## 5 Immunotherapy in Gynecologic Malignancies  
Chemotherapy has been a traditional systemic therapy for gynecologic malignancies with platinum-based chemotherapies, along with paclitaxel or topotecan, used as standard of care. The integration of targeted agents, such as bevacizumab, and immune checkpoint inhibitors (ICI) like pembrolizumab, have demonstrated promising results in improving overall survival and disease control in advanced or metastatic gynecologic malignancies. However, the synergistic potential of combining SBRT with ICIs remains largely unexplored in gynecologic cancers. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, in addition to traditional chemotherapies, showed a significant improvement in overall survival in metastatic, persistent or recurrent cervical cancer in the Gynecologic Oncology Group (GOG) 240 phase III trial [50]. Moreover, immune checkpoint inhibitors have also shown promise in oligometastatic disease. ICIs work by blocking the interaction between the programmed death 1 (PD-1) receptor on T-cells and its ligand, programmed death receptor ligand 1 (PD-L1) on cancer cells, an interaction which suppresses the immune response. By blocking this interaction, checkpoint inhibitors allow T-cells to recognize and attack cancer cells, thereby mounting an immune response. Pembrolizumab, a PD-1 receptor antagonist, has shown efficacy in recent trials in recurrent or metastatic endometrial cancer. The results of the KEYNOTE-028 study showed an objective response rate (ORR) of 13% in PD-L1 positive locally advanced or metastatic endometrial cancer [51]. The efficacy of pembrolizumab on PD-L1 positive tumors with high levels of microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) on a variety of primary advanced tumors types (the most common being endometrial, gastric and small intestine) was evaluated in the Phase II KEYNOTE-158 study, which showed an ORR of 30.8% with a median duration of response of 47.5 months [52]. The endometrial cohort showed an ORR of 58% and a median OS of 23.5 months [53]. The double-blind phase III KEYNOTE-826 [54] trial randomized patients with PD-L1 positive persistent, recurrent or metastatic cervical cancer to receive pembrolizumab vs. placebo in addition to standard of care chemotherapy with or without bevacizumab. Overall survival was significantly improved with the addition of pembrolizumab as compared to placebo, with a 2-year OS of 54.4% vs. 44.6% in 317 patients with PD-L1 combined positive score of 10 or more. Additionally, ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as well as nivolumab, another PD-1 receptor antagonist, have shown promise in recurrent, persistent, or metastatic ovarian and cervical cancer [55; 56]. Overall, the current literature regarding immunotherapy in select patients with advanced or metastatic gynecologic cancer shows moderate improvements in distant disease control without the addition of SBRT. There is one prospective clinical trial to our knowledge that evaluated SBRT with pembrolizumab in gynecologic malignancies. The Phase II PRIMMO study [57] treated patients with persistent, recurrent or metastatic cervical or endometrial cancer with pembrolizumab, SBRT and an immunomodulatory five-drug cocktail of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before concurrent radioimmunotherapy. The study consisted of 43 patients (cervical n = 18, endometrial n = 25) and the primary endpoint was the immune-related objective response rate (irORR). The results showed 11.1% and 12.0% irORR in the cervical and endometrial groups, respectively, but the median duration of response was not reached. Interestingly, patients with response had a significantly increased proportion of peripheral T-cells compared to non-responders. Although the toxicity was acceptable, with 56% grade \(\geq\)3 treatment-related toxicity, the results of this study were only modest.