Gynecologic Cancers Update from the 2011 Annual Oncology Meeting

This entry was posted on Friday, July 29, 2011 at 3:26 pm and is filed under Gynecologic Oncology. You can follow any responses to this entry through the RSS 2.0 feed. You can skip to the end and leave a response. Pinging is currently not allowed.

Over 100 studies in gynecologic cancer were presented at the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO) held in Chicago, June 3-7, 2011. These included numerous novel therapeutic approaches in not only ovarian cancer, but also in endometrial and cervical cancers. This report will highlight phase III randomized trials in ovarian cancer and other selected studies.
 

Phase III Randomized Trials in Ovarian Cancer

This year’s ASCO meeting was disappointing as only 1 “positive” randomized phase III trial was reported. However, 4 important updates of previously reported phase III studies were presented in poster form and a large trial of maintenance immunotherapy was negative.

The OCEANS trial investigated the ability of bevacizumab to prolong progression-free survival when added to approved doses and schedules of gemcitabine and carboplatin in treating second-line platinum sensitive recurrent ovarian cancer. Study participants who received bevacizumab during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo. The median progression-free survival (PFS) was 12.4 months with bevacizumab, compared with 8.4 months with placebo. Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs 57.4%, P<.0001) and longer duration of response (10.4 months vs 7.4 months, P<.0001). No new safety concerns were identified. Importantly, the survival data from this trial are not yet mature and quality of life was not measured.

Updates of 2 front-line bevacizumab studies were also presented. The results of an independent radiologic review of GOG218 confirmed the results presented at last year’s ASCO meeting where the addition of 15 mg/m2 of bevacizumab every 3 weeks during chemotherapy and as a maintenance drug alone (total duration = 15 months) prolonged PFS by 6 months (13.1 months for arm 1 versus 19.1 months for arm 3, hazard ratio (HR) = .63, P<.0001). An update of a second front-line study using bevacizumab for 12 months at 7.5 mg/m2 (ICON7) showed that it prolonged survival in the highest risk group of patients (large volume residual disease and stage IV). This subset analysis was mandated by European regulators and the survival data from the study as a whole are not yet mature. However, in the high risk sub-group, the survival HR was 0.64, with a 95% confidence interval from 0.48 to 0.85, which was significant at P = .002.

Clearly, survival is a higher bar than response rate and time to progression when evaluating new agents and combinations. Thus, mature survival data were presented from the CALYPSO study and OVA301. Interestingly, the former study showed no improvement in survival in treating platinum sensitive recurrent ovarian cancer with carboplatin and liposomal doxorubicin (PLD) compared to carboplatin and paclitaxel (median overall survival [OS] = 31.5 months, HR = 0.987, P = .87) despite a statistically significant difference in PFS presented at ASCO 2009. However, the use of trabectedin and PLD prolonged survival compared to PLD alone in treating patients second-line (adjusted HR = 0.82; 95% CI:0.69,0.98, P =.0285). The largest difference in survival was seen in the sub-set of women who recurred 6 months to 12 months after front-line platinum based therapy.

Finally, in a disappointing placebo controlled maintenance trial of abagovomab, a murine monoclonal anti-idiotypic antibody directed against CA125, there was no difference in the primary endpoint of PFS among 888 enrolled patients (P = .675).
 

Phase II Trials of Anti-Angiogenesis Agents in Ovarian Cancer

Agents that target the angiogenic pathway continue to generate interest in ovarian cancer. Simultaneous targeting of the MET and vascular endothelial growth factor (VEGF) signaling pathways with cabozantinib (XL184) was reported this year by Buckanovich, et al in women with platinum resistant (up to 2 prior regimens) and platinum sensitive (up to 3 prior regimens) recurrent ovarian cancer. Patients were required to have progressive measureable disease by RECIST and were treated with cabozantinib 100 mg daily over a 12-week lead-in. Patients with a partial response (PR) continued on open-label cabozantinib, while those with stable disease (SD) were randomized to cabozantinib or placebo. The primary endpoint was overall response rate (ORR) in the lead-in stage and PFS in the randomized period.

