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SGO Annual Meeting

Angeles Alvarez Secord, MD, gynecologic cancers specialist, Duke Cancer Center, discusses the importance of understanding patient preferences regarding treatment regimens.

If practitioners do not understand their patients’ goals for therapy, then they may not be delivering patients the best regimen, Secord says. While some patients deem survival the most important factor of their therapy, others may place quality of life higher on the list. Therefore, practitioners could possibly provide patients with a more toxic regimen that does not improve their survival in a clinically meaningful way, if they do not take their preferences into account.

What a physician thinks is an overly toxic regimen may not be the equivalent of what a patient believes is overly toxic, Secord explains. For example, one patient may be willing to accept severe toxicity in order to obtain additional time of living longer without disease, while some patients may not be able to tolerate any amount of toxicity.

As an example, Secord describes a patient who is an artist and soccer player with a preference to avoid therapy with neurotoxicity, since it will dramatically affect her livelihood and regular activities.

Angeles Alvarez Secord, MD, gynecologic cancers specialist, Duke Cancer Center, discusses the importance of understanding patient preferences regarding treatment regimens. 


Dr. Secord on Understanding Patient Preferences

Ursula A. Matulonis, MD, medical director, gynecologic oncology, Susan F. Smith Center for Women’s Cancers, institute physician, Dana-Farber Cancer Institute, discusses managing toxicities associated with olaparib for patients with ovarian cancer.

If a patient being treated with olaparib develops low-grade toxicities, such as grade I/II nausea or vomiting, Matulonis advises them to remain on the treatment. These side effects will typically improve over time.

However, if a patient has grade III/IV nausea, weight loss, abdominal pain, or loss of appetite, a break from olaparib is appropriate, she says. This is followed by a dosage reduction, such as 400 mg to 200 mg daily. This reduction is permitted to maintain for efficacy; however, if the dosage reduces to 100 mg daily, there are concerns for efficacy.

Clinicians can escalate a patient's dosage if the patient is easily managing the treatment and/or any side effects.

Ursula A. Matulonis, MD, medical director, gynecologic oncology, Susan F. Smith Center for Women's Cancers, institute physician, Dana-Farber Cancer Institute, discusses managing toxicities associated with olaparib for patients with ovarian cancer.


Dr. Matulonis on Toxicities With Olaparib for Patients With Ovarian Cancer

Pretreated patients with recurrent ovarian cancer had a 2.5-month progression-free survival (PFS) benefit when receiving the vascular disrupting agent (VDA) fosbretabulin plus bevacizumab compared with bevacizumab (Avastin) alone, according to data from the phase II GOG186i study; however, hypertension rates were double in patients receiving the combination regimen.

In the phase II trial, the risk of disease progression was reduced by 31.5% with fosbretabulin/bevacizumab compared with single-agent bevacizumab (7.3 vs 4.8 months; HR = 0.685; 90% CI, 0.47-1.00;). At the time of the analysis, data on overall survival (OS) were not yet mature (HR = 1.03; 90% CI, 0.56-1.89).

Bevacizumab is known to be active as a single agent against recurrent ovarian cancer, while fosbretabulin selectively targets pre-existing tumor vasculature with a resulting vascular shutdown that leads to cell death and necrosis. Given this mechanism of action, the rates of cardiac events were expectedly higher with the combination. The rate of grade >2 hypertension was 35% with the combination versus 16% with single-agent bevacizumab.

Bradley J. Monk, MD, presented findings during the Seminal Abstract Session at the 2015 Society of Gynecologic Oncology’s (SGO) Annual Meeting on Women’s Cancer.

“Based on the progression-free survival and tolerability of these two anti-vascular therapies, further evaluation is warranted for this chemotherapy-free regimen, with the understanding that fosbretabulin may increase the frequency of hypertension,” Monk, professor of gynecologic oncology at the University of Arizona Cancer Center, said at the conference. “Overall survival data are currently too early in the timeline to warrant any conclusions, because this was a hypothesis-generating trial. But, in general, we now know that vascular disruption is highly significant.”

In the trial, 107 patients with persistent or recurrent epithelial ovarian, fallopian tube or peritoneal carcinoma, measurable or detectable disease, and 1-3 prior regimens of chemotherapy were randomized to bevacizumab (n = 54; 15 mg/kg IV every 3 weeks) or bevacizumab (15 mg/kg IV every 3 weeks) plus fosbretabulin (n = 53; 60 mg/m2). Patients received treatment every three weeks until disease progression or unacceptable levels of toxicity occurred.

