0.554; P = .157). Paclitaxel-based regimens were better tolerated than those with gemcitabine (≥ 1 grade 3/4 adverse event in ≤ 6 cycles of therapy: paclitaxel/carboplatin, 24 of 43 [56%]; paclitaxel/carboplatin + pertuzumab, 23 of 49 [49%] vs. gemcitabine/carboplatin, 28 of 31 [90%]; gemcitabine/carboplatin + pertuzumab, 24 of 28 [86%]). The addition of pertuzumab to either chemotherapy regimen did not increase the frequency of grade 3/4 adverse events occurring with ≤ 6 cycles of therapy. The most common grade 3/4 hematologic toxicities were neutropenia (30%, 15%, 71%,
94
and 64%, respectively) and thrombocytopenia (5%, 2%, 32%, and 18%, respectively). Febrile neutropenia occurred in 6% of the patients receiving gemcitabine/carboplatin, 2% receiving paclitaxel/carboplatin, and 5% receiving paclitaxel/carboplatin/pertuzumab. Grade 3/4 gastrointestinal adverse events occurring in ≤ 6 cycles of therapy were more frequent with the addition of pertuzumab to paclitaxel/carboplatin (diarrhea, 3 patients [6%] vs. 0 with paclitaxel/carboplatin; vomiting, nausea, intestinal obstruction, gastrointestinal hemorrhage, and paralytic ileus: 1 patient [2%] each vs. 0). Among gemcitabine-treated patients, grade 3/4 diarrhea was experienced by 1 patient receiving chemotherapy alone and 2 patients receiving chemotherapy plus pertuzumab, grade 3/4 nausea by 3 patients and 0, respectively, abdominal pain by 2 patients and 1 patient, respectively, vomiting by 2 patients in each arm, and intestinal obstruction by 1 patient in each arm. No clinically significant cardiac toxicity was observed. Clinical Relevance Pertuzumab was assessed in combination with carboplatin-based chemotherapy as second-line treatment for platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancers in a randomized phase II trial. The combinations were feasible and well tolerated. No significant clinical benefit was noted with the addition of pertuzumab to either paclitaxel/carboplatin or gemcitabine/carboplatin chemotherapy in this disease setting. Expression levels of the HER3 mRNA were analyzed, and their correlations with PFS overall and in subgroups of patients with different DFIs were determined. It remains to be seen whether specific molecular subsets of patients with ovarian cancer will benefit from pertuzumab therapy. A Phase II Study of SingleAgent Sorafenib in Patients with Persistent/Recurrent Epithelial Ovarian or Primary Peritoneal Cancer Ovarian cancer is the most clinically challenging of all the gynecologic malignancies, with > 15,000 deaths and 21,000 new diagnoses estimated in 2008.29 Despite high response rates to initial chemotherapy, most patients will relapse and eventually develop platinumresistant disease. Patients who relapse after a Clinical Ovarian Cancer • December 2008
Table 4 Phase II Study of Sorafenib in Patients with Persistent or Recurrent Epithelial Ovarian or Primary Peritoneal Cancer: Toxicity Grade 3/4 Adverse Event
Number of Patients (N = 71)
Leukopenia
1*
Neutropenia
1*
Metabolic
10
Dermatologic
14*
PPE
9*
Rash
7*
Gastrointestinal
3*
Cardiovascular
2
Pulmonary
2
*Grade
3 only. Abbreviation: PPE = palmar-plantar erythrodysesthesia
Table 5 Phase II Study of Sorafenib in Patients with Persistent or Recurrent Epithelial Ovarian or Primary Peritoneal Cancer: Efficacy Efficacy Measure OR
Number of Patients (N = 59) 2
CR
0
PR
2
SD
20
6-Month PFS
14
Abbreviations: CR = complete response; OR = overall response; PFS = progression-free survival; PR = partial response; SD = stable disease
platinum-free interval (PFI) of ≥ 6 months are considered platinum sensitive and can receive platinum-based therapy at relapse until development of platinum-resistant disease, defined as a PFI of < 6 months. Treatment options for patients with platinum-resistant disease are limited; RRs for patients with platinum-resistant ovarian cancer tend to be low, highlighting the need for improved therapeutic targets and strategies for these patients. Targeting the tumor microenvironment— and specifically the angiogenic cascade—is an effective approach for many solid tumors. The vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) axis is an especially
Meeting Highlights appealing target because of its central role in regulating tumor angiogenesis. Increased tumor angiogenesis, as measured by microvessel density, correlates with decreased survival for patients with ovarian cancer.30-32 Sorafenib is a multitargeted TK inhibitor (TKI) that blocks the activity of Raf, VEGFR, platelet-derived growth factor receptor, Flt-3, and c-Kit. An open-label, multi-institutional phase II trial conducted by the GOG evaluated single-agent sorafenib in patients with persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer.33 Results from this trial were presented by Matei and colleagues at the 44th Annual Meeting of the American Society of Clinical Oncology. Patients were eligible for the trial if they had measurable disease, defined as ≥ 1 target lesion, or CA 125 level > twice the upper limit of normal, peritoneal ascites, pleural effusion, or a nontarget lesion. Patients were permitted to have 1 previous platinum-based regimen with a PFI < 12 months and 1 additional cytotoxic regimen. Patients were required to have a GOG PS of 0-2. Patients receiving oral anticoagulant therapy or with central nervous system metastases or chronic system disease were excluded. Treatment consisted of sorafenib 400 mg taken orally twice daily. Primary study endpoints included 6-month PFS and toxicity. Secondary endpoints included response rate, PFS, OS, and the relationship between prognostic variables and outcome. Biologic endpoints were also included in the evaluation. Assessments included phosphorylated Erk pre- and posttreatment, immunohistochemistry for Raf, Mek, and Erk, and B-Raf mutations in primary tumors. Seventy-three patients were enrolled; median patient age was 61 years (range, 33-80 years). Most patients had a PS of 0 (80%), were platinum resistant (70%), and had received 1 previous cytotoxic regimen (56%). Seventy-one patients were evaluable for toxicity. The most common grade 3/4 hematologic adverse events were leukopenia and neutropenia in 1 patient each (both grade 3 only; Table 4). The most common grade 3/4 nonhematologic adverse events were metabolic abnormalities (n = 10), palmar-plantar erythrodysesthesia (n = 9), rash (n = 7), and gastrointestinal toxicity (n = 3). Fifty-nine patients were assessable for response; 2 patients had a PR, and 20 patients had stable disease (Table 5). The 6-month PFS rate was 24%.