Randomization was halted and patients were unblinded based on an observed high rate of clinical activity, including an ORR of 24% (29% response rate [RR] in the platinum sensitive group and 18% in the platinum resistant group). The most common grade 3/4 adverse events included hand-foot syndrome (10%) and diarrhea (8%).

In 2 non-randomized phase II trials, bevacizumab was studied with pegylated liposomal doxorubicin (PLD) plus carboplatin in platinum-sensitive disease and with the VEGFR2/Raf kinase inhibitor, sorafenib, in bevacizumab-naïve patients with recurrence. In the former trial, the regimen included PLD 30 mg/m2 and carboplatin (AUC5) on day 1 plus bevacizumab 10 mg/kg on days 1 and 15 every 28 days. The ORR was 72.2% with a median PFS of 14 months. Thirty-nine patients (72.2%) discontinued therapy due to an adverse event. Grade 3 hand-foot syndrome, deep venous thrombosis, and intestinal perforation occurred in 1 patient each.

In the latter study, sorafenib 200 mg twice daily was given with bevacizumab 5 mg/kg every 2 weeks on a 28 day cycle. Lasting a median of 15.5 months, 24% experienced a PR. Hypertension (47%) and thromboses (13%) were the most common grade 3/4 toxicities. Although grade 3/4 hand-foot syndrome occurred in only 3%, skin toxicity was responsible for the majority of dose reductions of sorafenib.

Finally, Coleman, et al reported on the phase II experience of docetaxel plus aflibercept (VEGF-Trap) in platinum sensitive and platinum resistant patients. A confirmed ORR of 54% by RECIST included 10 complete responses (CR), 4 of whom have not recurred at a median 12 months off treatment. Response by platinum sensitivity included 77% platinum sensitive and 45% platinum resistant. Secondary endpoints included PFS (6.2 months) and OS (24.3 months). Neutropenia (72%), fatigue (50%), and dyspnea (22%) represented grade 3/4 toxicities.
 

Phase II Trials of Poly(ADP-ribose) Polymerase Inhibitors (PARPi) in Ovarian Cancer

Olaparib is an oral PARPi that is active in high-grade serous ovarian cancer with and without BRCA1 and BRCA2 mutations. Ledermann, et al evaluated maintenance olaparib (400 mg twice daily) in a randomized placebo-controlled phase II trial in platinum-sensitive disease. Eligible patients were those who had received 2 or more previous platinum regimens and had achieved a sustained partial or complete response. When the pre-determined 153 progression events (58%) had occurred, the investigators reported that PFS by RECIST was significantly longer in the olaparib than the placebo group (median 8.4 months vs 4.8 months; HR 0.35; 95% CI 0.25-0.49; P<.00001). Grade 3/4 adverse events associated with olaparib included fatigue (n = 9) and anemia (n = 7).

Despite promising phase II data indicating efficacy and tolerability of the intravenous PARPi, iniparib, in triple-negative breast cancer (TNBC), the phase III registration trial ground to a halt when it was reported at this year’s meeting that the combination of iniparib plus carboplatin and gemcitabine failed to meet its co-primary endpoints of PFS and OS in triple-negative breast cancer. In 2 non-randomized phase II studies of the iniparib-carboplatin-gemcitabine triplet in platinum-sensitive and platinum-resistant ovarian carcinoma, the ORRs were 70.6% and 31.6%, respectively. In the platinum sensitive group, preliminary analyses did not indicate a relationship between BRCA status and response. In the platinum resistant population, a median PFS of 5.9 months was achieved.
 

