While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Some patients, however, achieve lasting responses, emphasizing the need to understand how tumor microenvironment and molecular characteristics influence ICI response. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated stage IV HGSOC patients, who were scheduled for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation using multiplexed immunofluorescence and immune-related gene expression. Our findings show immune activation, evidenced by an increase in CD3 + , CD8 + , CD8 + /FOXP3+ ratio, TNF-α and interferon-γ signaling. Treatment was well-tolerated. We observed major pathologic responses in 9/33 patients (27%, 95%CI 14-46), with pathologic response strongly associated with immune activation and OS. At a median follow-up of 52.8 months, 8/9 major responders were alive, with 6 patients recurrence-free. In contrast, 4/24 minor responders survived, including one recurrence-free. ctDNA clearance was observed in all major responders and was associated with prolonged PFS and OS. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as biomarkers, warranting further exploration. These results suggest major responders may benefit from neo-adjuvant pembro.
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