PEMBRO With Chemo in Neo Adj Treatment of Ovarian Cancer .

There are several data suggesting that pembrolizumab and bevacizumab may be synergistic. Enhanced tumor angiogenesis is commonly associated with absence of tumor-infiltrating T cells in patients. There is evidence in OC that tumor expression of VEGF is negatively correlated to the density of CD3+TILs and this phenotype is associated with early recurrence, consistent with prior studies showing a correlation of VEGF to early recurrence and short survival. Furthermore, in ascites, high levels of VEGF correlate to low numbers of NK T-like CD3+CD56+ cells This randomized phase II study aims to evaluate the efficacy of pembrolizumab in combina-tion with the standard neo adjuvant chemotherapy followed by IDS and the safety of this strategy in patients with advanced ovarian cancer. We assume that its administration in the neo adjuvant setting combination with standard of care (4 cycles of standard chemotherapy) would improve the response rate and consequently will help to achieve optimal debulking rate at IDS. After surgery, patients will continue to be treated with standard of care (chemotherapy for 2 to 5 cycles plus or less bevacizumab) or the same combination plus pembrolizumab (keytruda).

The standard procedure for initial diagnosis recommends the realization of laparoscopy first for all suspicious advanced ovarian carcinoma. This procedure should able to confirm histo-logical diagnosis and to describe the all abdominal extension of the disease. For advanced stages, complete primary cyto-reductive surgery followed by 6 cycles of chemotherapy based remains the standard of care as first treatment in ovarian cancer. It is part of a large surgery including total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, lymphadenectomy and removal of all peritoneal carcinomatosis. More recently, complete resection of all macroscopic disease at primary debulking surgery has been shown to be the single most important independent prognostic factor in advanced ovarian carcinoma , and this was confirmed for interval debulking surgery (IDS) after neo adjuvant chemotherapy in the EORTC-GCG study . These results suggest that neo-adjuvant chemotherapy followed by surgical cytoreduction is an acceptable management strategy for patients with advanced ovarian cancer and is more and more frequently used in Europe in advanced ovarian cancer patients with high burden of tumor . Due to these confirmed results, the rate of patients receiving neo adjuvant chemotherapy increased over time compared to up front surgery Hence, we hypothesize that improving the response rate to neo adjuvant chemotherapy would improve the optimal debulking rate at IDS and ultimately the survival. This change of medical practices over time opened the possibility to explore new agent in combination with chemotherapy. For patients whose extent of disease is not amenable to complete or optimal upfront debulking surgery, neo adjuvant treatment with carboplatin plus paclitaxel should be considered, followed by an interval debulking surgery. A minimum of 3 cycles of carboplatin/paclitaxel must be administered before to propose interval surgery. After interval surgery, completion of the chemotherapy with 3 or 4 more chemotherapy regimen is proposed. For patients with macroscopic residual disease or when disease remains unresectable, combination with bevacizumab to adjuvant chemotherapy then a maintenance phase of bevacizumab alone can be proposed as a standard of care Given that facts, there is a strong rationale to introduce additional neo adjuvant therapies that would strengthen the tumor shrinkage and improve the resectability rate. Furthermore, immune surveillance plays an important role in tumor outcome of ovarian cancer patients. Indeed, clinical data in ovarian cancer patients have demonstrated that an antitumor immune response and immune evasion mechanisms are correlated, respectively, with a better and lower survival). Thus, immunotherapies are emerging as potential strategies to enhance classical EOC treatments. More recently, they also have demonstrated significant efficacy in aggressive cancers of other histology such as metastatic Lung Cancer , metastatic Renal Cell Cancer or metastatic Bladder Cancer . Approximately half of OC patients display a spontaneous antitumor immune response by antibodies and oligoclonal T-cells which recognize autologous tumor-associated antigens (TAAs). OC exhibits an extreme degree of heterogeneity of TAAs with an average of 60 private nonsynonymous mutations per tumor which are rarely shared among different tumors. Though data