Phase II Trials of other Novel Agents in Ovarian Cancer

The PRECEDENT trial was an international, open-label, randomized phase II study comparing pegylated liposomal doxorubicin (PLD) plus the folic acid/desacetylvinblastine hydrazide conjugate, EC145, to PLD alone in women with platinum resistant disease. Patients with less than 2 prior systemic regimens were randomized 2:1 to receive EC145 (2.5 mg IV weeks 1 and 3) plus PLD (50 mg/m2 IV q 28 days) or PLD (50 mg/m2 IV q 28 days). Folic receptor (FR) status was determined prior to randomization using technetium labeled EC20, an FR-targeted imaging agent. In the intent-to-treat population of patients with measureable disease, EC145 plus PLD was found to be the first combination to show a statistically significant impact on PFS over standard therapy in women with platinum sensitive disease (21.7 weeks vs 11.7 weeks; HR 0.626; P = .031). For patients with 100% EC20 positive tumors, the PFS was 24.0 weeks in the investigational arm and 6.6 weeks in the control arm (HR 0.381; P = .018). A phase III randomized trial in this population will be activated this year.

In another phase II trial, the hypomethylating agent, decitabine, was used in combination with carboplatin to reverse acquired platinum resistance. The ORR was 35% and included 1 CR and 5 PRs. The median PFS was 309 days. The most common grade 3/4 adverse events were hematologic along all principal cell lineages (11% to 23% of patients). In this study, demethylation of ovarian cancer-associated genes, MLH1, RASSF1a, HOXA10, and HOXA11 in tumors from day 1 to day 8 was positively correlated with PFS (P<.05). This trial constitutes the first-in-class proof of concept that epigenetic intervention can restore platinum sensitivity in ovarian cancer.

Eribulin mesylate is a tubulin inhibitor distinct from taxanes and is able to suppress microtubule growth without affecting depolymerization, resulting in the sequestration of tubulin into non-functional aggregates. Hensley, et al studied a platinum sensitive population with eribulin 1.4 mg/m2 intravenously on days 1 and 8 every 21 days. Partial responses were achieved in 19% and stable disease in 54%. The median PFS was 4.1 months. Grade 3/4 toxicity included neutropenia (54%) and pain (8%).
 

Phase II Trials in Locally Advanced and Metastatic/Recurrent Cervical Cancer

Several studies examined the efficacy and tolerability of combining anti-epidermal growth factor (EGF)–based therapy to chemoradiation and gene therapy to reconstitute wild-type p53 function for locally advanced cervical carcinoma. Erlotinib, a tyrosine kinase epidermal growth factor (EGFR) inhibitor, yielded no objective responses when studied previously by the Gynecologic Oncology Group in women with recurrent disease. However, Rodrigues, et al combined erlotinib 150 mg/d with chemoradiation plus brachytherapy and reported a 94.4% complete response rate and overall survival (OS) of 80% at 3 years. The most common grade 3 toxicity was skin rash in 13%. Two additional phase II trials in locally advanced tumors demonstrated the feasibility of weekly intra-tumoral recombinant adenoviral human p53 (rAd-p53) gene therapy in conjunction with pelvic radiation. In the randomized phase II trial reported by Pan, et al, the ORR of pelvic radiation therapy with and without gene therapy (1-4×1012 rAD-p53 viral particles x 6 weeks) was 100% versus 72.2%, respectively (P = .0149). Anticipated side effects reported in both studies included transient fever. Finally, the second generation platinum-based chemotherapy doublet of nedaplatin plus paclitaxel was associated with a 42.2% ORR and median OS of 8 months.
 