The randomization was stratified by disease status (measurable vs nonmeasurable), prior bevacizumab and platinum-free interval. The study’s primary objective was to assess whether the addition of fosbretabulin to bevacizumab prolongs the duration of PFS. Two secondary objectives were to compare response rates and OS and to evaluate AEs in each study arm.

The objective response rate (ORR) with bevacizumab alone was 28.2% (90% CI, 16.7%-42.3%) among 39 patients with measurable disease. The ORR with the combination regimen was 35.7% in 42 patients (90% CI, 23.5%-49.5%). The odds ratio for responding to the combination arm relative to the bevacizumab arm was 1.41 (90% CI 0.58-3.47).

Both regimens were well tolerated enough for patients to complete a relatively high number of cycles. The median number of cycles with bevacizumab was 7 versus 6 with the combination. Grade 3 hypertension in the bevacizumab arm was 19.6% compared with 32.7% in the combination arm. There was one grade 3 thromboembolic AE.

No grade 5 treatment-related AEs occurred in either study arm. One grade 4 AE occurred in each treatment arm: a metabolism/nutrition-related AE in the bevacizumab group and a hypertension-related AE in the bevacizumab and fosbretabulin group. Additionally, one bowel perforation occurred in the bevacizumab arm, but all adverse events were manageable.

Fosbretabulin is a potent and reversible tubulin depolymerizing agent. It selectively affects immature endothelial cells typically seen in solid tumors, which lack smooth muscle and pericytes and rely more on tubulin to maintain the vessel wall’s flat shape. Tubulin inhibition causes rounding in the affected epithelial cells, obstructing the blood vessel lumen. A blockage at any point in a vessel segment will shut off blood flow upstream and downstream, which leads to rapid death of cells.

“It’s possible that anti-angiogenesis agents like bevacizumab might prevent revascularization during and after VDA treatment,” Monk, professor of gynecologic oncology at the University of Arizona Cancer Center, said at the conference.

Although a phase III study to explore the combination of fosbretabulin and bevacizumab has not yet been initiated, a phase II study is exploring fosbretabulin in patients with gastrointestinal neuroendocrine tumors. Patients in this study are required to have elevations in specific biomarkers, such as serotonin, 5-hydroxyindoleacetic acid, chromogranin A, neurokinin A, and neuron-specific enolase.

	Monk, BJ. Randomized phase 2 evaluation of bevacizumab versus bevacizumab/fosbretabulin in recurrent ovarian, tubal or peritoneal carcinoma: a gynecologic oncology group study. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Seminal Abstract 4.

View more from the 2015 SGO Annual Meeting

Fosbretabulin plus bevacizumab lowered the risk of progression by 31.5% but doubled the rate of hypertension compared with bevacizumab alone in patients with recurrent ovarian cancer.

Fosbretabulin/Bevacizumab Combo Delays Progression, But Doubles Hypertension in Ovarian Cancer

Treatment with bevacizumab (Avastin) plus chemotherapy resulted in a non-statistically significant improvement in overall survival (OS) of nearly 5 months compared with chemotherapy alone for women with platinum-sensitive recurrent ovarian cancer, according to results from the phase III GOG0213 trial presented at the 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.

The clinical trial results mark the first time a phase III study has shown improvement in OS for this patient population. Although findings from GOG0213 narrowly missed statistical significance, they build upon evidence supporting the use of bevacizumab in recurrent platinum-sensitive settings. In November 2014, the FDA approved bevacizumab in combination with chemotherapy for the treatment of women with platinum-resistant recurrent ovarian cancer based upon an improvement in progression-free survival (PFS).

Lead author Robert L. Coleman, MD, professor and vice chair of Clinical Research, Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, is pleased with the findings. “Even though we narrowly missed statistical significance, we saw a strong trend toward improved overall survival,” Coleman said.

Coleman indicated the trial would address several persistent questions in the treatment of women with these cancers. “Platinum-based doublets have become a standard of care for women with platinum-sensitive recurrent ovarian cancer, but the roles of secondary bevacizumab and secondary surgery have yet to be defined,” he said at the conference. “There’s intense interest surrounding both of these issues, as well as a desire to understand bevacizumab’s effect on overall survival when other trials have largely assessed progression-free survival.”