Clinical Relevance Many targeted agents have been evaluated for patients with advanced ovarian cancer; antiangiogenic strategies have demonstrated the most clinical activity to date. The activity of single-agent anti-VEGF MoAb in ovarian cancer has been surprising given the limited single-agent activity observed in most other solid tumors. This has led to the clinical development of antiangiogenic TKIs such as sorafenib for patients with ovarian cancer. Early results from this trial of single-agent sorafenib indicate that it is tolerable and active in patients with ovarian cancer; continued evaluation in randomized clinical trials will further elucidate the role of this agent in the management of ovarian cancer. Furthermore, studies indicate that the addition of chemotherapy builds upon the single-agent efficacy observed with antiangiogenic agents and that this may prove to be another viable management strategy. References 1. Shih C, Chen VJ, Gossett LS, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 1997; 57:1116-23. 2. Solomon B, Bunn PA, Jr. Clinical activity of pemetrexed: a multitargeted antifolate anticancer agent. Future Oncol 2005; 1:733-46. 3. Rinaldi DA, Kuhn JG, Burris HA, et al. A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 1999; 44:372-80. 4. Niyikiza C, Baker SD, Seitz DE, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002; 1:545-52. 5. Mantovani LT, Miotti S, Menard S, et al. Folate binding protein distribution in normal tissues and biological fluids from ovarian carcinoma patients as detected by the monoclonal antibodies MOv18 and MOv19. Eur J Cancer 1994; 30A:363-9. 6. Miotti S, Canevari S, Menard S, et al. Characterization of human ovarian carcinoma-associated antigens defined by novel monoclonal antibodies with tumorrestricted specificity. Int J Cancer 1987; 39:297-303. 7. Jackman AL, Theti DS, Gibbs DD. Antifolates targeted specifically to the folate receptor. Adv Drug Deliv Rev 2004; 56:1111-25. 8. Hensley ML, Derosa F, Gerst SR, et al. A phase I study of pemetrexed (P) plus gemcitabine (G) in relapsed ovarian cancer (OC): Dosing results and evidence of activity. J Clin Oncol 2006; 24:276s (Abstract 5083). 9. Horowitz NS, Penson RT, Campos SM, et al. Combination carboplatin and pemetrexed for the treatment of platinum-sensitive recurrent ovarian cancer. J Clin Oncol 2008; 26:298s (Abstract 5523). 10. Vergote I. A randomized phase II Study of standard-versus high-dose pemetrexed in platinum-resistant epithelial ovarian cancer. Presented at: 39th Annual Meeting on Women’s Cancer organized by the Society of Gynecologic Oncologists; March 9-12, 2008; Tampa, FL. Abstract 256. 11. Miller DS, Blessing JA, Krasner CN, et al. A phase II evaluation of pemetrexed (LY231514, IND #40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: A study of the gynecologic oncology group. J Clin Oncol 2008; 26:298s (Abstract 5524). 12. Thigpen T. First-line therapy for ovarian carcinoma:
Clinical Ovarian Cancer • December 2008
what’s next? Cancer Invest 2004; 22(suppl 2):21-8. 13. Muggia FM. Relevance of chemotherapy dose and schedule to outcomes in ovarian cancer. Semin Oncol 2004; 31(6 suppl 15):19-24. 14. Ozols RF. Ovarian Cancer: Is dose intensity dead? J Clin Oncol 2007; 25:4157-8. 15. Thomas H, Rosenberg P. Role of weekly paclitaxel in the treatment of advanced ovarian cancer. Crit Rev Oncol Hematol 2002; 44(suppl):S43-51. 16. van der Burg ME, van der Gaast A, Vergote I, et al. What is the role of dose-dense therapy? Int J Gynecol Cancer 2005; 15(suppl 3):233-40. 17. Cadron I, Leunen K, Amant F, et al. The “Leuven” dosedense paclitaxel/carboplatin regimen in patients with recurrent ovarian cancer. Gynecol Oncol 2007; 106:354-61. 18. Sehouli J, Stengel D, Mustea A, et al. Weekly paclitaxel and carboplatin (PC-W) for patients with primary advanced ovarian cancer: results of a multicenter phase-II study of the NOGGO. Cancer Chemother Pharmacol 2008; 61:243-50. 19. Watanabe Y, Nakai H, Ueda H, et al. Evaluation of weekly low-dose paclitaxel and carboplatin treatment for patients with platinum-sensitive relapsed ovarian cancer. Gynecol Oncol 2005; 96:323-9. 20. Pignata S, Breda E, Scambia G, et al. A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian Trial in Ovarian cancer (MITO-5) study. Crit Rev Oncol Hematol 2008; 66:229-36. 21. Isonishi S, Yasuda M, Takahashi F, et al. Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology. J Clin Oncol 2008; 26(20 suppl):294s (Abstract 5506). 22. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244:707-12. 23. Steffensen KD, Waldstrom M, Andersen RF, et al. Protein levels and gene expressions of the epidermal growth factor receptors, HER1, HER2, HER3 and HER4 in benign and malignant ovarian tumors. Int J Oncol 2008; 33:195-204. 24. 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 1996; 16:5276-87. 25. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5:317-28. 26. Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel HER2 dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005; 23:2534-43. 27. Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 2006; 24:4324-32. 28. Kaye SB, Poole CJ, Bidzinksi M, et al. A randomised phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab (P) versus carboplatin-based therapy alone in patients with relapsed, platinum sensitive ovarian cancer. J Clin Oncol 2008; 26(15 suppl):297s (Abstract 5520). 29. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin 2008; 58:71-96. 30. Abulafia O, Triest WE, Sherer DM. Angiogenesis in primary and metastatic epithelial ovarian carcinoma. Am J Obstet Gynecol 1997; 177:541-7. 31. Alvarez AA, Krigman HR, Whitaker RS, et al. The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res 1999; 5:587-91. 32. Hollingsworth HC, Kohn EC, Steinberg SM, et al. Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 1995; 147:33-41. 33. Matei D, Sill MW, DeGeest K, et al. Phase II trial of sorafenib in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study. J Clin Oncol 2008; 26(suppl):301s (Abstract 5537).
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Prepared by: Aarati Ranganathan, PhD; Marissa Shrader, PhD Reviewed by: J. Tate Thigpen, MD
Highlights from: The 44th Annual Meeting of the American Society of Clinical Oncology May 30-June 3, 2008; Chicago, IL
Results from a Phase II Trial of Pemetrexed in Persistent or Recurrent PlatinumResistant Ovarian or Primary Peritoneal Cancers Pemetrexed is a multitargeted antifolate that blocks folate-dependent enzymes involved in DNA synthesis1; its primary mechanism of action is the inhibition of thymidylate synthase, an enzyme that catalyzes the transformation of deoxyuridine monophosphate to deoxythymidine monophosphate. Early clinical data have demonstrated that antifolates have antitumor activity against a variety of tumor types,2 and pemetrexed is approved by the US Food and Drug Administration for the treatment of malignant pleural mesothelioma and non–smallcell lung cancer. During clinical development of pemetrexed, toxicities included bone marrow suppression, fatigue, diarrhea, mucositis, and rash.3 These side effects were often life threatening and occasionally lethal. After it was determined that increased baseline homocysteine and methylmalonic acid levels strongly correlated with these severe toxicities,4 all patients enrolled in clinical trials with antifolates have received folic acid and vitamin B12 supplementation. This intervention results in a clinically relevant reduction in the rate of severe and life-threatening toxicities from antifolates. In preclinical studies, ovarian cancer cell lines and sera from patients with ovarian cancer have shown high expression of the folate receptor compared with normal tissue,5,6 making ovarian cancer an attractive target for pemetrexed therapy.7 In early-phase trials, pemetrexed has been evaluated as a single agent and in combination with other cytotoxic agents such as gemcitabine and carboplatin in the treatment of recurrent/relapsed ovarian cancer.8-10 Miller and colleagues conducted a single-arm phase II trial of pemetrexed in persistent or recurrent platinum-resistant or -refractory ovarian or primary peritoneal can-
cers.11 The results of this trial were recently presented at the 2008 Annual Meeting of the American Society of Clinical Oncology held May 30 through June 3 in Chicago, IL, and are summarized herein. Patients whose disease had progressed on or within 6 months of therapy with 1 previous platinum-based chemotherapeutic regimen and had a Gynecologic Oncology Group (GOG) performance status (PS) of 0-2 were enrolled. Patients not treated with first-line paclitaxel who received second-line therapy with a paclitaxel-based regimen or patients who had received 1 additional noncytotoxic treatment regimen such as radiation therapy or biologic agents were eligible. The primary endpoint of the trial was antitumor activity of pemetrexed, and the secondary endpoint was safety. Of 51 patients enrolled, 48 received pemetrexed 900 mg/m2 intravenously on day 1 every 21 days until disease progression or unacceptable toxicity occurred. Pretreatment with dexamethasone as prophylaxis against rash and folic acid and vitamin B12 to reduce hematologic toxicities were given to all patients. Thirty patients had GOG PS 0, 15 had GOG PS 1, and 3 had GOG PS 2. A majority of the patients had serous histology (34 of 48 patients) and grade 3 disease (31 of 48 patients). Median platinum-free interval was 3 months. Nineteen patients received > 5 courses of pemetrexed therapy. Ten of 48 patients (21%) had responses (complete response, 1 patient [2%]; partial responses [PRs], 9 patients [19%]; Table 1). Median duration of response was 6.8 months. Disease stabilization for a median of 4.1 months was noted in an additional 17 patients (35%); of these, 1 patient remained on therapy at the time of analysis. Median progression-free survival (PFS) was 3+ months, and median overall survival (OS) was 11.4+ months. Grade 3/4 hematologic toxicities included leukopenia in 12 patients (25%), thrombocytopenia in 6 patients (12.5%), neutropenia in 20 patients