remains scarce, high IHC PD-L1 expression (score 2 \& 3) has been detected in 68% of ovarian cancer patients (n=70) and that expression of PD-L1 had a strong prognostic value . The authors found also that the density of intraepithelial CD8+ T cells was inversely correlated to expression of PD-L1 by tumors, suggesting that the expres-sion of PD-L1 on tumor cells may inhibit invasion of tumor epithelium by CD8+ T cells. In addition, PD-1 expression at the surface of intra-tumoral CD4+ FOXP3+ Tregs was found to show the highest levels in ovarian cancer (around 20% of the cells) compared to other tumor types, including melanoma, renal cell cancer or hepatoma . Thus targeting PD-1/PD-L1 pathway may inhibit Treg expression, one of the major component of ovarian cancer immunosuppression. Also Curiel et al showed that myeloid dendritic cells (MDCs) from ovarian cancer express PD-1 and that blockade of PD-1 enhanced MDC-mediated T-cell activation, including upregulation of IL-2 and interferon-gamma, and down regulation of IL-10, which resulted in enhanced T-cell immunity against autologous ovarian human tumors into NOD-SCID mice. Together with the aforementioned data on immune infiltration, these data provide the rationale for a therapeutic PD-1/PD-L1 pathway blockade in ovarian cancer. In ovarian carcinoma patients, the anti-PD1 compound nivolumab has been reported to achieve 3 objectives responses out of 13 (23%) heavily pre-treated patients. Response was prolonged over 1 year in 2 out of the 3 responders. Similarly, the anti-PD1 pembrozilumab achieved 3 confirmed responses (11.5% \[(95% CI, 2.4-30.2\]) in 26 patients treated in a phase IB study and 3 additional patients had a tumor reduction of at least 30%. Most common AEs were fatigue (42.3%), anemia (30.8%), and decreased appetite (30.8%). Drug-related AEs occurred in 69.2% of pts (grade ≥ 3, 1/26 pts). The anti-PD-L1 avelumab has reported a 10.7% objective response and a 44% stabilization rate in 75 patients with ovarian cancer in relapse. In this study, con-firmed or unconfirmed responses (n=11) tend to be more frequently observed in patients with low burden of tumor, limited number of prior lines of chemotherapy and in the setting of platinum-sensitivity. Toxicity was minimal. Considering all grades, fatigue was observed in 16% of the patients, chills in 12%, nausea in 10.7%, diarrhea in 10.7%, rash in 8% and hypothyroidism in 5.3%. Rationale for combining pembrolizumab and standard chemotherapy Kryczek et al compared the PD-1 expression level at the surface of intra-tumoral CD4+ FOXP3+ Tregs among many cancer types. Interestingly, the higher level of PD-1 expression (around 20%) was found on Tregs of ovarian cancers whereas it was much lower (\<10%) in other cancer types (Colon cancer, Hepatic cancer, Melanoma, Pancreatic carcinoma, Renal cell carcinoma). PD-L1 expression has also been detected in ovarian cancer tissue analysis by Immunohistochemistry staining and its level of expression has been correlated to a bad outcome of patients (59). Together with the aforementioned data on immune infiltration, these results provide rationale for a therapeutic PD-1/PD-L1 pathway blockade in ovarian cancer. In the published trials on such compounds, addition of pembrolizumab to chemotherapy or using alone has been shown to improve the response rates with a median time to response at 8 weeks (60,61). Rationale for combining pembrolizumab and bevacizumab There are several data suggesting that pembrolizumab and bevacizumab may be synergistic. Enhanced tumor angiogenesis is commonly associated with absence of tumor-infiltrating T cells in patients. There is evidence in OC that tumor expression of VEGF is negatively correlated to the density of CD3+TILs and this phenotype is associated with early recurrence, consistent with prior studies showing a correlation of VEGF to early recurrence and short survival. Furthermore, in ascites, high levels of VEGF correlate to low numbers of NK T-like CD3+CD56+ cells. This randomized phase II study aims to evaluate the efficacy of pembrolizumab in combina-tion with the standard neo adjuvant chemotherapy followed by IDS and the safety of this strategy in patients with advanced ovarian cancer. We assume that its administration in the neo adjuvant setting combination with standard of care (4 cycles of standard chemotherapy) would improve the response rate and consequently will help to achieve optimal debulking rate at IDS. After surgery, patients will continue to be treated with standard of care (chemotherapy for 2 to 5 cycles plus or less bevacizumab) or the same combination plus pembrolizumab (keytruda).