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Abstracts that I will discuss in this section revolve around that of screening, PARP inhibitors, bevacizumab, and newer chemotherapy agents.
Abstract 5003: A prospective U.S. ovarian cancer screening study using the risk of ovarian cancer algorithm (ROCA)
Lu et al presented data from an ovarian cancer screening study based on the premise that ovarian cancer usually presents with advanced disease and that 60% to 90% of women with stage I or II cancer are cured. The prevalence of ovarian cancer is 1 in 2500 postmenopausal women. The minimal requirements for ovarian cancer screening in the general population to achieve a positive predictive value of >10% would be a very high sensitivity of >75% and very high specificity of >99%. Although CA-125 and transvaginal sonography have been studied in the setting of screening for high-risk women, they are limited by low sensitivity and a high false-positive rate. The authors describe an algorithm, which is called the Risk of Ovarian Cancer Algorithm (ROCA), and it incorporates age and CA-125. The risk is recalculated with each new CA-125 test. Those with high scores are referred for transvaginal ultrasounds (TVU).
The purpose of this prospective, multicenter, single-arm study was to assess the specificity and positive predictive value of a 2-stage screening strategy to detect ovarian cancer in postmenopausal women. To be eligible, women needed to be postmenopausal and between the ages of 50-74. They have to have at least 1 ovary and have no significant family history of breast cancer or ovarian cancer. Women on the study underwent an annual CA-125 testing. The absolute number of the marker, plus incorporation of that information into the algorithm placed women into a low-risk, intermediate, or high-risk group. Those with low risk continued to undergo an annual CA-125. Those at intermediate risk had a repeat CA-125 in 3 months, and those at high risk underwent a TVU and referral to a gynecologic oncologist. In this study, 3252 women underwent up to 9 different screens. Of those, 2.6% or 85 women were referred for clinical assessment. Eight of the women underwent surgery where 3 were found to have invasive cancers, 2 with borderline tumors, and 3 with benign ovarian tumors. The specificity was 99.7%, and the positive predictive value was 37.5%. Of the 3 invasive cancers, 2 were stage IC, and 1 was stage IIB. The authors noted that there was an ongoing study in the UK, which is using the ROCA and is examining mortality as a primary statistical endpoint. That trial is evaluating over 100,000 women, so it should have the power to show a mortality benefit if one exists with this current algorithm.
Abstract LBA1: 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
Burger et al presented the results of the Gynecologic Oncology Group (GOG)-0218 Trial. This long-awaited trial randomized 1800 women with stage III optimal (macroscopic residual disease) debulked, or stage III suboptimal, or stage IV with either epithelial ovarian, primary peritoneal, or fallopian tube cancer.
The women were randomized to 1 of 3 arms:
Arm 1 Carboplatin AUC 6 + paclitaxel 175 mg/m2 intravenous (IV) for 6 cycles
Arm 2 Carboplatin AUC 6 + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg every 3 weeks during cycles 2-6 of the chemotherapy
Arm 3 Carboplatin ACU 6 + paclitaxel 175 mg/m2 IV for 6 cycles with bevacizumab beginning on cycle 2-6 and then continuously for a total of 15 months
The primary statistical analysis was to compare the investigator-assessed progression-free survival (PFS) for each bevacizumab arm versus control. The protocol defined assessment included RECIST criteria, or global clinical deterioration, or CA-125. Per a regulatory mandate, only the first 2 evaluation criteria were used. A protocol amendment changed to PFS from overall survival as the primary endpoint. The median follow-up was 17.4 months.
Results: Median PFS for the 3 arms were as follows:
Arm 1 10.3 months
Arm 2 11.2 months P = .08
Arm 3 14.1 months P<.001
There was no difference in overall survival.
Toxicity was similar to that seen on other bevacizumab trials in other malignancies. There was significantly more hypertension at 7.2%, 16.5%, and 22.9% for the 3 arms. Gastrointestinal perforations were slightly more common in the 2 bevacizumab arms at 1.2%, 2.8%, and 2.6%.
The conclusions of the authors were that GOG-0218 met the primary objective in the front-line treatment of advanced ovarian cancer as the PFS of carboplatin-paclitaxel + bevacizumab followed by bevacizumab maintenance (Arm 3) was statistically superior to carboplatin-paclitaxel alone (Arm 1). The PFS with carboplatin-paclitaxel + bevacizumab (Arm 2) was not superior to carboplatin-paclitaxel alone.
A large international study – ICON7 is still ongoing with a very similar design, and it is anticipated that it will report data within the next year or so. That trial is randomizing 1520 women with high-grade stage I-IIA, stage IIB/C, stage III, or IV epithelial ovarian cancer. Women will be randomized to carboplatin and paclitaxel at the same doses and schedule as GOG-0218, but the experimental arm delivers bevacizumab 7.5 mg/kg IV every 3 weeks for a total of 1 year. The primary statistical endpoint is PFS. The results of these 2 trials together should inform us as to whether the use of bevacizumab along with IV carboplatin and paclitaxel in the front-line for high-risk ovarian cancer should become a standard of care.
