The general webchat topics addressed by the Dana-Farber doctors are listed below. For your convenience, we also provided the approximate video start time associated with each discussion topic. The entire video runs 49 minutes and 20 seconds.
Various types/subtypes of ovarian cancer and treatment differences. [1:40 minutes]
CA-125 and other ovarian cancer biomarkers. [5:10 minutes]
Areas of ongoing ovarian cancer research. [9:28 minutes]
Ovarian cancer treatment alternatives to standard of care chemotherapy. [13:55 minutes]
PARP Inhibitors & Immunotherapy. [15:03 minutes]
Mechanisms to reverse platinum drug resistance. [17:15 minutes]
Correlation between ovarian cancer and HPV (Human papillomavirus). [19:30 minutes]
The use of clinical trials for the treatment of ovarian cancer. [19:43 minutes]
Stage 1 ovarian cancer prognosis. [21:47 minutes]
Gene mutations related to hereditary ovarian cancer risk. [22:55 minutes]
Treatment options for platinum drug refractory/resistant ovarian cancer. [25:27 minutes]
Treatment of BRCA gene-mutated ovarian cancer patients. [27:50 minutes]
Ovarian cancer prevention. [30:18 minutes]
Promising treatments for ovarian clear cell cancer. [31:43 minutes]
Proper nutrition during and after ovarian cancer treatment. [33:47 minutes]
Symptoms associated with an ovarian cancer recurrence. [35:06 minutes]
Ovarian neuroendocrine cancer. [36:16 minutes]
Small-cell ovarian cancer. [39:22 minutes]
Origin of ovarian cancer. [42:41 minutes]
Treatment options for isolated or limited recurrent ovarian cancer tumors/lesions. [45:26 minutes]
Closing: Most Exciting Ovarian Cancer Developments. [47:07 minutes]
Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the recent 2011 American Society of Clinical Oncology Annual Meeting. The overall solid tumor Phase 2 safety and tolerability data reference six deaths, including two ovarian cancer patients.
Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan
On May 19, 2011, we reported promising cabozantinib phase 2 solid tumor (including ovarian) data, which was presented at an ASCO press briefing held in advance of the 2011 ASCO Annual Meeting. As noted in our May 19 article, cabozantinib demonstrated excellent activity against several solid tumors, including ovarian cancer. In addition, we reported that cabozantinib showed promising activity in ovarian cancer patients independent of prior response to platinum drug-based therapies.
Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan, presented the expanded cabozantinib Phase 2 data relating to use of the drug in advanced ovarian cancer patients, on June 4 at the 2011 ASCO Annual Meeting.
Ovarian Cancer Patient Population & Overall Response Rate
(Image Source: Exelixis, Inc.)
The cabozantinib trial is an ongoing phase 2 adaptive randomized discontinuation trial. As of the February 11, 2011 cut-off date, accrual in the cabozantinib study cohort was complete at 70 patients.
The 70 patients enrolled in the ovarian cancer cohort received oral cabozantinib (100 mg) daily over a 12 week “Lead-in Stage.” These patients had a minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacyendpoint of response per RECIST (Response Evaluation Criteria in Solid Tumors).
Patient tumor response was assessed every 6 weeks. Receipt of cabozantinib treatment beyond the 12 week open label Lead-in Stage was based upon patient response: (1) patients with a partial response (PR) or complete response (CR) continued taking cabozantinib, (2) patients with stable disease (SD) were randomized to the cabozantinib treatment arm or the placebo treatment arm (collectively referred to as the “Blinded Randomized Stage”), and (iii) patients with progressive disease (PD) discontinued study treatment. The study primary endpoint was overall response rate (ORR) per RECIST in the Lead-in Stage, and progression free survival (PFS) in the Blinded Randomized Stage. Accrual in any cohort could be halted for high ORR or PD.
Approximately half of the 70 patients enrolled in the cohort were considered platinum drug-refractory/-resistant (49%), defined as a platinum drug-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months.
The baseline patient tumor histologiccharacteristics are as follows: serous ovarian cancer (79%), clear cell ovarian cancer (4%), endometrioid ovarian cancer (6%), and other forms of ovarian cancer (11%)
More than half the patients (57%) received 2 or more prior lines of platinum therapy prior to trial enrollment. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin (brand name: Doxil®) or topotecan (brand name: Hycamtin®) (32%), gemcitabine (brand name: Gemzar®) (29%), and VEGF (vascular endothelial growth factor) pathway inhibitors (10%).
Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline medical imaging scan. The best overall response rate per RECIST criteria was 24% (16 PRs and 1 CR). The overall Week-12 disease control rate (DRC = CR + PR + SD) was 53%. The Week-12 DCRs in the platinum drug-refractory, -resistant, and -sensitive groups were 36%, 39%, and 67%, respectively.
Based on an observed high rate of clinical activity, randomization was halted, and randomized patients were unblinded. At this point, the unblinded randomized patients that were treated with placebo were allowed to “cross-over” to treatment with cabozantinib. Disease stabilization was experienced by some ovarian cancer patients who had progressive disease prior to treatment cross-over.
