Pembrolizumab (trade name Keytruda) is a humanized antibody that targets programmed cell death protein 1 (PD-1) on lymphocytes. In 2014, the US Food and Drug Administration approved pembrolizumab for treatment of melanoma, non-small cell lung cancer, head and neck squamous cell cancer, Hodgkin lymphoma, urothelial carcinoma, stomach cancer, solid tumors with mismatch repair deficiency or microsatellite instability, and recurrent or metastatic cervical cancer expressing PD-L1, but the drug was not approved for ovarian cancer . The phase II KEYNOTE-100 study (ClinicalTrials.gov identifier: NCT02674061) recruited 376 patients with recurrent ovarian cancer for pembrolizumab monotherapy (intravenous, triweekly, 200 mg for 35 cycles). The objective response rate was only 8.0% (1.9% complete response and 6.1% partial response). The median progression-free survival was 2.1 months (95% CI, 2.1–4.1) . According to the KEYNOTE-100 study, PD-L1 expression was considered a predictive biomarker for the therapeutic response of pembrolizumab. However, our patient was negative for PD-L1 expression in the tumor. Her unexpected excellent response supports the need to identify other theranostic biomarkers for checkpoint inhibitors . Because OCCC is prevalent in Asia , a subgroup analysis of 21 Japanese patients with OCCC in the KEYNOTE-100 trial revealed a better objective response rate of these patients (19.0, 95% CI: 5.4–41.9). The hypothesis and the reasons why OCCC showed a better response to immune checkpoint inhibitors require further investigation.
Mutations in ARID1A may be predictive for immune checkpoint inhibitors in OCCC . ARID1A (AT-rich interactive domain-containing protein 1A), an important subunit of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex, can alter the positions of nucleosomes along DNA . The mammalian SWI/SNF complex is considered a tumor suppressor in several human malignancies and plays an important role in endometriosis-associated ovarian cancer . ARID1A can recruit MSH2 to chromatin during DNA replication and promote mismatch repair, and ARID1A inactivation compromises mismatch repair and increases mutagenesis and neoantigen levels . In a syngeneic mouse model, an ARID1A-deficient ovarian cancer tumor displayed an increased mutation load, increased PD-L1 expression, and elevated numbers of tumor-infiltrating lymphocytes because of neoantigen production. Treatment with an anti-PD-L1 antibody reduced the tumor burden and prolonged the survival of mice bearing ARID1A-deficient but not ARID1A wild-type ovarian tumors. In addition to increased PD-L1, ARID1A may regulate other factors associated with oncogenic pathways such as PIK3CA-activating mutations, DNA methylation, or VEGF . The levels of these signatures and markers should be determined after therapy using a liquid biopsy with genetic/epigenetic analysis in the future. Our patient had two frame shifts in ARID1A (p.M1154fs*7 and p.Y788*). In a clinical cohort report, progression-free survival after immune checkpoint blockade therapy was significantly longer in patients with ARID1A-altered tumors (n = 46) than in patients with wild-type ARID1A (n = 329) (p = 0.006) . In multivariate analyses, ARID1A alterations could predict longer progression-free survival after checkpoint blockade (95% CI 0.39 to 0.94, p = 0.02), independent of microsatellite instability or the mutational burden. These reports demonstrate that the functional loss of ARID1A may act in conjunction with immune checkpoint blockade therapy.
Bevacizumab (trade name Avastin) is an angiogenesis inhibitor that blocks vascular endothelial growth factor A . In recent years, bevacizumab has been added to chemotherapy as a “maintenance” strategy in front-line, recurrent cisplatin-sensitive, or cisplatin-resistant settings of ovarian cancer . Two single-agent bevacizumab phase II trials (GOG-0170D and Genentech AVF 2949 g) revealed response rates of only 16–21% in recurrent ovarian cancer. Later phase III trials (GOG-0218, OCEANS, AURELIA, ICON7) suggested that bevacizumab is effective in combination with chemotherapy. An open-label phase II clinical trial on a three-factor combination (pembrolizumab, 200 mg, combined with bevacizumab, 15 mg/kg every 3 weeks, and oral cyclophosphamide, 50 mg every day) in 40 patients with platinum-sensitive or platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer was presented at the annual meeting of the 2019 Society of Gynecologic Oncology . The scientific rationale for this three-drug treatment is that lymphocyte trafficking is improved and that dendritic cell function is restored using bevacizumab. Additionally, circulating regulatory T cells become depleted, while the cytotoxic potential of T cells and natural killer cells is simultaneously restored. These effects help increase the efficacy of pembrolizumab. The 6-month progression-free survival rate was 70%, which included 15 patients who achieved a partial response and 13 who had stable disease. The investigators described the combination as “well-tolerated”. Another multicenter, randomized phase 2 study (Clinical Trial NCT02337491) of recurrent glioblastoma patients treated with pembrolizumab with (cohort A) and without bevacizumab (cohort B) revealed a median follow-up of 25.3 months and median progression-free survival of 4.1 months in cohort A and 1.4 months in cohort B. The proportion of 6-month progression-free survival was 26.0% in cohort A (95% CI, 16.3–41.5) and 6.7% in cohort B (95% CI, 1.8–25.4), suggesting an advantage of the combination of pembrolizumab and bevacizumab . Both trials demonstrated tolerable side effect profiles. The current patient was not administered oral cyclophosphamide because of concerns regarding side effects from conventional chemotherapy. She did not have hypertension or other common side effects, such as pneumonitis, colitis, or hepatitis, but had only mild polyarthritis in both hands.
In conclusion, OCCC is a subtype of EOC that is prevalent in Asia and has a poor prognosis. Combination treatment with pembrolizumab and bevacizumab may be considered in OCCC, particularly with ARID1A mutations. Many clinical trials (NCT03596281 and NCT04361370) to determine the efficacy of this combination therapy for ovarian cancer are on the way. Since our manuscript was submitted, a phase 2 nonrandomized clinical trial (NCT02853318 study collaborated by National Cancer Institute) testing pembrolizumab combined with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer was published . While this study only included four patients diagnosed with OCCC (2 pure and 2 mixed subtypes), it is not clear how they fared in the trial. The present report may provide insight into the design of further trials that test the combination of pembrolizumab and bevacizumab for OCCC.