Primary results of a phase 2 study of cisplatin-sensitized radiation therapy and pembrolizumab for unresectable vulvar cancer.

5511 Background: Locally advanced vulvar cancer is a rare but lethal disease more common in underserved populations. In contrast to other gynecologic cancers, the incidence and mortality of this disease has increased over the past decade. Treatment for locoregional disease involves surgery and chemoradiation, while systemic chemotherapy and immunotherapy are reserved for patients with distant metastases. Cisplatin and radiation (cis-RT) have been reported to have anti-tumor immunomodulatory properties in addition to their cytotoxic effects. We hypothesized that immune checkpoint inhibitors could synergize with chemotherapy and improve outcomes for this disease. Methods: In this single-arm phase II trial (NCT04430699), patients with primary unresectable, incompletely resected, recurrent, or metastatic squamous cell carcinoma of the vulva undergoing RT were eligible. Patients who had received prior chemotherapy were also eligible. Patients received cisplatin 40 mg/m2 weekly concurrently with intensity modulated (IM) RT, and pembrolizumab 200 mg was administered every three weeks for a total of 12 cycles. The primary endpoint was overall response rate (ORR), and the secondary objective was six-month recurrence free survival (RFS). PD-L1 expression and T-cell receptor beta clonality were assessed among other translational endpoints. An ORR ≥ 60% was considered worthy of further study. Results: The study closed to accrual on 10/11/2024 after 24 patients had enrolled. Twenty-two patients (92%) had primary unresectable disease and two (8%) had recurrent disease. All patients were treated with definitive intent RT, with a median dose to the primary of 68.4 Gy (range, 26.2, 70.2) and 45 Gy to pelvic, inguinal, vulva CTV (range, 21.6, 50.4). One patient stopped RT early due to disease progression. At the data cutoff on 01/22/2025, the ORR (CR+PR) was 75%. The 6-month RFS rate was 70% (95% CI: 48 – 85%). The median PFS has not been reached. Any grade adverse events (AE) occurred in all patients. Grade (G) 3 or 4 AEs occurred in 19 (78.6%) patients, most of which were related to cisplatin. The most common treatment-emergent adverse events were nausea (88%), diarrhea (71%), fatigue (67%) and anemia (50%). There were 6 serious AEs, only 2 of which were related the treatment (both AKI). Most immune related toxicities were G1/2, except for G3 diarrhea (4%). Immune mediated colitis led to discontinuation in 1 patient (4%). PD-L1 (CPS ≥ 1) was positive in all patients. There was an increase in mean TCR clonality after 2 cycles. Conclusions: The study met its primary endpoint. Concurrent treatment with chemoradiation and pembrolizumab improved ORR and 6-month RFS in vulvar cancer. The addition of pembrolizumab did not lead to any unexpected AEs. Chemoradiation with pembrolizumab could be considered in patients with primary unresectable or incompletely resected vulvar cancer. Clinical trial information: NCT04430699 .