“These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication.”
Activity in Platinum Drug-Sensitive, -Refractory, and -Resistant Disease
Ignace Vergote, M.D., Ph.D., senior author of the cabozantinib (XL184) ASCO presentation & Chairman, Leuven Cancer Institute, University of Leuven, European Union
(Image Source: Exelixis, Inc.)
Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 CR and 1 PR).
In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR.
Ten of 36 patients (28%) with platinum sensitive disease achieved a PR.
A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA-125 (cancer antigen-125), including 8 with decreases greater than 50%. There is no consistent concordance between CA-125 changes and tumor regression. The median duration of response has not yet been reached with 36 weeks of median follow-up.
“The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs [tyrosine kinase inhibitors], and cabozantinib has the potential to be an important new treatment for ovarian cancer,” said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. “The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer.”
Six Deaths Reported (Including Two Ovarian Cancer Patients)
If you examine the Exelixis press release dated June 4 (entitled, Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer — Disease control rate of 53% at week 12, response rate of 24%), which addresses data for cabozantinib use in advanced ovarian cancer patients, pay particular attention to the wording under the heading entitled, “Safety and Tolerability.” Within the wording set forth under that heading, you will find the following statement: “Two cabozantinib-related grade 5 AEs [adverse events], one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase.” Pursuant to the CTCAE guidelines, a “grade 5 adverse event” is defined as “death related to AE [adverse event].”
We should also note that the two ovarian cancer deaths were summarized briefly in the ASCO presentation regarding cabozantinib use in advanced ovarian cancer.
The reporting of all six deaths is set forth in the Exelixis press release, dated June 5, 2011 (entitled, Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types), in similar fashion. Within this release, the sentence provided under the heading “Safety and Tolerability” states: “There were 6 (1%) cabozantinib-related grade 5 [adverse] events, all of which were reported after the Lead-In phase of the trial: respiratory compromise (breast cancer), hemorrhage (NSCLC [non-small cell lung cancer]), enterocutaneous perforation (ovarian cancer), intestinal perforation (ovarian cancer), gastrointestinal hemorrhage (pancreatic cancer), and death (CRPC [castrate resistant prostate cancer]).”
Exelixis Chief Executive Michael Morrissey said the safety statistics are consistent with targeted cancer therapies like cabozantinib that block a pathway used by tumor cells to secure blood vessels.
Cowen & Co analyst Eric Schmidt said the rate of cabozantinib treatment-related deaths — 1 percent — was “no different from what we have seen for every other Phase 1 and 2 trials here at ASCO.”
“While drug safety is of less concern in cancer indications than in others, the apparent morbidities associated with cabo[zantinib] use will confound interpretation of clinical benefit in a trial designed to show anything less than overall survival,” Canaccord analyst George Farmer said in a research note.
In a note to investors, Piper Jaffray analyst Edward Tenthoff said: “The company is exploring lower doses, but the concern is that cabo[zantinib] will not retain the impressive efficacy seen to date.”
Mr. Morrissey said Exelixis plans to move forward with the current daily 100 mg dose of the drug.
Dr. Nicholas J. Vogelzang (Director, Comprehensive Cancer Centers of Nevada) Discusses Mortalities in the Cabozantinib (XL184) Trial
Take Away Message
Cabozantinib demonstrates promising activity in both platinum drug-sensitive and platinum drug-resistant/-refractory ovarian cancer.
Week 12 overall disease control rate of 53%.
Response rates of 18% in platinum-refractory, 22% in platinum-resistant and 28% in platinum-sensitive patients.
Cabozantinib shows encouraging duration of response.
After 36 weeks of follow-up, median duration of response not reached.
Tolerability profile is consistent with that of other tyrosine kinase inhibitors (6 solid tumor patient deaths (1% of all solid tumor pts), including 2 ovarian cancer patients (3% of ovarian cancer pts)).
Discordant effects observed between CA-125 changes and clinical activity.
Simultaneous targeting of MET and VEGFR2 with cabozantinib results in robust effects in patients with advanced ovarian cancer.
Non-randomized expansion cohort is currently accruing in platinum-resistant/-refractory ovarian cancer.
About the MET & VEGFR2 Pathways
To learn more about (i) the role of MET in cancer, (ii) the relationship between the MET and VEGFR pathways, and (iii) the dual inhibition of MET and VEGFR2, visit http://www.metinhibition.com/.
About Cabozantinib (XL184)
Cabozantinib (XL184) is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions (i.e., deprivation of adequate oxygen supply) in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, anti-metastatic and anti-angiogenic effects, including: (i) extensive apoptosis of malignant cells; (ii) decreased tumor invasiveness and metastasis; (iii) decreased tumor and endothelial cell proliferation; (iv) blockade of metastatic bone lesion progression; and (v) disruption of tumor vasculature.
Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer. Exelixis is focusing its resources and development efforts exclusively on cabozantinib, its most advanced solely-owned product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs. For more information, please visit the company’s web site at www.exelixis.com
Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.
A diagram illustrating the role of the VEGF protein in the formation of new blood vessels that support tumor growth. Click on the picture above to view a video regarding the mechanism of action with respect to bevacizumab (Avastin®). (Photo: Genentech)
“Angiogenesis” refers to the process of new blood vessel formation. When tissues need more oxygen, they release molecules that encourage blood vessel growth. Angiogenesis is a normal and vital process in human growth and development, as well as in wound healing. Unfortunately, cancer tumors also utilize this same process to enhance their own blood supply in order to nourish their aberrant growth.
Ovarian cancer is associated with high concentrations of vascular endothelial growth factor (VEGF), a protein associated with tumor growth and spread. Studies have shown a correlation between a high concentration of VEGF and ascites (excess fluid in the body cavity) development, disease worsening, and a poorer prognosis in women with ovarian cancer.[1-2]
Bevacizumab is a humanized monoclonal antibody designed to specifically bind to the VEGF protein, which plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels through angiogenesis. The drug interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).
Bevacizumab is the first U.S. Food and Drug Administration (FDA) approved therapy designed to inhibit angiogenesis. Although FDA-approved for several forms of cancer, bevacizumab is not yet approved for the treatment of ovarian cancer. Patients treated with bevacizumab may experience side effects. In past clinical trials, some people treated with bevacizumab experienced serious and sometimes fatal side effects, related to gastrointestinal (GI) perforation, surgery and wound healing, and severe bleeding. For more information, review the Avastin BOXED WARNINGS and Additional Important Safety Information.
OCEANS Phase III Clinical Study: Women with Recurrent Platinum Sensitive Ovarian Cancer Experience 78% Response Rate & 52% Reduction In Disease Progression Risk
About the OCEANS Study
“OCEANS” is a multicenter, randomized, double-blind, placebo-controlled Phase III study in 484 women with platinum drug-sensitive recurrent ovarian, primary peritoneal or fallopian tube cancer. Women in the OCEANS study received no more than one treatment regimen prior to study enrollment. The OCEANS study randomized enrolled women to one of two clinical study arms:
Arm A: Intravenous carboplatin (area under the curve (AUC) 4; Day 1) + gemcitabine (1,000 mg/m2; Day 1 & 8; brand name: Gemzar®) + placebo (Day 1) every 21 days x 6 cycles, followed by placebo maintenance every 21 days, until disease progression or unacceptable toxicity occurred.
Arm B: Carboplatin + gemcitabine + bevacizumab (15 mg/kg; Day 1) every 21 days x 6 cycles, followed by single agent bevacizumab maintenance every 21 days, until disease progression or unacceptable toxicity occurred.
Carol Aghajanian, M.D. speaks during the Oral Abstract Session: Gynecologic Cancer at the American Society of Clinical Oncology Annual Meeting on Saturday June 4, 2011. (Photo: ASCO/GMG/Silas Crews 2011)
Two hundred forty-two women were allocated to each study arm and the median follow-up period was 24 months. Patient characteristics were well-matched in the two treatment groups with regard to age (median age ~60), race (~91% white), performance status (~75%, PS = 0), histologic subtype (~80% serous), cytoreductive surgery (~11%), and platinum-free interval (defined as the time between finishing front-line platinum-based therapy and starting second-line chemotherapy) of more than 12 months (~60%). The study stratification variables were platinum-free interval (6 to 12 months vs. more than 12) and cytoreductive surgery for recurrent disease (yes vs. no).
The median number of chemotherapy cycles was six for each group, and a median of 11 cycles of bevacizumab or placebo was given. At least one-third of the patients received more than six cycles of carboplatin and gemcitabine, although slightly more of the placebo-treated group continued chemotherapy beyond six cycles.
Progression-free survival was significantly longer for women given bevacizumab (12.4 months vs. 8.4 months in the placebo-treated group (hazard ratio [HR]: 0.484; 95% confidence interval (CI) [0.388, 0.605]; p < 0.0001). These results were corroborated by the analyses of an independent review committee. Analyses according to platinum-free interval, cytoreductive surgery, age, and baseline performance status indicate a consistent benefit in all subgroups.
Objective response rate increased by 21.1% (p < 0.0001), from 57.4% in the placebo group to 78.5% in the bevacizumab treated group; duration of response increased from a median of 7.4 months to 10.4 months, respectively (HR: 0.534; 95% CI [0.408, 0.698]; p < 0.0001). Overall survival data are still premature, with median survival of 29.9 months in the placebo group and 35.5 months in the bevacizumab treatment group.
Sixty-five percent of the patients in the placebo group were withdrawn from the protocol due to disease progression, compared with only 41% of the treatment group, but 23% of the discontinuations in the bevacizumab group were due to adverse events, compared with only 5% in the placebo group. Much of this increase was due to grade 3 (or worse) adverse events; specifically hypertension and proteinuria associated with bevacizumab therapy. Overall, the safety profile of bevacizumab was consistent with past trials.
