Frontline Bevacizumab Plus Chemotherapy Elicits PFS, OS Benefit in Ovarian Clear Cell Carcinoma

Bevacizumab (Avastin) combined with first-line chemotherapy was shown to improve progression-free survival (PFS) and overall survival (OS) in patients with advanced ovarian clear cell carcinoma (OCCC), according to findings from a multicenter, retrospective analysis that were presented at the 2022 ASCO Annual Meeting.¹

“The addition of bevacizumab to platinum-based chemotherapy improved PFS and OS in [patients with] advanced OCCC,” said Toshiyuki Seki, MD, of the Department of Obstetrics and Gynecology, Kashiwa Hospital, The Jikei University School of Medicine, Chiba, Kashiwa, Japan. “The benefit was especially significant in stage IIIA and IIIB disease.”

OCCC is a rare histological type of epithelial ovarian cancer that is typically resistant to chemotherapy, accounting for its historically poor prognosis for patients. Most patients will have early-stage disease, but about 30% have advanced disease. Seki also noted that the frequency of OCCC is more common in Asian countries, especially in Japan.

Bevacizumab has shown an impact on treating patients with epithelial ovarian cancers and was first approved in Japan in November 2013 for the treatment of patients with ovarian cancer.² Moreover, A prior analysis in a small group of patients with OCCC showed that treatment with bevacizumab added to first-line chemotherapy led to a significant difference in PFS.³

Additionally, a study of 2 potential subtypes of OCCC by gene expression signatures suggested that patients with a mesenchymal type, where angiogenesis and the PI3K-AKT and IL-6 signaling pathways were activated, may benefit more from bevacizumab than those with more epithelial expression (HR, 0.5; P = .1978), despite higher stages of disease.⁴

The investigators sought to determine if the addition of bevacizumab to platinum-based chemotherapy in the front-line setting could then benefit patients with advanced OCCC. They enrolled patients with stage III or IV OCCC who were treated between 2008 and 2018 at 8 institutions across Japan and compared survival outcomes for those who were treated with bevacizumab (n = 43) to those who did not receive bevacizumab (n = 102), as they were treated before the drug’s approval in Japan.

In the bevacizumab-treated group, the median age was 56 years (interquartile range [IQR], 49-65). The majority of patients had FIGO stage III disease (74%), a performance status of 0 or 1 (81%), and absent thrombosis (67%). Ninety-eight percent of the group underwent debulking surgery with a median surgical complexity score of 5 (IQR, 3-7) and no residual tumor in 67% of patients. Frontline chemotherapy consisted of 175 mg/m² of paclitaxel and 6 area under the curve carboplatin triweekly in 33% of patients, weekly paclitaxel and carboplatin in 42%, dose-dense paclitaxel and carboplatin in 21%, and a different platinum-based regimen in 5%. Patients in this group received a median of 16 cycles (IQR, 6-21) of bevacizumab.

In the non–bevacizumab-treated group, the median age was 53 years (IQR, 46-61). Most patients had FIGO stage III disease (87%), a performance status of 0 or 1 (98%), and absent thrombosis (64%). Ninety-six percent of the group underwent debulking surgery with a median surgical complexity score of 4 (IQR, 2-5) and no residual tumor in 51% of patients. Frontline chemotherapy consisted of triweekly paclitaxel and carboplatin in 63% of patients, weekly paclitaxel and carboplatin in 12%, dose-dense paclitaxel and carboplatin in 16%, and a different platinum-based regimen in 10%.

Significant improvement was seen with the addition of bevacizumab to first-line platinum-based chemotherapy in terms of both PFS (P = .023) and OS (P = .027).

By multivariate analysis, the most significant factors for PFS and OS benefit were surgical outcome followed by performance status and bevacizumab use. “Complete tumor resection is still the strongest factor for improving survival,” Seki added.

In patients who had no residual disease after surgery compared with those who did have residual disease, the hazard ratio (HR) for PFS was 0.33 (95% CI, 0.22-0.52; P < .001) and the HR for OS was 0.29 (95% CI, 0.18-0.46; P < .001). For patients with a lower performance status of 0 to 1 compared with those with a performance status of 2 or higher, the HR for PFS was 0.36 (95% CI, 0.16-0.83; P = .017) and the HR for OS was 0.32 (95% CI, 0.14-0.73; P = .007). In terms of bevacizumab use, treatment with bevacizumab vs without led to an HR for PFS of 0.51 (95% CI, 0.29-0.89; P = .019) and an HR for OS of 0.49 (95% CI, 0.27-0.90; P = .02).

Subgroup analysis for PFS showed benefit for bevacizumab across all groups analyzed, but patients with lower stages of disease demonstrated a significant benefit from the addition of bevacizumab with an HR of 0.35 (95% CI, 0.15-0.78) for patients with stage IIIA or IIIB disease compared with 0.77 (95% CI, 0.45-1.30) in those with stage IIIC or IV disease.

Additionally, patients with a smaller amount of ascites benefited more from bevacizumab use, which Seki commented was an expected result. Patients with fewer than 300 cc ascites had an HR of 0.46 (95% CI, 0.36-1.06) compared with 0.91 (95% CI, 0.51-1.63) in those with at least 300 cc ascites. Younger patients also showed a greater benefit from the addition of bevacizumab at 0.46 (95% CI, 0.24-0.88) for patients 53 years or younger and 0.82 (95% CI, 0.46-1.48) for ages 54 years and up.

Grade 3 or higher toxicities observed with bevacizumab treatment included hypertension in 19% of patients, proteinuria in 12%, ileus in 5%, recto-vaginal fistula in 2%, and intestinal bleeding in 2%. There were no cases of treatment-related death in the analysis.

Seki said that possible limitations of the analysis included potential differences in the quality of care between the 2 groups with the quality of surgical skill and supportive care improving over time. Also, there may have been undocumented reasons for why physicians chose to avoid bevacizumab use in certain patients. He suggested that other studies are needed to confirm the results of this analysis.

References

1. Seki T, Tate S, Nishikimi K, et al. Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: A multicenter, retrospective analysis. J Clin Oncol. 2022;40(suppl 16):5502. doi:10.1200/JCO.2022.40.16_suppl.5502
2. Anti-Cancer Agent “Avastin," Obtained Approval for Additional Indication of Ovarian Cancer. News release translation. Chugai Pharmaceutical Co., Ltd. November 22, 2013. Accessed June 6, 2022. https://bit.ly/3MlkMVR
3. Tate S, Nishikimi K, Matsuoka A, et al. Bevacizumab in first-line chemotherapy improves progression-free survival for advanced ovarian clear cell carcinoma. Cancers (Basel). 2021;13(13):3177. doi:10.3390/cancers13133177
4. Tan TZ, Ye J, Yee CV, et al. Analysis of gene expression signatures identifies prognostic and functionally distinct ovarian clear cell carcinoma subtypes. EBioMedicine. 2019;50:203-210. doi:10.1016/j.ebiom.2019.11.017