Table 1 Phase II Trial of Pemetrexed in Persistent or Recurrent PlatinumResistant Ovarian or Primary Peritoneal Cancers: Results Result (N = 48)
Pemetrexed 900 mg/m2
Efficacy CR, n (%)
1 (2)
PR, n (%)
9 (19)
ORR, %
21
Median DOR, months
6.8
SD, n (%)
17 (35)
Median duration of disease stabilization, months
4.1
Median PFS, months
3+
Median OS, months
11.4+
Grade 3/4 Adverse Events, n (%) Hematologic Neutropenia
20 (42)
Leukopenia
12 (25)
Thrombocytopenia
6 (12.5)
Anemia
7 (15)
Nonhematologic Constitutional
7 (15)
Infection
5 (10)
Neurologic
5 (10)
Abbreviations: CR = complete response; DOR = duration of response; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease
(42%), and anemia in 7 patients (15%). Most common grade 3/4 nonhematologic adverse events were constitutional (15%), infection (10%), and neurologic (10%). Clinical Relevance In this phase II trial of pemetrexed alone in women with previously treated platinum-refrac-
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Clinical Ovarian Cancer • December 2008
91
Meeting Highlights tory or -resistant ovarian or primary peritoneal cancers, pemetrexed demonstrated encouraging antitumor activity with manageable hematologic toxicity. The efficacy and safety of different doses of pemetrexed (500 mg/m2 vs. 900 mg/m2) have also been assessed in pretreated patients.10 In a recent report of the results from the phase II trial randomizing patients with platinumresistant epithelial ovarian cancer to high-dose (n = 51) or low-dose (n = 51) pemetrexed, no significant difference in efficacy was noted between the treatment arms (overall response rate, 10% vs. 9%; median PFS, 2.8 months in both arms; median OS, 10.3 months vs. 11.9 months). As expected, overall toxicity was increased with high-dose pemetrexed; 6 deaths occurred in the high-dose arm (2 possibly related to treatment) and 1 in the low-dose arm, and serious adverse events were more frequent in the high-dose arm compared with the lowdose arm (14 patients [27.5%] vs. 8 patients [16%]). Based on the promising results of early-phase trials in epithelial ovarian cancer, further evaluation of pemetrexed, especially in combination with other agents, is warranted in different clinical settings. Phase III Trial Comparing Conventional-Dose Versus Dose-Dense Weekly Paclitaxel/Carboplatin in Advanced Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancers: JGOG 3016 The first-line standard of care for patients with advanced ovarian cancers includes platinum/taxane doublet chemotherapy administered every 3 weeks for a maximum of 6 cycles.12 Ovarian cancer is very chemosensitive; hence, increasing the total delivered dose of chemotherapy has the potential to enhance clinical benefit in patients with ovarian cancer.13 High-dose regimens of platinum agent–based chemotherapy have been investigated in several studies, including randomized phase III trials, but have not shown improvement in survival compared with conventional-dose regimens in advanced ovarian cancer.14 Administration of a dose-dense weekly paclitaxel combination regimen is another strategy that has been attempted to increase the total dose of chemotherapy delivered.15,16 Because the individual doses of paclitaxel are lower in this case versus the 3-weekly regimen, there is also a potential for reducing treatment-related toxicities with the strategy.15
92
Table 2 Results of JGOG 3016 Conventional Regimen
Dose-Dense Weekly Regimen
Efficacy
n = 319
n = 312
CR*
16%
Result
Hazard Ratio
P Value
20%
_
_ _
PR*
38%
36%
_
ORR*
53%
56%
_
SD*
31%
29%
.72 _
Median PFS, months
17.2
28
0.714
.0015
0.735
.0496
2-Year OS rate
_
78%
84%
Grade 3/4 AEs
n = 314
n = 312
Neutropenia
80%
92%
_
.15
Thrombocytopenia
38%
44%
_
.19 .0001
Anemia
44%
69%
_
Motor neuropathy
14%
12%
_
.55
23%
_
.20
Sensory neuropathy
27%
Conventional regimen: paclitaxel 180 mg/m2 and carboplatin area under the curve (AUC) 6 on day 1 every 21 days for 6-9 cycles. Dose-dense weekly regimen: paclitaxel 80 mg/m2 on days 1, 8, and 15 and carboplatin AUC 6 on day 1 every 21 days for 6-9 cycles. *N evaluable for response: conventional regimen, 135 patients; dose-dense weekly regimen, 147 patients. Abbreviations: AEs = adverse events; CR = complete response; JGOG = Japanese Gynecologic Oncology Group; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease
In early-phase single-arm trials with dosedense paclitaxel/carboplatin in pretreated advanced ovarian cancer, treatment was well tolerated and effective, with response rates (RRs) ranging from 48% to 88%.15-19 Median PFS ranged between 5 months and 21 months and median OS between 8 months and 43 months.15,17,18 A recent phase II trial reported the efficacy and safety of the dosedense weekly paclitaxel/carboplatin combination as initial therapy in elderly patients with advanced ovarian cancer.20 Of the 26 patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0/1 who received treatment, 13 were evaluable for response; 5 patients (38%) showed PRs. Median estimated PFS and OS were 13.6 months and 32 months, respectively. Dr. Isonishi and colleagues from the Japanese Gynecologic Oncology Group (JGOG) conducted a randomized phase III NOVEL trial (JGOG 3016) to compare the efficacy and safety of conventional-dose paclitaxel/carboplatin with a dose-dense weekly regimen in previously untreated women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers.21 A total of 637 patients with International Federation of Gynecology and Obstetrics (FIGO) stage II-IV disease and ECOG PS 0-3 were randomized to receive paClinical Ovarian Cancer • December 2008
clitaxel 180 mg/m2 and carboplatin area under the curve (AUC) 6 on day 1 (conventional regimen, n = 320) or paclitaxel 80 mg/m2 on days 1, 8, and 15 and carboplatin AUC 6 on day 1 (dose-dense weekly regimen, n = 317) every 21 days for 6 cycles. Responding patients received an additional 3 cycles of chemotherapy. Patients were stratified based on residual disease (≤ 1 cm vs. > 1 cm), FIGO stage (II vs. III vs. IV), and histology (clear-cell/mucinous vs. serous/others). Interval or secondary debulking surgery was allowed. The primary endpoint of the trial was PFS, and secondary endpoints included OS and toxicity. Baseline patient characteristics were well balanced between the treatment arms. Median age of all eligible patients (conventional regimen, n = 319; dose-dense weekly regimen, n = 312) was 57 years. Ninety percent of the patients in both arms had an ECOG PS of 0/1, 89% had undergone primary debulking surgery, and approximately 10% had undergone interval debulking. Stage II disease was noted in 17% and 20% of patients in the conventional-dose and dose-dense arms, respectively; stage III disease in 67% and 65%, respectively; and stage IV disease in 16% and 15%, respectively. Over half of the patients in both arms (conventional-dose, 55%; dose-dense weekly, 54%) had
Meeting Highlights Table 3 Randomized Phase II Trial Comparing Carboplatin-Based Chemotherapy with or Without Pertuzumab in Women with Relapsed Platinum-Sensitive Disease: Efficacy Efficacy Measure
Chemotherapy Chemotherapy + Pertuzumab Alone
HR/OR
P Value
Response Rate Overall confirmed
47 of 74 (63.5%)
39 of 75 (52%)
RECIST
40 of 74 (61%)
37 of 75 (59%)
CA 125
13 of 74 (24%)
7 of 75 (14%)
7.85 Months _
7.2 Months _
HER3 q 0.65; all evaluable patients, N = 59
_
_
HER3 < 0.65; patients with DFI 6-12 months, n = 27
_
_
HER3 q 0.65; patients with DFI 6-12 months, n = 22
_
_
HER3 < 0.65; patients with DFI > 12 months, n = 31
_
_
HER3 q 0.65; patients with DFI > 12 months, n = 37
_
_
1.61 80% CI, .1549 1.05-2.47 _ _ _
_
Median PFS Overall HER3 < 0.65; all evaluable patients, N = 58
1.00
.9799
0.813
.5086
1.377
.3295
0.554
.157
1.272
.6078
1.043
.9197
0.934
.8650
Abbreviations: CA = cancer antigen; DFI = disease-free interval; HR = hazard ratio; OR = odds ratio; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors
residual disease > 1 cm. Nearly 85% of patients in both arms had serous/other histologies. Median PFS was significantly improved in patients receiving dose-dense weekly paclitaxel/carboplatin (28 months vs. 17.2 months with conventional-dose paclitaxel/carboplatin, hazard ratio [HR], 0.714; P = .0015; Table 2). Moreover, the relative risk of disease progression was reduced with the dose-dense weekly regimen among all subgroups analyzed except in patients with clear-cell/mucinous histology. At the time of analysis, OS data were not mature; however, the 2-year OS rate was significantly higher in the dose-dense arm (84% vs. 78% in the conventional-dose arm, HR, 0.735; P = .0496). Among patients evaluable for clinical response, no significant difference in the overall RR was noted between the treatment arms (conventional dose, 53% of 135 patients vs. dose-dense weekly, 56% of 147 patients; P = .72). Complete responses were experienced in 16% and 20% of the patients receiving conventional and dose-dense regimens, respectively, and PRs in 38% and 36%, respectively. Additionally, 31% and 29% of the patients in the conventional and dose-dense arms, respectively, showed disease stabilization. Adverse events were assessed among all patients in the dose-dense arm and among 314 patients in the conventional-dose arm. More patients in