OCEANS Study Commentary
Dr. Aghajanian concluded that the OCEANS study results demonstrate a statistically significant and clinically relevant benefit when bevacizumab is added to carboplatin and gemcitabine. Aghajanian stated that this regimen should be considered a new option for the treatment of recurrent, platinum drug-sensitive ovarian cancer. As expected, the rate of adverse events was higher among patients who received bevacizumab, explained Dr. Aghajanian. “Hypertension and proteinuria were increased, but febrile neutropenia was the same in both arms.” “The safety data are reassuring and consistent with the known bevacizumab side-effect profile, and there were no new safety signals,” said Dr. Aghajanian.
“In advanced ovarian cancer, just as in advanced breast cancer, there is often an opportunity to intervene with different lines of chemotherapy,” said Andrew Seidman, M.D., attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Medical College of Cornell University. “There are many chapters in the story, so to speak,” said Dr. Seidman, who moderated a press briefing held in advance of the presentation. “We want to prolong each and every chapter in the disease, and make the story longer and ultimately improve survival. These trials results are certainly an important step in that direction.”
“Women with recurrent ovarian cancer need new treatment options, and it is therefore an important advance to halve the risk of disease progression in this incurable cancer,” said Hal Barron, M.D., chief medical officer and head of Roche Holdings Global Product Development. “These data add to the growing body of evidence supporting Avastin’s potential role in this disease, which includes two previously presented Phase III clinical trials [Gynecologic Oncology Group (GOG)-218 & ICON7] in women with newly diagnosed ovarian cancer.”
In his discussion of the study, Anil K. Sood, M.D., professor and director of the Blanton-Davis Ovarian Cancer Research Program in the Departments of Gynecologic Oncology and Cancer Biology at the University of Texas M.D. Anderson Cancer Center, suggested that further understanding of the timing and dosing of bevacizumab should be pursued in light of (i) its great financial cost, and (ii) reports that inhibition of angiogenesis in animal models reduces primary cancer tumor growth, but accelerates invasion and metastasis — unintended consequences that might be linked to the failure of bevacizumab to extend overall survival in most clinical trials.
ICON7 Phase III Clinical Study: Newly-Diagnosed Women with High-Risk Ovarian Cancer Experience 36% Reduction in Risk of Death
Gunnar Kristensen M.D., Ph.D. speaks during the Women's Cancers Press Briefing at the American Society of Clinical Oncology Annual Meeting on June 4, 2011. (Photo: ASCO/GMG/Scott Morgan 2011)
ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer.  Gunnar Kristensen, M.D, Ph.D., senior consultant in the Department for Gynecologic Oncology of the Norwegian Radium Hospital located in Oslo, reported the Phase III clinical study results.
Arm A: 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone; or
Arm B: Same chemotherapy as in Arm A, given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles, followed by continued 3-weekly single-agent bevacizumab maintenance therapy for 12 additional cycles (up to 12 months) or until disease progression (whichever event occurs first).
The baseline patient characteristics were balanced between both study arms: median age (57 years); ECOG Performance Status 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell).
Updated ICON7 Progression Free Survival Data
Data from the ICON7 study were presented for the first time at the 2010 European Society of Medical Oncology (ESMO) Congress. As reported at ESMO, chemotherapy-naïve ovarian cancer patients who received bevacizumab in combination with standard chemotherapy, and then continued with single agent bevacizumab maintenance therapy, experienced approximately 27% improvement (18.3 months versus 16 months) in the likelihood of living longer without the disease worsening (i.e., progression-free survival) compared to those women who received only chemotherapy (hazard ratio = 0.79, p=<0.0010), which corresponds to a 21% reduction in risk of cancer progression or death. The ICON7 data presented at ESMO was based upon mature progression-free survival results.
The updated ICON7 progression-free survival data presented at the ASCO annual meeting were consistent with the data reported last year at ESMO. In the updated analysis, women assigned to the bevacizumab arm experienced longer progression-free survival than those in the control group (19.8 months vs 17.4 months; HR, 0.87; p =.039). “There is a substantial prolongation of time to progression,” said Dr. Kristensen, adding that the gain was 2.4 months.
ICON7 Overall Survival Data Immature; But Clear Benefit To Women With “Poor Prognosis.”
At a median follow-up of 28 months, there were fewer deaths among women who received bevacizumab than among those who received standard chemotherapy (178 vs 200). Although this represents a 15% overall reduction in mortality risk, the difference did not reach statistical significance (hazard ratio [HR], 0.85; P = .11). The final analyses for overall survival will be performed when 715 patient deaths have occurred. The current analysis was conducted because an interim analysis with at least 365 deaths was requested by the FDA and the European Medicines Agency for licensing consideration.