GOG0213, which was initiated in December 2007, accrued 674 women with epithelial ovarian, primary peritoneal, or fallopian tube cancers whose disease recurred after frontline or maintenance therapy that could have included prior bevacizumab. Nearly 70% of the participants were aged 50-69 years.

The study’s primary objective was to examine the role of bevacizumab (15 mg/kg) in combination with paclitaxel (175 mg/m

) plus carboplatin (AUC5) followed by maintenance with bevacizumab versus the same chemotherapy doublet. Both arms received paclitaxel and carboplatin for six cycles, and the study arm patients then continued with bevacizumab maintenance. Chemotherapy randomization terminated in August 2011 and matured for OS (n = 214 events in the control arm) in November 2014.

Median OS for patients in the bevacizumab treatment group was 42.2 months, compared with 37.3 months for those receiving chemotherapy alone (HR = 0.83; 

 = .056). PFS improved by nearly 3.5 months with bevacizumab: 13.8 months compared with 10.4 months for patients on chemotherapy alone (HR = 0.61; 

 <.0001). The risk reduction for progression and death with bevacizumab were 39% and 17%, respectively.

The study’s second objective is to examine the role of secondary cytoreduction before chemotherapy is initiated. Enrollment for this objective is ongoing; accordingly, results are pending. Both objectives share the same primary endpoint of OS; secondary endpoints for both include safety and toxicity, PFS, and intervention-dependent quality of life (QoL).

During the trial, patients were randomized to chemotherapy (n = 337) or chemotherapy plus bevacizumab (n = 337). Each treatment arm had equal representation among three strata that had been prospectively defined: cytoreductive surgery as part of the study’s second objective (8%); prior platinum-free interval (6-12 months, 31%; >12 months, 69%); and previous bevacizumab exposure (yes, 10%; no, 90%).

Adverse events (AEs) increased with the bevacizumab-containing regimen but all remained within expected parameters. AEs of special interest (grade â‰¥3) for the bevacizumab arm versus chemotherapy alone, respectively, included thromboembolisms (4% vs 1%), infections (13% vs 6%), hypertension (12% vs <1%), proteinuria (8% vs 0%), and any grade of GI perforation or fistula/abscess (15% vs 4%). All-cause deaths were 2 in the chemotherapy group versus 9 in the bevacizumab group; of these, 7 were possibly related to study treatment.

During his presentation, Coleman compared outcomes from six studies that had sought to improve treatments for women with recurrent ovarian cancer. Improvements in PFS have established platinum-based doublets as the standard of care but none of the studies showed an improvement in OS.

Similarly, bevacizumab enhanced PFS when added to gemcitabine and carboplatin compared with the chemotherapy combination alone in the phase III OCEANS trial but did not demonstrate a statistically significant OS improvement.Â 

, Coleman answered the question of whether he believes GOG 213’s findings are already practice changing. “Yes, because we have pushed the median survival past 40 months in patients with recurrent disease,” he said. “We’re starting to find strategies and treatments that ultimately are quite strong.”

			Coleman RL, Brady RF, Herzog TJ, et al. A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer. Presented at: Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer 2015; March 28-31, 2015; Chicago, IL. Abstract 3 (late breaking).

			Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase iii trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer [published online April 23, 2012]. 

Treatment with bevacizumab plus a chemotherapy doublet extended overall survival by nearly 5 months compared with chemotherapy alone for women with platinum-sensitive recurrent ovarian cancer.

Bevacizumab Regimen Shows Survival Trend in Phase III Ovarian Cancer Trial

Treatment with the immunotherapy Vigil, formally known as FANG, delayed time to progression in all patients with stage III/IV ovarian cancer who were treated with the autologous tumor cell vaccine compared with those who were not, according to an open-label phase II trial.

In the 31-patient trial, which was presented at the 2015 SGO Annual Meeting, patients were randomized to receive the vaccine or no treatment following surgery. Of the 20 patients who received the vaccine, a median time to progression had not yet been reached compared with a median of 14.5 months in those who were not treated.

Additionally, the Vigil vaccine, composed of granulocyte macrophage colony-stimulating factor [GM-CSF] bi-shRNAi furin vector-transfected autologous tumor cells, demonstrated an acceptable safety profile, and participants showed a high rate of immune response via T-cell activation.

