The dose-dense delivery of chemotherapy (greater frequency of drug delivery) was explored in women with advanced ovarian cancer. All patients received carboplatin; half received paclitaxel weekly and ...half every 3 weeks. There were no between-group differences in progression-free survival.
Ovarian cancer, the most lethal gynecologic cancer, is responsible for approximately 14,000 deaths in the United States annually.
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The incorporation of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in the treatment regimen prolongs progression-free survival but not overall survival.
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A dose-dense regimen of paclitaxel involving greater frequency of drug delivery may enhance its antineoplastic effect by eliciting antiangiogenic and proapoptotic properties.
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Weekly paclitaxel therapy prolonged survival among patients with early-stage breast cancer and those with metastatic breast cancer.
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In a study involving patients with ovarian cancer, Japanese investigators found that dose-dense weekly paclitaxel prolonged progression-free . . .
In a large randomized clinical trial, the median survival among women with recurrent cervical cancer was 17 months when bevacizumab was added to their chemotherapy regimen, as compared with 13 months ...with chemotherapy alone.
Rates of cervical cancer in developed countries have decreased dramatically because of cytologic screening and DNA testing for high-risk human papillomavirus (HPV) types. Approximately 12,000 cases of cervical cancer are diagnosed in the United States annually, and with continued increases in HPV vaccination, numbers of cases are expected to decrease further.
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However, for vulnerable populations without access to health care in the United States and throughout the world, cervical cancer remains a considerable problem, with 500,000 new cases and 250,000 deaths annually.
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Although early-stage and locally advanced cancers may be cured with radical surgery, chemoradiotherapy, or both, patients with metastatic . . .
Summary Background Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA -deficient cells. We aimed to assess the ...efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. Methods In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged ≥18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov , number NCT00494442. Findings Patients had been given a median of three (range 1–16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20–51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4–31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 42%; grade 3 or 4, two 6%), fatigue (grade 1 or 2, ten 30%; grade 3 or 4, one 3%), and anaemia (grade 1 or two, five 15%; grade 3 or 4, one 3%). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven 29%; grade 3 or 4, two 8%) and fatigue (grade 1 or 2, nine 38%; none grade 3 or 4). Interpretation Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA -mutated advanced ovarian cancer. Funding AstraZeneca.
A phase II study (ClinicalTrials.gov identifier: NCT00628251) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or ...partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.
In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician's choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population.
Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2%
51.4%; odds ratio OR, 2.53 95% CI, 1.40 to 4.58;
= .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 95% CI, 1.42 to 8.54). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 95% CI, 0.43 to 0.91;
= .013; median, 13.4
9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy.
Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.
We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression ...during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin.
No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST).
Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment.
Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.
Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II ...trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.
Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously IV once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups.
The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio HR, 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806).
Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the ...second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events.
In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1–3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062.
Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 50% in the two chemotherapy-alone groups and 227 50% in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 95% CI 0·62–0·95; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 0·37–1·10; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 0·66–1·05; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death.
The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer.
National Cancer Institute.
To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, ...and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer.
Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined.
Sixty-six patients, with a median of 3 prior lines of therapy (range, 1–8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1–2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months).
The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations.
•Combining mirvetuximab soravtansine and bevacizumab is a promising approach for platinum-resistant ovarian cancer.•The combination is well tolerated, with a differentiated safety profile compared to bevacizumab with chemotherapy.•The efficacy measures compare favorably to reported outcomes for bevacizumab/chemotherapy in similar patient populations.
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