Although the overall survival data is not mature, a subgroup analysis of women with a “poor prognosis” (defined as FIGO stage III patients debulked to >1.0cm of visible diease or FIGO stage IV with debulking) was performed. Within this subgroup, there were 79 deaths within the bevacizumab arm and 109 deaths in the control arm. Based on this data, there was a 36% reduction in the risk of death (HR=0.64, 95% CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group)) among the poor prognosis subgroup. This result was statistically significant. “We have previously shown that [the high-risk] group has a greater benefit from bevacizumab than the other patients,” said Dr. Kristensen. “For this group, there is a very clear gain for overall survival.”
ICON7 Study Commentary
“We conclude that the addition of concurrent and continued bevacizumab for 12 months does improve progression-free survival,” said Dr. Kristensen. Kristensen also noted that, on the basis of an interim analysis involving approximately 53% of the number of deaths needed for the final analysis, there is an overall trend for improvement in overall survival.
“In this study, we see the ability of antiangiogenic therapy to delay the progression of ovarian cancer, this time in the first-line setting,” said Andrew Seidman, M.D. He added that previous studies have demonstrated the efficacy of bevacizumab in ovarian cancer. “These lend support to a potential role for bevacizumab as the first biologic agent to be used in this disease,” said Seidman, who moderated a press briefing during which study highlights were presented.
There are many strengths in a study like this, in that it addresses questions about the role of anti-VEGF therapies in this setting, said Anil Sood, M.D., who served as a discussant for this paper. “The randomized design is obviously a major strength.”
However, there are potential issues to examine, explained Dr. Sood. “One is the role of bevacizumab in the combination setting, compared with the maintenance setting.”
“How useful is bevacizumab in the combination setting up front? Is the real role for bevacizumab in the maintenance setting following initial chemotherapy,” he asked.
The issue of bevacizumab dosing was also raised by Dr. Sood. “One of the questions is whether higher doses are needed,” he said. “There are data emerging from other studies showing that lower doses are as efficacious, if not more so.”
EntreMed, Inc. announced that ENMD-2076 demonstrated clinical activity — a six-month progression free survival rate of 19% — when administered as a single agent to platinum drug-resistant recurrent ovarian cancer patients. The announcement is based upon interim phase 2 data presented today at the 2011 American Society of Clinical Oncology Annual Meeting.
Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School
ENMD-2076 demonstrated clinical activity when administered daily orally as a single agent. Interim data from 57 evaluable patients showed a six-month progression free survival rate of 19 percent. Of the evaluable patients, four patients achieved a partial response and 30 patients achieved stable disease as measured by RECISTv1.1. Median overall survival has not yet been reached. The side effect profile was consistent with activity against ENMD-2076’s molecular targets, in particular, VEGFR2 (vascular endothelial growth factor receptor-2) and Aurora A. Studies to evaluate potential markers of ENMD-2076 in this patient group are ongoing.
Dr. Matulonis commented on the results of the study, “ENMD-2076 has demonstrated impressive anti-cancer activity in platinum-resistant ovarian cancer which is notoriously difficult to treat, and these patients have few options.”
EntreMed’s chief medical officer, Carolyn F. Sidor, M.D., M.B.A., added, “These results are very encouraging as they support further development of ENMD-2076 and also help us clarify its developmental path in ovarian cancer. We are currently designing the next clinical trial in this indication and look forward to opportunities to make ENMD-2076 available to ovarian cancer patients in the future.”
ENMD-2076 is an orally-active, Aurora A/angiogenickinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in phase I clinical trials in solid tumor cancers, leukemia, and multiple myeloma. While ENMD-2076 is currently in a phase 2 trial in ovarian cancer, preclinical and clinical activities are ongoing in assessing the compound’s applicability in other forms of cancer.
EntreMed, Inc. is a clinical-stage pharmaceutical company committed to developing ENMD-2076, a selective angiogenic kinase inhibitor, for the treatment of cancer. ENMD-2076 is currently in a multi-center phase 2 study in ovarian cancer and in several phase 1 studies in solid tumors, multiple myeloma, and leukemia.
The March 2011 supplemental issue of Gynecologic Oncology sets forth the ovarian cancer and ovarian cancer-related medical abstracts selected by the Society of Gynecologic Oncologists for presentation at its 42nd Annual Meeting on Women’s Cancer™, which is being held in Orlando, Florida from March 6-9, 2011.
In connection with this premier gynecologic cancer event, 651 abstracts, and 27 surgical films were submitted for consideration. After careful discussion and deliberation, the SGO selected 51 abstracts for oral presentation (27 Plenary session papers, 24 Focused Plenary papers, and 42 Featured Posters, presented in a new, electronic format), along with 227 for poster presentation. Of the 27 surgical films originally submitted, five films were selected for presentation during a featured Focused Plenary session.