Lead author Jonathan Oh, MD, of Texas Oncology in Dallas, called the study findings encouraging. “Results in phase II ovarian cancer suggest Vigil-mediated prolongation of time to recurrence,” he said during a scientific plenary session.

A preceding trial discovered longer-than-expected survival duration that correlated with ELISPOT reactivity. This earlier trial examined a variety of advanced tumors, ranging from adenoid cystic carcinoma to synovial sarcoma. Ovarian cancers represented a small percentage of the study total.

“We believe further randomized assessment is justified based on a 93% ELISPOT [Enzyme-Linked ImmunoSPOT assay] conversion in phase II to minimal residual disease in ovarian cancer. That’s compared to a phase I result of 54% conversion in patients with bulky disease.”

Oh et al narrowed the phase II study’s focus to ovarian cancer for several reasons. “Approximately 75% of stage III/IV patients with ovarian cancer who achieve clinical complete response (cCR) relapse within 2 years, and there is no standard of care for maintenance therapy,” he noted. “We thought there was potential to determine regression-free survival (RFS) difference by running a 2:1 randomized phase II trial.”

Study participants were patients with stage III/IV ovarian cancer who achieved cCR following surgical debulking and chemotherapy. Tumor tissue was harvested during surgical debulking to use in vaccine construction. Once patients achieved cCR and were confirmed to be ELISPOT-negative, 20 patients were randomized to receive the Vigil treatment, and 11 patients were randomized to the non-Vigil group.

Patients in the active treatment group received 1.0 x 10

cells/intradermal injection once monthly for up to 12 doses. Patients in the control group received no maintenance therapy. The trial design allowed for patients to be transferred to the active treatment group if they experienced disease progression during the trial.

Adverse events (AEs) were minimal. During phase I, phase II, and phase II crossover combined, 50 patients with ovarian cancer received a total of 141 Vigil injections. No grade 3 or 4 AEs were recorded in the phase II study. Only one grade 2 AE was reported (erythema). The most common grade 1 AEs were indurations (28), injection-site reactions (14), and erythema (23).

The phase II trial’s key endpoints were patient safety, immune response, and RFS. Noting that the historical average of RFS is 13 to 18 months, the team discontinued this trial when the active treatment group’s median RFS reached 19.3 months compared with 12.4 months in the control group.

With the 3-year disease-recurrence rate of 60% in the active treatment group compared with 91% in the control group, researchers will pursue a phase III trial involving 382 evaluable patients.

“It’s especially important to note that approximately 93% of patients demonstrated T-cell activation against their tumor antigen as early as 1 month after vaccination,” Oh said. “This is an area of great potential.”

In February 2015, a phase III study was initiated to explore Vigil as a treatment for women with stages III/IV high-grade ovarian cancer following cytoreduction and 5 to 6 cycles of standard of care chemotherapy. The company developing the vaccine, Gradalis, plans to submit findings from this study to regulatory authorities, if they are positive.

	Oh J, Barve M, Grosen EA, et al. Randomized phase II trial of maintenance autologous tumor cell vaccine (FANG

) following clinical complete response (cCR) in stage III/IV ovarian cancer: preliminary results. Presented at: Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer 2015; March 28-31, 2015; Chicago, IL. Abstract No 1.

Treatment with the immunotherapy Vigil delayed time to progression in all patients with stage III/IV ovarian cancer who were treated with the autologous tumor cell vaccine compared with those who were not in an open-label phase II trial.

Autologous Vaccine Delays Progression Following Surgery for Ovarian Cancer

Analyses of clinical trials continue to illuminate the role of the PARP inhibitor olaparib (Lynparza) in the treatment of women with ovarian cancer, Ursula A. Matulonis, MD, explained during a plenary session at the 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.

Matulonis presented findings from a post-hoc exploratory analysis of interim phase II trial results and a pooled analysis of six clinical trials looking at olaparib monotherapy at time of relapse. Full findings from the phase II investigation led to an accelerated approval from the FDA for olaparib as a treatment for women with BRCA-positive advanced ovarian cancer following three or more prior lines of chemotherapy in December 2014.