the dose-dense arm compared with the conventional dose arm discontinued protocol therapy because of adverse events (113 of 312 [36%] vs. 69 of 319 [22%]). Grade 3/4 hematologic toxicities, including neutropenia, thrombocytopenia, and anemia, were increased with dose-dense weekly paclitaxel/carboplatin compared with conventional-dose paclitaxel/carboplatin; grade 3/4 anemia was significantly higher (137 of 314 patients [44%] vs. 214 of 312 patients [69%]; P < .0001). The frequency of grade 3/4 neuropathy was similar in the treatment groups. Clinical Relevance The phase III JGOG 3016 trial evaluating conventional-dose paclitaxel/carboplatin versus dose-dense weekly paclitaxel/carboplatin in chemotherapy-naive women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers met its primary endpoint and significantly prolonged median PFS among patients receiving the dose-dense regimen (P = .0015). Benefit in PFS was observed among all subgroups analyzed except patients with clear-cell/mucinous histology. Although OS data are not yet mature, significant increase in the 2-year OS rate with the dose-dense regimen was noted (P = .0496). Hematologic toxicities were higher in the dose-dense weekly arm; however, the incidence of grade 3/4 neuropathy was not Clinical Ovarian Cancer • December 2008
increased. The administration of a dose-dense weekly paclitaxel/carboplatin regimen as firstline therapy in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancers should be considered in eligible patients. Randomized Phase II Trial Assessing the Addition of Pertuzumab to CarboplatinBased Second-Line Therapy in Platinum-Sensitive Women with Ovarian, Fallopian Tube, or Primary Peritoneal Cancers The HER family of tyrosine kinases (TKs) are aberrantly expressed in ovarian cancer and have been correlated with poor prognosis.22,23 The HER2/neu TK is the preferred dimerization partner for the other HER family members24; hence, it is an attractive target for receptor-directed antitumor therapy. The humanized monoclonal antibody (MoAb) pertuzumab binds to the HER2 dimerization domain and prevents its interaction with the other HERs, thereby blocking signaling through multiple HER-mediated pathways.25 Pertuzumab alone has been assessed in several early-phase trials in advanced cancers, including ovarian carcinoma.26,27 In a phase I study including 3 patients with ovarian cancer, 1 patient with platinum-resistant disease had a PR lasting 11 months. There was no HER2 amplification in this patient, and cancer antigen (CA) 125 level was unchanged from baseline.26 In a phase II trial, 5 of 117 patients (4%) had PRs, and 8 patients (7%) had disease stabilization for ≥ 6 months. Ten patients showed ≥ 50% decline in CA 125 levels from baseline. Median PFS was 1.5 months among all patients, 4.8 months among phosphorylated HER2 (pHER2)+ patients (8 of 28 evaluable), and 1.3 months among pHER2– patients (20 of 28). Median OS was 12.1 months, 17.2 months, and 8.5 months, respectively (pHER2+ vs. pHER2–; P = .365). Kaye and colleagues conducted a randomized phase II trial to compare the efficacy and safety of combining pertuzumab with secondline carboplatin-based doublet chemotherapy in patients with platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancers.28 Women with an ECOG PS of 0/1 who had relapsed ≥ 6 months from first-line platinum-based chemotherapy were randomized to receive carboplatin-based chemotherapy with (n = 74) or without (n = 75) pertuzumab 420 mg every 3 weeks (loading dose 820 mg) for a maximum of 52 cycles. Chemotherapy
93
Meeting Highlights consisted of carboplatin AUC 5 plus paclitaxel 175 mg/m2 on day 1 or carboplatin AUC 4 on day 1 plus gemcitabine 100 mg/m2 on days 1 and 8 every 3 weeks for a maximum of 6 cycles. The primary endpoint of the trial was PFS. Median age of patients in the chemotherapy plus pertuzumab arm was 59 years, and in the chemotherapy-alone arm, it was 54 years. The median disease-free interval (DFI) was 14.3 months and 13.5 months, respectively. Approximately 60% of the patients in both arms had DFI > 12 months. Overall confirmed responses were noted in 47 of 74 (63.5%) patients receiving chemotherapy plus pertuzumab and 39 of 75 (52%) patients receiving chemotherapy alone (odds ratio, 1.61; 80% CI, 1.05-2.47; P = .1549; Table 3). Response rate by Response Evaluation Criteria in Solid Tumors was 61% with and 59% without pertuzumab. CA 125 response was observed in 24% and 14% of patients, respectively. In the overall patient population, median PFS was similar between the treatment groups (7.85 months with pertuzumab vs. 7.2 months without pertuzumab, HR, 1.00; 80% CI, 0.78-1.28; P = .9799). Blocking signaling from the HER2-HER3 pathways is associated with increased expression of the HER3 mRNA. When median PFS was analyzed based on HER3 expression levels in this study, no significant differences in the median PFS were noted based on treatment among patients with low (< 0.65) or high (≥ 0.65) HER3 mRNA expressions (chemotherapy + pertuzumab vs. chemotherapy alone: low subgroup HR, 0.813; P = .5086; high subgroup HR, 1.377; P = .3295). However, among