Phase II Trials of Mammalian Target of Rapamycin Inhibitors (mTORi) in Endometrial Cancer

Loss of phosphatase and tensin homolog (PTEN) protein function occurs in 26% to 83% of endometrial carcinomas leading to deregulation of the PI3K/AKT/mTOR signaling. Four phase II studies were presented this year that evaluated the response, survival, and toxicity among women with advanced and recurrent disease. Two randomized phase II trials studied mTORi(s) versus hormonal therapy. Oza, et al randomized patients to oral ridaforolimus 40 mg for 5 days/week versus medroxyprogesterone 200 mg/d or megestrol 60 mg/d. Inclusion criteria was unresectable stage III or IVA disease treated with 1 or 2 prior lines of chemotherapy. A protocol amendment allowed chemotherapy as a control towards the end of the study. The primary endpoint was PFS and an interim analysis of the first 114 patients treated demonstrated a median PFS of 36 months for ridaforolimus and 1.9 months for progestin therapy (HR 0.53, P = .008). The most common grade 3/4 adverse events associated with the mTORi included hyperglycemia in 19% and anemia in 9%. The second randomized phase II study compared intravenous temsirolimus to temsirolimus plus megestrol acetate alternating with tamoxifen. The combined regimen was closed due to the unacceptable rate of venous thromboses, but with at least 4 responses documented for the monotherapy, a second stage of accrual was opened. Finally, a non-randomized phase II study of daily everolimus plus letrozole was associated with an objective RR of 21% and a clinical benefit response of 42%.
 

Screening Still Paramount

Clearly, the key to effective control of gynecologic cancer is effective screening and prevention. Two studies were presented. First, dual screening for ovarian cancer among average-risk women failed to reduce the rate of mortality from this disease. These findings came from the National Cancer Institute (NCI)–sponsored Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial that enrolled 78,216 women, ages 55 to 74. In fact, patients screened annually with CA-125 antigen testing and transvaginal ultrasound had a slightly higher ovarian cancer mortality risk as compared with usual care (3.1 versus 2.5 per 10,000 person-years). Moreover, screening was associated with increased use of invasive procedures and avoidable complications related to workup following false-positive results.

Finally, one of the highlights from the meeting was a large-scale study that showed the effectiveness of human papillomavirus (HPV) testing alone or in combination with cytology testing for identifying women at high-risk for the development cervical cancer. The authors estimated cumulative 5-year incidence of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 at Kaiser Permanente Northern California for 331,818 women. Overall, the study showed that a single HPV test was superior to a single Pap test for predicting which women would develop CIN 3 or cancer within 5 years. Cytology testing only modified the risks for women whose cervical tests were HPV-positive. The authors suggested that HPV-based screening is a feasible practice in routine clinical care.