In this phase II trial, maintenance monotherapy with 400-mg, twice-daily olaparib led to a significant improvement in progression-free survival versus placebo, especially in patients with a 

 mutation (BRCAm); however, no statistically significant increase in overall survival (OS) was seen in either the overall or the BRCAm populations. Investigators hypothesized that with 12% of patients in the placebo arm receiving a PARP inhibitor after disease progression, this may have confounded the results.

In the post-hoc 198-patient analysis reported at SGO, all patients from trial sites where at least one patient received post-progression treatment with a PARP inhibitor were excluded. This resulted in a change in the OS hazard ratio (HR) in BRCA-positive patients at a 95% confidence interval as follows: OS HR all sites = 0.73 (0.45-1.17); PARP inhibitor sites excluded = 0.52 (0.28-0.97). Due to small sample sizes and data immaturity (currently 58%), further analysis will follow when the data mature.

Matulonis, medical director of gynecologic oncology at Dana-Farber Cancer Institute, said the findings from the post-hoc analysis might support the initial hypothesis that patients switching treatments due to disease progression may have confounded the beneficial impact of olaparib on OS.

“This analysis showed that placebo patients had longer treatment with a subsequent PARP inhibitor than with placebo,” she said at the conference. “Despite the later use of a PARP inhibitor in the course of their disease, patients still received benefit.”

In the pooled analysis of 300 women with relapsed ovarian, peritoneal, or fallopian tube cancer, all patients had received olaparib 400-mg capsules twice daily as monotherapy in one of six prospective clinical trials. The analysis used germline BRCAm status and patient outcomes data based on definitions from the original trials and assessed objective response rate (ORR) using RECIST criteria and duration of response (DoR) based on CT/MRI imaging at baseline.

Median DoR was 7.4 months in the overall study population and 7.8 months in patients who received ≥3 prior chemotherapy regimens; ORR was 36% and 31%, respectively.

Adverse events (AEs) were recorded throughout the six trials and graded by NCI CTCAE. AEs of any grade were seen in more than 25% of patients, ranging from 26% with abdominal pain (n = 79) to up to 65% with nausea (n = 196). Grade 3 or 4 AEs ranged from 1% with diarrhea (n = 4) to 14% with anemia (n = 43).

Serious AEs (SAEs) were reported in 30% of patients overall and 34% of those who had received three or more lines of chemotherapy. Causally related SAEs occurred in 10% of patients. Eight patients had an AE that led to death, but none was considered causally related to olaparib. Olaparib’s overall tolerability profile was similar in patients with and without the germline BRCA mutation.

“It’s important to note that adverse events were generally low grade and manageable without olaparib discontinuation,” lead author Matulonis said. “And duration of response was not reduced in patients who had received three or more prior lines of chemotherapy. Further, olaparib treatment benefits were observed in all patient subgroups.”

Phase III studies of the agent in patients with ovarian cancer and a germline BRCAm are ongoing. SOLO1 (NCT01844986) is a randomized, double-blind, placebo-controlled trial in patients who are in response following first-line platinum-based chemotherapy. SOLO2 (NCT01874353) is a randomized, double-blind, placebo-controlled trial in patients with platinum-sensitive relapsed disease who are in response following platinum-based therapy (having completed ≥2 lines of platinum-based therapy). SOLO3 (NCT02282020) is a a randomized, open-label trial of olaparib versus single-agent chemotherapy (physician’s choice) in patients with platinum-sensitive relapsed disease (who have completed ≥2 lines of platinum-based therapy).

			Matulonis UA, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation: overall survival adjusted for post-progression PARP inhibitor therapy. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Abstract 13.

			Matulonis UA, Penson RT, Domchek SM, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multi-study sub-analysis.  Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Abstract 14.

Analyses of clinical trials continue to illuminate the role of the PARP inhibitor olaparib in the treatment of women with ovarian cancer, according to Ursula A. Matulonis, MD.

SGO Annual Meeting | Conference

Dr. Secord on Understanding Patient Preferences

Dr. Matulonis on Toxicities With Olaparib for Patients With Ovarian Cancer

Fosbretabulin/Bevacizumab Combo Delays Progression, But Doubles Hypertension in Ovarian Cancer

Bevacizumab Regimen Shows Survival Trend in Phase III Ovarian Cancer Trial

Autologous Vaccine Delays Progression Following Surgery for Ovarian Cancer

Studies Illuminate Olaparib's Continued Role in Ovarian Cancer