The SGO is a national medical specialty organization of physicians and allied healthcare professionals who are trained in the comprehensive management of women with malignancies of the reproductive tract. Its purpose is to improve the care of women with gynecologic cancer by encouraging research, disseminating knowledge which will raise the standards of practice in the prevention and treatment of gynecologic malignancies, and cooperating with other organizations interested in women’s health care, oncology and related fields. The Society’s membership, totaling more than 1,400, is primarily comprised of gynecologic oncologists, as well as other related medical specialists including medical oncologists, radiation oncologists, nurses, social workers and pathologists. SGO members provide multidisciplinary cancer treatment including chemotherapy, radiation therapy, surgery and supportive care. More information on the SGO can be found at www.sgo.org.
About Gynecologic Oncologists
Gynecologic oncologists are physicians committed to the comprehensive treatment of women with cancer. After completing four years of medical school and four years of residency in obstetrics and gynecology, these physicians pursue an additional three to four years of training in gynecologic oncology through a rigorous fellowship program overseen by the American Board of Obstetrics and Gynecology. Gynecologic oncologists are not only trained to be skilled surgeons capable of performing wide-ranging cancer operations, but they are also trained in prescribing the appropriate chemotherapy for those conditions and/or radiation therapy when indicated. Frequently, gynecologic oncologists are involved in research studies and clinical trials that are aimed at finding more effective and less toxic treatments to further advance the field and improve cure rates.
Studies on outcomes from gynecologic cancers demonstrate that women treated by a gynecologic oncologist have a better likelihood of prolonged survival compared to care rendered by non-specialists. Due to their extensive training and expertise, gynecologic oncologists often serve as the “team captain” who coordinates all aspects of a woman’s cancer care and recovery. Gynecologic oncologists understand the impact of cancer and its treatments on all aspects of women’s lives including future childbearing, sexuality, physical and emotional well-being—and the impact cancer can have on the patient’s whole family.
Exelixis reports promising interim data from ovarian cancer patients treated with XL184, including: a 32% confirmed response rate per RECIST in patients with platinum-resistant or platinum-sensitive disease, and a 64% overall week-12 disease control rate.
Ignace Vergote, M.D., Ph.D., Head, Department of Obstetrics & Gynecology and Gynecologic Oncology, Catholic University Hospital, Leuven, Belgium
XL184 is an oral, potent inhibitor of MET, VEGFR2 and RET. MET overexpression has been observed in advanced ovarian cancer, and anti-VEGF pathway agents have shown clinical benefit in ovarian cancer patients. For these reasons, co-targeting of the MET and VEGF signaling pathways using XL184 may represent a promising treatment strategy.
As of the November 1, 2010 cut-off date, a total of 51 patients were enrolled into the ovarian cancer cohort, with 31 evaluable for response, and 41 evaluable for safety. The median number of prior systemic treatments was 2. Tumor shrinkage was observed in 30 of 37 (81%) patients with measurable metastatic lesions. Of 31 patients evaluable for response per RECIST (Response Evaluation Criteria In Solid Tumors), 10 (32%) achieved a confirmed partial response (PR). Stable disease (SD) was reported in 15 patients (48%) including 3 patients who achieved unconfirmed PRs. The overall week-12 disease control rate (DCR)(complete responses + partial responses + stable disease responses = DCR) was 64%.
Upon subset analysis, 5 of 17 platinum–refractory or –resistant patients (29%) evaluable for response per RECIST achieved a confirmed PR. SD was reported in 7 patients (41%) including 2 patients with unconfirmed PRs. The week-12 DCR was 59% in platinum-resistant/refractory patients. Durable responses have been observed, including 2 patients with platinum-refractory or resistant disease who remain on study for 34+ and 36+ weeks, and 3 patients with platinum-sensitive disease on study for 24, 24+, and 28+ weeks. Some patients have experienced reductions in the ovarian cancer blood marker CA125, but in general no clear concordance between CA125 changes and tumor shrinkage has been observed.
Safety data are available for 49 patients who had at least 6 weeks of follow-up. The most common grade greater-than or equal to 3 adverse events, regardless of causality were PPE (Palmar-Plantar Erythrodysesthesia) syndrome (also referred to as “hand-foot syndrome”) (12%), diarrhea (7%), fatigue, vomiting (each 5%), nausea, rash, abdominal pain, hypertension, and hypomagnesemia (each 2%).
“The activity of XL184 in women with both platinum-sensitive and platinum-resistant/refractory disease is unique and encouraging. The response rate and overall disease control rate of this oral agent are impressive especially in the group of patients with platinum refractory/resistant ovarian cancer, and compare favorably to other targeted and systemic agents in development,” said, Dr. Vergote. “I believe these encouraging data warrant further evaluation of XL184 in ovarian cancer.”
Michael M. Morrissey, Ph.D., President & Chief Executive Officer, Exelixis, Inc.
“The high response rate in patients with ovarian cancer is reflective of the broad anti-tumor activity of XL184 observed in multiple tumor types to date,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “The data from the RDT underscore the novel and differentiated clinical activity of XL184 in diverse tumor indications with predominance of either soft tissue or bone involvement.”
