Enfortumab Vedotin/Pembrolizumab Display Frontline Efficacy in PD-L1+ HNSCC

The median progression-free survival was 5.1 months, and the median overall survival was not yet reached at the time of analysis.

Enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) exhibited meaningful frontline clinical activity as a therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who had a PD-L1 combined positive score (CPS) of 1 or higher, according to a presentation of findings from a cohort analysis of the phase 2 EV-202 trial (NCT04225117) at the 2025 European Society of Medical Oncology (ESMO) Congress.1

Findings demonstrated that evaluable patients (n = 41) achieved an investigator-assessed objective response rate (ORR) of 39.0% (95% CI, 24.2%-55.5%), including responses across PD-L1 and HPV subgroups. In the overall group, the CR and PR rates were 9.8% and 29.3%, respectively. Additionally, patients had a best response of stable disease (36.6%), progressive disease (17.1%), or were not evaluable for response (7.3%). The disease control rate (DCR) was 75.6% (95% CI, 59.7%-87.6%). The median progression-free survival (PFS) was 5.1 months (95% CI, 3.5-not evaluable). Median overall survival (OS) was not yet reached at the time of analysis, and follow-up remains ongoing.

“The combination of [enfortumab vedotin] plus pembrolizumab [demonstrated] clinical activity as [first-line] treatment in patients with [PD-L1–positive] recurrent or metastatic head and neck [squamous] cell carcinoma. Treatment led to [an antitumor] response, with durable responses noted in some patients,” lead study author Paul L. Swiecicki, MD, noted in the conclusion of his presentation. “Confirmed responses were achieved in 16 patients, [which exceeded the prespecified protocol threshold for activity]. Median OS was not reached, and patient follow-up is ongoing.”

Swiecicki is an associate clinical professor of medical oncology and internal medicine at the Comprehensive Cancer Center at the University of Michigan in Ann Arbor.

What Was the Design of the EV-202 Trial?

EV-202 was an open-label, multicohort, multicenter study designed to evaluate enfortumab vedotin in patients with advanced solid tumors, including recurrent or metastatic HNSCC.2

Cohort 9 of EV-202 enrolled patients with histologically or cytologically confirmed recurrent or metastatic HNSCC who had not received prior systemic therapy and had an ECOG performance status of 0 to 1.1 Additional inclusion criteria required PD-L1 expression with a CPS of 1 or higher, as well as adequate renal, hematologic, and hepatic function. Patients with oropharyngeal tumors were required to have HPV status confirmed by p16 testing. Exclusion criteria included pre-existing sensory or motor neuropathy of grade 2 or higher and/or uncontrolled diabetes mellitus.

Patients in cohort 9 received enfortumab vedotin at 1.25 mg/kg intravenously on days 1 and 8 plus pembrolizumab at 200 mg intravenously on day 1 of each 21-day cycle. Treatment was administered until disease progression, unacceptable toxicity, or completion of the maximum number of cycles as defined by protocol.

The primary end point was investigator-assessed confirmed ORR per RECIST 1.1 criteria. Secondary end points included duration of response (DOR), DCR, and PFS, all assessed by investigators per RECIST 1.1 criteria, along with OS and safety.

A total of 41 patients were enrolled in this cohort of the EV-202 trial. At the data cutoff date, 11 patients remained on treatment with enfortumab vedotin plus pembrolizumab, and 2 patients continued on enfortumab vedotin monotherapy.

The median relative dose intensity (RDI) for enfortumab vedotin was 89.0% (range, 42.1%–100.2%). Patients received a median of 6.0 cycles (range, 1-17) of enfortumab vedotin and a median of 6.0 cycles (range, 1-21) of pembrolizumab. The median duration of treatment for both agents was 4.9 months, ranging from 0.7 to 13.6 months for enfortumab vedotin and 0.7 to 15.4 months for pembrolizumab.

How Did Responses Vary Between Subgroups?

Among patients with PD-L1 CPS of 1 to 19 (n = 16), the ORR was 43.8% (95% CI, 19.8%-70.1%), and among those with PD-L1 CPS greater than 20 (n = 25), the ORR was 36.0% (95% CI, 18.0%-57.5%). By HPV status, responses were observed in 81.8% (95% CI, 48.2%-97.7%) of HPV-positive patients (n = 11) and 23.3% (95% CI, 9.9%–42.3%) of HPV-negative patients (n = 30).

The median time to confirmed response with enfortumab vedotin plus pembrolizumab was 2.3 months (range, 1.9-5.0 months). The median DOR was not yet reached at the time of analysis. At 6 months, the DOR rate was 81.7% (95% CI, 42.0%-95.4%).

What Was the Safety Profile of the Combination?

Swiecicki noted that the safety profile of enfortumab vedotin plus pembrolizumab was consistent with prior experience with this combination. Grade 3 or higher treatment-related adverse effects (TRAEs) were reported in 41.5% of patients. Dose reductions of enfortumab vedotin due to TRAEs occurred in 22.0% of patients, and 14.6% experienced TRAEs that led to the discontinuation of any study drug.

Overall, 92.7% of patients experienced a TRAE. The most frequently reported any-grade TRAEs included fatigue (43.9%), pruritus (39.0%), alopecia (29.3%), nausea (24.4%), maculopapular rash (24.4%), and diarrhea (22.0%). Other notable TRAEs included rash (22.0%), increased aspartate aminotransferase levels (19.5%), decreased appetite (19.5%), peripheral sensory neuropathy (19.5%), increased alanine aminotransferase levels (17.1%), and dry skin (17.1%). Grade 3 or higher TRAEs were most commonly fatigue (4.9%), maculopapular rash (7.3%), and nausea (2.4%).

References

1. Swiecicki PL, Hanna GJ, Geiger JL, et al. Enfortumab vedotin plus pembrolizumab as first-line treatment in recurrent or metastatic head and neck squamous cell carcinoma: results from a cohort of the EV-202 trial. Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Presentation 1329MO.
2. A study to evaluate enfortumab vedotin in subjects with locally advanced or metastatic malignant solid tumors (EV-202). Clinicaltrials.gov. Updated August 22, 2025. Accessed October 19, 2025. https://www.clinicaltrials.gov/study/NCT04225117