Following Pivotal Trials, Questions Remain With Bevacizumab in Recurrent Ovarian Cancer

Valerie Sugiyama, MD

Patients with recurrent ovarian cancer have various treatment options, the choice of which may depend on the way the cancer presents. Although many patients benefit from cytoreductive surgery and chemotherapy and experience prolonged remissions, some histologies retain a poor prognosis.

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Valerie Sugiyama, MD, clinical assistant professor of obstetrics and gynecology and gynecologic oncology at Stanford Healthcare, discussed the treatment of patients with recurrent ovarian cancer.

Some standard chemotherapy agents used in patients with recurrent disease are gemcitabine, topotecan, docetaxel, etoposide, liposomal doxorubicin, taxane, and platinum. However, patients who are resistant to platinum tend to experience recurrence within 6 months of their frontline chemotherapy. Resistant patients tend to have shortened progression-free survival (PFS) and overall survival (OS).

Papillary serous carcinomas are the most common and frequent in the United States, but the many other types of epithelial ovarian cancers include clear cell and mucinous.

Clear cell histologies represent about 15% of all epithelial ovarian cancers. These cancers tend to be higher in Asian populations and carry a poorer prognosis, with OS for advanced, stage III/IV clear cell cancers of about 23 months, Sugiyama said. The treatment-free interval is about 10 to 11 months. Patients are often treated with carboplatin plus paclitaxel or oxaliplatin, and bevacizumab (Avastin) is being considered, but for now, response rates for these patients are significantly less compared with those of patients with serous ovarian cancer.

Mucinous histologies represent 5% to 10% of all epithelial ovarian cancers. Patients with these histologies also tend to respond poorly to frontline chemotherapy, with response rates of about 36%—about half that of the response rates of those with nonmucinous ovarian cancers. Some experts speculate that recurrent low-grade mucinous ovarian cancers can benefit from cytoreductive surgery followed by chemotherapy, said Sugiyama. These tumors are more resistant to platinum, although studies are limited. Responses have been observed with taxanes.

“Sadly, there still is a significantly decreased progression-free interval for each ovarian cancer recurrence,” said Sugiyama. “Heavily pretreated women may respond better to divided-dose chemotherapies, which might elicit antiangiogenic properties and have improved tolerability compared with their full-dose single components.”

Utilizing Assays

Lower-dose chemotherapy, as well as chemotherapy holidays, are also considered for heavily pretreated patients.Chemoresponse assays, including ChemoFx from Precision Therapeutics, are also available. In a prospective study evaluating the clinical relevance of a chemoresponse assay for the treatment of patients with recurrent ovarian cancer, investigators found that patients treated with an assay-sensitive regimen had improvements in both PFS and OS.¹ Median PFS was 8.8 months for those treated with an assay-sensitive regimen compared with 5.9 months for those treated with an assay-resistant regimen. Median OS was 37.5 months versus 23.9 months, respectively.

“These are compelling data…it may be reasonable to prospectively utilize chemotherapy agent—response assays to assist clinicians in the optimal prioritization of therapy, rather than just kind of clinically guessing the next line of chemotherapy,” said Sugiyama.

Chemosignature assays and pathway enrichment analyses, too, may be used to identify molecular pathways associated with cancer transformation and proliferation, explained Sugiyama. Some genes, such as POLE mutations, are associated with improved OS, while others, such as GCNT1 and DROSHA, are associated with decreased OS. Creating prediction models may help anticipate response to chemotherapy and outcomes, and they can be used for clinical trial design, added Sugiyama.

Decision Making From Clinical Trials

“All cancers, just like all people, are not genetically the same. Gene expression panels can be useful,” Sugiyama said. “[This area is] likely in its infancy, but as we obtain more and more data, we might one day be able to personalize each individual treatment plan based on how a tumor behaves molecularly.”Several trials have evaluated the use of bevacizumab in the setting of recurrent ovarian cancer. In her presentation, Sugiyama discussed 3 of the randomized clinical trials: OCEANS, GOG-0213, and AURELIA.

OCEANS was a phase III trial of gemcitabine/carboplatin plus bevacizumab followed by bevacizumab plus placebo until progression. Median PFS was 12.4 months for bevacizumab with chemotherapy versus 8.4 months for placebo plus chemotherapy (HR, 0.46; 95% CI, 0.37-0.58; P <.0001). However, the secondary endpoint of OS did not show a statistically significant improvement (HR, 0.95).²

Findings from the GOG-0213 study showed that the addition of bevacizumab to chemotherapy led to a median PFS of 13.8 months compared with 10.4 months for chemotherapy alone (HR, 0.61; 95% CI, 0.51-0.72).³ There was a nonstatistically significant difference in median OS of 5 months between bevacizumab plus chemotherapy (42.2 months) and chemotherapy alone (37.3 months).

“The intention-to-treat analysis for OS was not significant, but the corrected treatment-free interval stratification indicates that this may be a reasonable strategy,” said Sugiyama.

Phase III data from the AURELIA trial led to the November 2016 FDA approval of bevacizumab in combination with chemotherapy for the treatment of patients with platinum-resistant recurrent ovarian cancer. In this trial, median PFS with the addition of bevacizumab was 6.7 months compared with 3.4 months with chemotherapy alone, representing a 62% improvement.⁴

“The risks in all 3 of these trials are about the same for bevacizumab, including hypertension, proteinuria, posterior leukoencephalopathy syndrome, fistulas, blood clots, and wound healing issues,” Sugiyama explained. “In summary, all 3 trials—whether patients were platinum-sensitive or platinum-resistant&mdash;showed a PFS benefit of bevacizumab, but OS was still a little bit limited and not statistically significant.”

Although many other trials have shown bevacizumab to be helpful in the recurrent setting of ovarian cancer, its risks as well as potential overall cost must be considered, concluded Sugiyama.

References

1. Rutherford T, Orr J Jr, Grendys E Jr, et al. A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. Gynecol Oncol. 2013;131(2):362-367. doi: 10.1016/ j.ygyno.2013.08.009.
2. 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. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/ JCO.2012.42.0505.
3. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multi- centere, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-6.
4. Pujade-Lauraine E, Hilpert F, Weber B, et al; AURELIA Investigators. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol. 2012;30(suppl; abstr LBA5002). doi: 10.1200/jco.2012.30.18_suppl.lba5002.