patients whose DFI was between 6 and 12 months, median PFS showed a nonsignificant trend toward improvement based on treatment in patients with low HER3 mRNA expression levels (chemotherapy + pertuzumab vs. chemotherapy alone: HR, 0.554; P = .157). Paclitaxel-based regimens were better tolerated than those with gemcitabine (≥ 1 grade 3/4 adverse event in ≤ 6 cycles of therapy: paclitaxel/carboplatin, 24 of 43 [56%]; paclitaxel/carboplatin + pertuzumab, 23 of 49 [49%] vs. gemcitabine/carboplatin, 28 of 31 [90%]; gemcitabine/carboplatin + pertuzumab, 24 of 28 [86%]). The addition of pertuzumab to either chemotherapy regimen did not increase the frequency of grade 3/4 adverse events occurring with ≤ 6 cycles of therapy. The most common grade 3/4 hematologic toxicities were neutropenia (30%, 15%, 71%,
94
and 64%, respectively) and thrombocytopenia (5%, 2%, 32%, and 18%, respectively). Febrile neutropenia occurred in 6% of the patients receiving gemcitabine/carboplatin, 2% receiving paclitaxel/carboplatin, and 5% receiving paclitaxel/carboplatin/pertuzumab. Grade 3/4 gastrointestinal adverse events occurring in ≤ 6 cycles of therapy were more frequent with the addition of pertuzumab to paclitaxel/carboplatin (diarrhea, 3 patients [6%] vs. 0 with paclitaxel/carboplatin; vomiting, nausea, intestinal obstruction, gastrointestinal hemorrhage, and paralytic ileus: 1 patient [2%] each vs. 0). Among gemcitabine-treated patients, grade 3/4 diarrhea was experienced by 1 patient receiving chemotherapy alone and 2 patients receiving chemotherapy plus pertuzumab, grade 3/4 nausea by 3 patients and 0, respectively, abdominal pain by 2 patients and 1 patient, respectively, vomiting by 2 patients in each arm, and intestinal obstruction by 1 patient in each arm. No clinically significant cardiac toxicity was observed. Clinical Relevance Pertuzumab was assessed in combination with carboplatin-based chemotherapy as second-line treatment for platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancers in a randomized phase II trial. The combinations were feasible and well tolerated. No significant clinical benefit was noted with the addition of pertuzumab to either paclitaxel/carboplatin or gemcitabine/carboplatin chemotherapy in this disease setting. Expression levels of the HER3 mRNA were analyzed, and their correlations with PFS overall and in subgroups of patients with different DFIs were determined. It remains to be seen whether specific molecular subsets of patients with ovarian cancer will benefit from pertuzumab therapy. A Phase II Study of SingleAgent Sorafenib in Patients with Persistent/Recurrent Epithelial Ovarian or Primary Peritoneal Cancer Ovarian cancer is the most clinically challenging of all the gynecologic malignancies, with > 15,000 deaths and 21,000 new diagnoses estimated in 2008.29 Despite high response rates to initial chemotherapy, most patients will relapse and eventually develop platinumresistant disease. Patients who relapse after a Clinical Ovarian Cancer • December 2008
Table 4 Phase II Study of Sorafenib in Patients with Persistent or Recurrent Epithelial Ovarian or Primary Peritoneal Cancer: Toxicity Grade 3/4 Adverse Event
Number of Patients (N = 71)
Leukopenia
1*
Neutropenia
1*
Metabolic
10
Dermatologic
14*
PPE
9*
Rash
7*
Gastrointestinal
3*
Cardiovascular
2
Pulmonary
2
*Grade
3 only. Abbreviation: PPE = palmar-plantar erythrodysesthesia
Table 5 Phase II Study of Sorafenib in Patients with Persistent or Recurrent Epithelial Ovarian or Primary Peritoneal Cancer: Efficacy Efficacy Measure OR
Number of Patients (N = 59) 2
CR
0
PR
2
SD
20
6-Month PFS
14
Abbreviations: CR = complete response; OR = overall response; PFS = progression-free survival; PR = partial response; SD = stable disease
platinum-free interval (PFI) of ≥ 6 months are considered platinum sensitive and can receive platinum-based therapy at relapse until development of platinum-resistant disease, defined as a PFI of < 6 months. Treatment options for patients with platinum-resistant disease are limited; RRs for patients with platinum-resistant ovarian cancer tend to be low, highlighting the need for improved therapeutic targets and strategies for these patients. Targeting the tumor microenvironment— and specifically the angiogenic cascade—is an effective approach for many solid tumors. The vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) axis is an especially