To access the clinical data poster mentioned in this press release, please visit www.exelixis.com.
Broad Clinical Activity of XL184 – Randomized Discontinuation Trial
XL184 has demonstrated anti-tumor activity in 9 of 12 indications studied to date. In ongoing trials, compelling activity has been observed in medullary thyroid cancer, glioblastoma, and clear cell renal cancer. In the RDT, XL184 is being evaluated in nine different tumor types, with clear signals of activity in six: prostate, ovarian, hepatocellular, breast, non-small cell lung cancer and melanoma. The adaptive RDT design allowed for rapid simultaneous assessment of the activity of XL184 across nine different tumor indications. As of the November 1, 2010 cut-off date, a total of 397 patients have been enrolled into the nine disease-specific cohorts, with 273 evaluable for response, and 312 evaluable for safety. Of 273 patients evaluable for response per RECIST, 39 achieved a PR (either confirmed or unconfirmed) and 100 had SD at week 12. The week-12 DCR for the overall population was 49%, with the highest rates occurring in hepatocellular cancer (75%), castration-resistant prostate cancer (71%), ovarian cancer (64%), melanoma (45%), non-small cell lung cancer (42%) and breast cancer (42%). Of note, a breast cancer patient with evidence of bone metastasis on bone scan demonstrated evidence of resolution on bone scan accompanied by 29% reduction in tumor size. XL184 has been generally well tolerated with a consistent adverse event profile across the nine different RDT tumor types.
XL184, an inhibitor of tumor growth, metastasis and angiogenesis, simultaneously targets MET and VEGFR2, key kinases involved in the development and progression of many cancers, including ovarian cancer. It has recently been shown in preclinical models that treatment with selective inhibitors of VEGF signaling can result in tumors that are more invasive and aggressive compared to control treatment. In preclinical studies, upregulation of MET has been shown to occur in concert with development of invasiveness after selective anti-VEGF therapy, and may constitute a mechanism of acquired or evasive resistance to agents that target VEGF signaling. Accordingly, treatment with XL184 in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. Therefore, XL184 has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity.
Exelixis, Inc. is a development-stage biotechnology company dedicated to the discovery and development of novel small molecule therapeutics for the treatment of cancer. The company is leveraging its biological expertise and integrated research and development capabilities to generate a pipeline of development compounds with significant therapeutic and commercial potential for the treatment of cancer. Currently, Exelixis’ broad product pipeline includes investigational compounds in phase 3, phase 2, and phase 1 clinical development. Exelixis has established strategic corporate alliances with major pharmaceutical and biotechnology companies, including Bristol-Myers Squibb Company, sanofi-aventis, GlaxoSmithKline, Genentech (a wholly owned member of the Roche Group), Boehringer Ingelheim, and Daiichi-Sankyo. For more information, please visit the company’s web site at http://www.exelixis.com.
1/Rosner GL, Stadler W, Ratain MJ. et. al. Randomized discontinuation design: Application to cytostatic antineoplastic agents. J Clin Oncol 20:4478-4484, 2002. Pursuant to this design, all patients receive the investigational drug for an initial period of time. Patients with standard radiologic tumor shrinkage within that timeframe would continue investigational therapy, while those with radiologic progression or unacceptable toxicity would discontinue therapy. All patients with radiologic stable disease after the initial therapy period are then randomized to continuing or discontinuing therapy in a double-blind placebo-controlled manner. This is an enrichment strategy in which patients with the end point of interest are preferentially enrolled in the randomized portion and in which the heterogeneity of the randomized population is decreased. These two factors result in an increased power for detecting a clinically relevant difference and decrease the number of patients exposed to placebo. Importantly, the enrichment is driven by the properties of the investigational drug as opposed to clinical prognostic factors identified in historical untreated patients or patients treated with a different class of agents. In addition, the statistical behavior of the trial is not highly dependent on investigators’ assumptions regarding the “no dose effect” (i.e., non-receipt of drug = no effect) for time to progression or stable disease rate, and thus effectively deals with uncertainty in this variable. Finally, patients may find such a trial design more appealing, resulting in brisk accrual.
AMG 386 is a first-in-class investigational “peptibody” (i.e., a combination of a peptide + an antibody) that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 & Ang2). Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are thought to play opposing roles, and the maturation of blood vessels appears to be controlled by their precise balance.
Gary E. Richardson, M.D., Associate Professor of Medicine, Monash University, Victoria, Australia
“Currently the prognosis for ovarian cancer patients is poor,” Professor Richardson said. “Over 75% of patients diagnosed with ovarian cancer present with advanced disease. Current treatments will cure only about a quarter of these patients.”
“The phase 2 trials show that AMG 386 combined with paclitaxel extends survival of heavily pre-treated patients by almost two thirds (4.6 to 7.2 months). In practical terms, this does not add significantly to survival time for terminal patients, but importantly indicates real potential as a first line treatment immediately following surgery.”