Abstract 5013: Phase II study of NKTR-102 in women with platinum-resistant/refractory ovarian cancer
Vergote and colleagues presented phase II data on an innovative topoisomerase I inhibitor-polymer conjugate. NKTR-102 uses irinotecan as the backbone, and with the polymer conjugate, changes the pharmacologic concentration to extend the half-life of the active metabolite for up to 50 days, compared to 2 days for irinotecan alone. This allows for continuous long-term exposure with markedly reduced peak concentration. The trial was run with a 2-stage design in platinum resistant/refractory ovarian cancer. Patients received either NKTR-102 at 145 mg/m2 either every 14 days or 21 days. During stage 1 (20 patients accrued), if any patient responded, then the treatment regimen proceeded to the next stage where an additional 15 patients were enrolled. If >5 patients out of 35 respond, then the drug had met its efficacy threshold. The primary endpoints were Gynecologic Cancer InterGroup (GCIG) response rate, which incorporates RECIST with CA-125.
Results: Of the 34 patients who received the drug every 14 days, the confirmed GCIG response rate was 29%, and of the 34 patients who received the drug every 21 days, the response rate was 38%. Clinical benefit rate (CR + PR + SD >3 months) was seen in 52% and 45%, respectively. Common related grade 3/4 toxicities for the q14d/q21d schedules were diarrhea (22%/11%), hypokalemia (14%/6%), nausea (14%/3%), and neutropenia (8%/9%). This product appears quite promising because of the rapid and frequent responses in a heavily pretreated group of patients, with manageable toxicity.
Abstract LBA5012b: PRECEDENT: A randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer
There is compelling preclinical data to suggest that targeting the folate receptor in advanced ovarian cancer may be clinically useful. The folate receptor is found on >90% of epithelial ovarian cancer. EC145 is a folate-vinca conjugate that binds with high affinity to the folate receptor. Naumann et al presented data from an interim analysis of a randomized phase II trial in platinum-resistant ovarian cancer. Patients were not allowed to have more than 2 prior chemotherapy regimens. Patients were randomly assigned to PLD 50 mg/m2 every 28 days, or the same PLD dose + EC145 2.5 mg on weeks 1 and 3 on a 28 day cycle.
Results: PFS was 11.7 weeks in the PLD arm alone, and 24 weeks in the PLD + EC145 arm (P = .014). Toxicity was similar in both arms for adverse events, serious adverse events, or drug discontinuation. The authors suggested that EC145 and PLD is the first combination to show a statistically significant delay in PFS over standard therapy in women with platinum-resistant ovarian cancer.
Poly (ADP-ribose) polymerase (PARP) is a key regulator of DNA damage repair processes. It binds directly to DNA damage and is involved in DNA base-excision repair. Inhibition of PARP-1 prevents recruitment of DNA repair enzymes and leads to failure of single strand break repair and ac***ulation of single strand breaks. There are multiple PARP inhibitors in clinical trials, and they seem particularly appropriate for patients with known BRCA 1 or 2 deleterious mutations.
Abstract 3002: Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer
Gelmon and colleagues presented data in order to understand whether it was possible to define tumors that will respond to PARP inhibitors. Tumors thought to be most sensitive to the PARP inhibitors are those with a BRCA 1/2 deleterious mutation or somatic mutation. But there is an emerging definition of tumors with BRCAness characteristics. These include epigenetic silencing of BRCA 1/2, FANCR methylation, EMSY amplification, p53 mutation, c-myc amplification, and genomic instability. A phenotypic definition includes tumors with a high overall response rate (ORR) to platinum-based treatments, long progression-free intervals between treatments, improved OS, predominantly serous histology. Gelmon’s group presented results of a phase II translational study that evaluated tumor response with serial tumor biopsies to determine markers of response in women with measurable breast or ovarian cancer receiving the PARP inhibitor olaparib. Eligible women with advanced breast or ovarian cancer were enrolled in 4 cohorts. Two cohorts were women with BRCA-negative or unknown with either high-grade serous ovarian cancer (Arm A) or triple-negative breast cancer (Arm B). Two other cohorts had identified BRCA mutations and had recurrent ovarian cancer (Arm C) or breast cancer (Arm D). Ninety-one evaluable patients were enrolled. Arm A enrolled 55 patients after evidence of response in the first 15. Arm B closed after the first 15 patients. Arms C and D enrolled a predetermined number of 10 and 11 patients, respectively. For the patients with ovarian cancer, 41% of the Arm C patients and 24% of the Arm A patients met the RESIST criteria for response. None of the patients with breast cancer on either arm met RESIST response criteria; although several of the patients with breast cancer who had BRCA mutations had minor responses. Further genomic and biologic analysis will be presented in the future to understand the relationship between response and tumor characteristics pre-treatment and post-treatment.
Lu KH, Skates S, Bevers TB, et al. A prospective U.S. ovarian cancer screening study using the risk of ovarian cancer algorithm (ROCA). J Clin Oncol. 2010;28(18s). Abstract 5003.
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. J Clin Oncol. 2010;28(18s). Abstract LBA1.
Vergote IB, Micha JP, Pippitt CH, et al. Phase II study of NKTR-102 in women with platinum-resistant/refractory ovarian cancer. J Clin Oncol. 2010;28(18s). Abstract 5013.
Naumann RW, Symanowski JT, Ghamande SA, et al. PRECEDENT: A randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer. J Clin Oncol. 2010;28(18s). Abstract LBA5012b.
Gelmon KA, Hirte HW, Robidoux A, et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. J Clin Oncol. 2010;28(18s). Abstract 3002.