Meeting Highlights appealing target because of its central role in regulating tumor angiogenesis. Increased tumor angiogenesis, as measured by microvessel density, correlates with decreased survival for patients with ovarian cancer.30-32 Sorafenib is a multitargeted TK inhibitor (TKI) that blocks the activity of Raf, VEGFR, platelet-derived growth factor receptor, Flt-3, and c-Kit. An open-label, multi-institutional phase II trial conducted by the GOG evaluated single-agent sorafenib in patients with persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer.33 Results from this trial were presented by Matei and colleagues at the 44th Annual Meeting of the American Society of Clinical Oncology. Patients were eligible for the trial if they had measurable disease, defined as ≥ 1 target lesion, or CA 125 level > twice the upper limit of normal, peritoneal ascites, pleural effusion, or a nontarget lesion. Patients were permitted to have 1 previous platinum-based regimen with a PFI < 12 months and 1 additional cytotoxic regimen. Patients were required to have a GOG PS of 0-2. Patients receiving oral anticoagulant therapy or with central nervous system metastases or chronic system disease were excluded. Treatment consisted of sorafenib 400 mg taken orally twice daily. Primary study endpoints included 6-month PFS and toxicity. Secondary endpoints included response rate, PFS, OS, and the relationship between prognostic variables and outcome. Biologic endpoints were also included in the evaluation. Assessments included phosphorylated Erk pre- and posttreatment, immunohistochemistry for Raf, Mek, and Erk, and B-Raf mutations in primary tumors. Seventy-three patients were enrolled; median patient age was 61 years (range, 33-80 years). Most patients had a PS of 0 (80%), were platinum resistant (70%), and had received 1 previous cytotoxic regimen (56%). Seventy-one patients were evaluable for toxicity. The most common grade 3/4 hematologic adverse events were leukopenia and neutropenia in 1 patient each (both grade 3 only; Table 4). The most common grade 3/4 nonhematologic adverse events were metabolic abnormalities (n = 10), palmar-plantar erythrodysesthesia (n = 9), rash (n = 7), and gastrointestinal toxicity (n = 3). Fifty-nine patients were assessable for response; 2 patients had a PR, and 20 patients had stable disease (Table 5). The 6-month PFS rate was 24%.
Clinical Relevance Many targeted agents have been evaluated for patients with advanced ovarian cancer; antiangiogenic strategies have demonstrated the most clinical activity to date. The activity of single-agent anti-VEGF MoAb in ovarian cancer has been surprising given the limited single-agent activity observed in most other solid tumors. This has led to the clinical development of antiangiogenic TKIs such as sorafenib for patients with ovarian cancer. Early results from this trial of single-agent sorafenib indicate that it is tolerable and active in patients with ovarian cancer; continued evaluation in randomized clinical trials will further elucidate the role of this agent in the management of ovarian cancer. Furthermore, studies indicate that the addition of chemotherapy builds upon the single-agent efficacy observed with antiangiogenic agents and that this may prove to be another viable management strategy. References 1. Shih C, Chen VJ, Gossett LS, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 1997; 57:1116-23. 2. Solomon B, Bunn PA, Jr. Clinical activity of pemetrexed: a multitargeted antifolate anticancer agent. Future Oncol 2005; 1:733-46. 3. Rinaldi DA, Kuhn JG, Burris HA, et al. A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 1999; 44:372-80. 4. Niyikiza C, Baker SD, Seitz DE, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002; 1:545-52. 5. Mantovani LT, Miotti S, Menard S, et al. Folate binding protein distribution in normal tissues and biological fluids from ovarian carcinoma patients as detected by the monoclonal antibodies MOv18 and MOv19. Eur J Cancer 1994; 30A:363-9. 6. Miotti S, Canevari S, Menard S, et al. Characterization of human ovarian carcinoma-associated antigens defined by novel monoclonal antibodies with tumorrestricted specificity. Int J Cancer 1987; 39:297-303. 7. Jackman AL, Theti DS, Gibbs DD. Antifolates targeted specifically to the folate receptor. Adv Drug Deliv Rev 2004; 56:1111-25. 8. Hensley ML, Derosa F, Gerst SR, et al. A phase I study of pemetrexed (P) plus gemcitabine (G) in relapsed ovarian cancer (OC): Dosing results and evidence of activity. J Clin Oncol 2006; 24:276s (Abstract 5083). 9. Horowitz NS, Penson RT, Campos SM, et al. Combination carboplatin and pemetrexed for the treatment of platinum-sensitive recurrent ovarian cancer. J Clin Oncol 2008; 26:298s (Abstract 5523). 10. Vergote I. A randomized phase II Study of standard-versus high-dose pemetrexed in platinum-resistant epithelial ovarian cancer. Presented at: 39th Annual Meeting on Women’s Cancer organized by the Society of Gynecologic Oncologists; March 9-12, 2008; Tampa, FL. Abstract 256. 11. Miller DS, Blessing JA, Krasner CN, et al. A phase II evaluation of pemetrexed (LY231514, IND #40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: A study of the gynecologic oncology group. J Clin Oncol 2008; 26:298s (Abstract 5524). 12. Thigpen T. First-line therapy for ovarian carcinoma:
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