Professor Richardson said the treatment worked by inhibiting angiogenesis, the process by which new blood vessels grow from existing blood vessels. “By starving the cancer cells of blood supply, they will die in greater numbers. This form of therapy is complementary to current chemotherapy treatment as it uses a different mechanism to target the cancer.”
Professor Richardson said the phase 3 trial would commence by the end of this year and involve more than 1,000 patients in Australia, Canada and western Europe.
Bruce Mann, M.D., President, Clinical Oncological Society of Australia
Clinical Oncological Society of Australia President, Professor Bruce Mann, said clinicians had been frustrated by the lack of progress in treatment for ovarian cancer. “We don’t want to get ahead of ourselves, but novel approaches like this have the potential to make a real difference in patient survival from this devastating disease.”
The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces anti-tumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF.
Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research
The trial investigators concluded that combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The trial investigators also noted that the rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.
In solid tumors, [vascular disrupting agents] VDA’s, such as ZYBRESTAT™, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies (e.g., bevacizumab/Avastin™), which are designed to prevent new blood vessel formation. … Specifically, Zybrestat™ was tested on advanced solid malignancies in Phase Iclinical trial involving 14 patients. … Nine of fourteen patients experienced disease stabilization for greater than 12 weeks. Three patients experienced disease stabilization for greater than 24 weeks, with two of these patients continuing with stable disease at 47 and 29 weeks, respectively.
Vascular disruption represents a new approach to a validated therapeutic strategy: depriving tumors of blood supply. In solid tumors, VDA’s, such as ZYBRESTAT™, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies (e.g., bevacizumab/Avastin™), which are designed to prevent new blood vessel formation. OXiGENE Inc. (OXiGENE) believes its VDA product candidates may offer advantages over current anti-angiogenic drugs, including superior efficacy and reduced side-effects.
In addition, there is a strong scientific rationale for combining VDA and anti-angiogenesis therapies. OXiGENE and its scientific collaborators have published preclinical research results showing that the combination of OXiGENE VDAs and certain anti-angiogenic drugs (i.e., monoclonal antibodies targeting vascular endothelial growth factor, or VEGF) have synergistic anti-tumor effects. Building upon these results, OXiGENE has undertaken the first-ever human clinical trial of a VDA (ZYBRESTAT) in combination with an anti-angiogenic agent (bevacizumab / AVASTIN.) The additional benefits of vascular disrupting agents include:
This method of treatment is designed to target newly formed abnormal blood vessels, rather than the established blood vessels found in healthy tissue, resulting in fewer side effects in the oncology setting than conventional disease treatments such as radiation and chemotherapy. VDAs are designed to address the complete spectrum of solid tumors, whereas other approaches, which directly target tumor cells, require the development of different drugs for different types of solid tumors.
VDAs are designed to target endothelial cells associated with new blood vessel formation, so drug resistant mutations are unlikely to occur.
Damaging one or two blood vessels can cause thousands of tumor cells to die.
The ability of VDAs to selectively target newly formed or abnormal blood vessels makes them well-suited for certain ocular diseases, such as age-related macular degeneration, in which the formation of new, abnormal blood vessels in the eye plays a key role in disease.
Specifically, Zybrestat™ was tested on advanced solid malignancies in Phase I clinical trial involving 14 patients. The patients were divided into three separate dosage cohorts, representing 45mg/m2 (cohort 1), 54mg/m2 (cohort 2) or 63mg/m2 (cohort 3) of Zybrestat™ every 14 days followed by bevacizumab (Avastin™) at a dosage of 10mg/kg four hours later. The study results indicated two grade 3/4 drug dosage limiting toxicities. Nine of fourteen patients experienced disease stabilization for greater than 12 weeks. Three patients experienced disease stabilization for greater than 24 weeks, with two of these patients continuing with stable disease at 47 and 29 weeks, respectively. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed statistically significant reductions in tumor perfusion/vascular permeability which reversed when Zybrestat™ was used as a monotherapy, but were sustained following the use of bevacizumab (Avastin™). The clinical trial investigators concluded that Zybrestat™ was safe and tolerable at the three dosage levels used, and noted that Zybrestat™ induced profound vascular changes in the solid tumor which were maintained by the presence of bevacizumab (Avastin™).
Comment: ZYBRESTAT™ has broad potential therapeutic utility across a wide range of different solid tumor types, and can potentially be combined with mainstay oncology treatment modalities: chemotherapy, radiation therapy and newer, “molecularly-targeted therapies,” such as tumor angiogenesis inhibitors. Preclinical studies have demonstrated that ZYBRESTAT™ has synergistic or additive effects when incorporated in various combination regimens with all of these treatment modalities. There is a strong scientific rationale for combining ZYBRESTAT™ and tumor angiogenesis inhibiting drugs, and ZYBRESTAT™ is the first VDA to be tested in humans in combination with a tumor-angiogenesis-inhibiting drug (bevacizumab / AVASTIN®).