Pembrolizumab Plus Chemoradiation Hits ORR End Point in Unresectable Vulvar Cancer

Vulvar Cancer | Image
Credit: © freshidea -
stock.adobe.com

The addition of pembrolizumab (Keytruda) to standard-of-care cisplatin and radiation, followed by maintenance pembrolizumab, led to high response rates in patients with unresectable vulvar cancer, according to data from a phase 2 study (NCT04430699) presented during the 2025 ASCO Annual Meeting.

The primary results of the study demonstrated that patients who received pembrolizumab in combination with cisplatin-sensitized radiation followed by pembrolizumab maintenance (n = 24) achieved an objective response rate (ORR) of 75%, including a complete response rate of 37.5%. The 6-month recurrence-free survival (RFS) rate was 70% (95% CI, 48%-85%).

“The study met its primary end point, demonstrating an ORR of 75%,” Oladapo Yeku, MD, PhD, FACP, said during the presentation. “This regimen is a reasonable option for patients with locally advanced or unresectable disease.”

Yeku is the director of translational research of the Gynecologic Oncology Program at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School, both in Boston.

In order to be eligible for the single-arm study, patients needed to have histologically or cytologically confirmed, unresectable, incompletely resected, or metastatic squamous cell carcinoma of the vulva. Unresectable disease was defined as T2 or T3 primary tumors (N0-3, M0) not amenable to surgical resection via standard radical vulvectomy. Patients with recurrent disease were permitted to have received up to 2 prior lines of cytotoxic therapy; prior irradiation was permitted if the site being considered for study treatment was not previously irradiated. Those who could not safely receive a minimum of 30 Gy of radiation in 10 fractions were not eligible for the trial.

Enrolled patients received 40 mg/m2 of cisplatin weekly with concurrent intensity-modulated radiation therapy. Pembrolizumab was administered at a dose of 200 mg every 3 weeks. During cycles 4 through 12, patients received maintenance pembrolizumab every 3 weeks.

All patients received radiation therapy with definitive intent. The median dose to the primary site was 68.4 Gy (range, 26.2-70.2). Patients also received a median dose of 45 Gy (range, 21.6-50.4) to the pelvic, inguinal, and vulva clinical target volume.

The primary end point was ORR. Six-month RFS rate was a secondary end point. Increase in T-cell receptor beta clonality, changes in circulating cytotoxic T cells, cytokine profiling, HMGB-1, PD-L1 expression, mismatch repair status, HPV status, and TP53 mutational status were all evaluated as exploratory end points.

At baseline, the median age was 63 years (range, 49-88). Most patients were White and non-Hispanic (92%), had FIGO stage II or III disease (71%), had HPV-negative disease (63%), did not receive a prior therapy (71%), had low tumor mutational burden (54%), and had microsatellite stable disease (75%). Prior lines of therapy consisted of surgical resection (21%) and cisplatin plus radiation (8%). Patients had PD-L1 combined positive scores of more than 10 (63%) or 1 to 10 (38%).

In terms of safety, common grade 1 or 2 treatment-emergent adverse effects (TEAEs) included nausea (88%), diarrhea (71%), anemia (50%), constipation (50%), and decreased platelet count (38%). Grade 3 or 4 TEAEs included anemia (33%), decreased neutrophil count (17%), and diarrhea (17%). There were no grade 1 or 2 serious AEs (SAEs); grade 3 or 4 SAEs consisted of acute kidney injury (8%), thromboembolic event (4%), urinary tract infection (4%), stroke (4%), and dysarthria (4%).

Grade 1 or 2 immune-related AEs (irAEs) included fatigue (33%), diarrhea (25%), pruritus (13%), maculopapular rash (13%), and hypothyroidism (13%). Grade 3 or 4 irAEs consisted of diarrhea (8%), radiation dermatitis (4%), and fatigue (4%).

“This was a smaller study [that] enrolled 24 patients,” Yeku said. “However, this is a rare disease, and this number is not far from what we typically see [in the clinic]. The population was heterogeneous, but this was by design. Even though this was a single-institution study, patients were treated at many different community sites.”

Reference

Yeku OO, Russo AL, Bregar A, et al. Primary results of a phase 2 study of cisplatin-sensitized radiation therapy and pembrolizumab for unresectable vulvar cancer. J Clin Oncol. 2025;43(suppl 16):5511. doi:10.1200/JCO.2025.43.16_suppl.5511