References

  1. Aghajanian C, Finkler NJ, Rutherford T. OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). J Clin Oncol. 2011;29(suppl). Abstract LBA5007 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  2. Burger RA, Brady MF, Rhee J, et al. Independent radiologic review of GOG218, a phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian (EOC), primary peritoneal (PPC) or Fallopian tube cancer (FTC). J Clin Oncol. 2011;29(suppl). Abstract 5023 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  3. Kristensen G, Perren T, Qian W, et al. Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. J Clin Oncol. 2011;29(suppl). Abstract LBA5006 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  4. Marth C, Alexandre J, Hanker LC, et al. Pegylated liposomal doxorubicin and carboplatin (C-PLD) versus paclitaxel and carboplatin (C-P) in platinum-sensitive ovarian cancer (OC) patients (pts): Treatment at recurrence and overall survival (OS) final analysis from CALYPSO phase III GCIG trial. J Clin Oncol. 2011;29(suppl). Abstract 5052 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  5. Monk BJ, Herzog TJ, Kaye SB, et al. Final survival results of the randomized phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer. J Clin Oncol. 2011;29(suppl). Abstract 5046 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  6. Pfisterer J, Berek JS, Casado A, et al. Randomized double-blind placebo-controlled international trial of abago-vomab maintenance therapy in patients with advanced ovarian cancer after complete response to first-line chemotherapy: The Monoclonal Antibody Immunotherapy for Malignancies of the Ovary by Subcutaneous Abago-vomab (MIMOSA) trial. J Clin Oncol. 2011;29(suppl). Abstract LBA5002 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  7. Buckanovich RJ, Berger R, Sella A, et al. Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2011;29(suppl). Abstract 5008 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  8. del Carmen MG, Micha JP, Small LA, et al. Pegylated liposomal doxorubicin and carboplatin plus bevacizumab in patients with platinum sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancers: Results of a phase II study. J Clin Oncol. 2011;29(suppl). Abstract 5061 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  9. Kohn EC, Lee J, Annunziata CM, et al. A phase II study of intermittent sorafenib with bevacizumab in bevacizumab-naive epithelial ovarian cancer (EOC) patients. J Clin Oncol. 2011;29(suppl). Abstract 5019 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  10. Coleman RL, Duska LR, Ramirez PT, et al. Phase II multi-institutional study of docetaxel plus aflibercept (AVE0005, NSC# 724770) in patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer. J Clin Oncol. 2011;29(suppl). Abstract 5017 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  11. Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol. 2011;29(suppl). Abstract 5003 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  12. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29(suppl). Abstract 1007 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  13. Penson RT, Whalen C, Lasonde B, et al. A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-sensitive recurrent ovarian cancer. J Clin Oncol. 2011;29(suppl). Abstract 5004 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  14. Naumann RW, Coleman RL, Burger RA, 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. 2011;29(suppl). Abstract 5045 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  15. Matei D, Shen C, Fang F, et al. A phase II study of decitabine and carboplatin in recurrent platinum (Pt)-resistant ovarian cancer (OC). J Clin Oncol. 2011;29(suppl). Abstract 5011 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  16. Hensley ML, Kravetz SJ, Jia X, et al. Eribulin mesylate (halichondrin B analog E7389) in platinum-sensitive ovarian cancer: A phase II study, CTEP #7431. J Clin Oncol. 2011;29(suppl). Abstract 5090 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  17. Rodrigues AN, Small IA, Carmo CC, et al. INCA-GYN001: Erlotinib added to cisplatin and definitive radiotherapy in untreated patients with locally advanced squamous cell cervical carcinoma—Final report of a phase II trial. J Clin Oncol. 2011;29(suppl). Abstract 5033 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  18. Pan J. A phase II study of recombinant adeno-viral human p53 gene combined with radiotherapy in treatment of patients with locally advanced cervical carcinoma. J Clin Oncol. 2011;29(suppl). Abstract 5097 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  19. Takekuma M, Hirashima Y, Ito K, et al. Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: A Kansai Clinical Oncology Group study. J Clin Oncol. 2011;29(suppl). Abstract 5102 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  20. Oza Am, Poveda A, Clap AR, et al. A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotheraphy (C) in female adult patients with advanced endometrial carcinoma. J Clin Oncol. 2011;29(suppl). Abstract 5009 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  21. Fleming GF, Filiaci VL, Hanjani P, et al. Hormone therapy plus temsirolimus for endometrial carcinoma (EC): Gynecologic Oncology Group trial #248. J Clin Oncol. 2011;29(suppl). Abstract 5014 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  22. Slomovitz BM, Brown J, Johnston TA, et al. A phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2011;29(suppl). Abstract 5012 and poster presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  23. Buys SS, Patridge E, Black A, et al. Effect of screening on ovarian cancer mortality in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer randomized screening trial. J Clin Oncol. 2011;29(suppl). Abstract 5001 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

  24. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for 330,000 women undergoing concurrent HPV testing and cervical cytology in routine clinical practice. J Clin Oncol. 2011;29(suppl). Abstract 1508 and oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL.

 

 

Tags: , ,

About

The Division of Gynecologic Oncology
University of Arizona Cancer Center
Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center
A Dignity Health Member
Phoenix, Arizona

More posts by

Have a correction or something you'd like to add? Send us an email or leave a comment below.

One Comment

Gynecologic Cancers Update from the 2011 Annual Oncology Meeting

leave a comment

  1. Great information! This is very helpful! … especially for those who suffer from cancer, they need to know this. Their knowledge about the cancer, will determine their actions and to care continue. And for those who are healthy will seek to prevent.

Leave a Reply

*