Ficerafusp alfa plus pembrolizumab generated a 54% ORR and 21.7-month median DOR in first-line HPV-negative recurrent or metastatic HNSCC.
Ficerafusp alfa (BCA101) plus pembrolizumab (Keytruda) elicited deep and durable responses when used in the first-line treatment of patients with PD-L1–positive, recurrent or metastatic (R/M)
The data, which were published in the Journal of Clinical Oncology, showed that in the efficacy-evaluable HPV-negative subgroup (n = 28), the confirmed objective response rate (ORR) was 54% (95% CI, 34%-73%); this included a complete response (CR) rate of 21%. The clinical benefit rate (CBR) was 86% (95% CI, 67-96).
Moreover, at a median follow-up of 26.3 months (range, 23.9-29.4), the median duration of response (DOR) was 21.7 months (95% CI, 6.0-not estimable [NE]), the median progression-free survival (PFS) was 9.9 months (95% CI, 4.4-22.7), and the median overall survival (OS) was 21.3 months (95% CI, 9.9-NE) in this subgroup.
“Overall, these results suggest that ficerafusp alfa plus pembrolizumab could provide a chemotherapy-free regimen for patients with R/M HNSCC, including those with symptomatic locoregional disease in whom a rapid and durable treatment response would be beneficial,” Glenn J. Hanna, MD, and colleagues wrote in the paper.
Hanna is the director of the Center for Cancer Therapeutic Innovation and the Center for Salivary and Rare Head and Neck Cancers, and a physician at Dana-Farber Cancer Institute, in Boston, Massachusetts. He is also an associate professor of medicine at Harvard Medical School.
HPV-negative R/M HNSCC is characterized by EGFR overexpression, TGF-β signaling, and poor immune-cell penetration of the tumor microenvironment, features linked with markedly worse survival and resistance to anti–PD-1 and anti-EGFR therapy. Ficerafusp alfa is a bifunctional immunoglobulin G1 anti-EGFR antibody fused to the TGF-β receptor II ectodomain, designed to selectively neutralize TGF-β in the tumor microenvironment and strengthen tumor penetration of CD8-positive T cells.
Frontline treatment for patients with R/M HNSCC comprises single-agent pembrolizumab or the immunotherapy combined with platinum-based chemotherapy, depending on PD-L1 combined positive score (CPS).
In the phase 3
“New treatments are needed to improve outcomes in patients with HPV-negative tumors,” the study authors wrote.
The open-label, multicenter, nonrandomized, first-in-human study evaluated ficerafusp alfa as monotherapy and paired with pembrolizumab in EGFR-driven solid tumors; this analysis reports the HNSCC dose-expansion cohort treated with the combination.1
Eligible patients were 18 years or older with unresectable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx. That had measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and a tumor PD-L1 CPS of 1 or higher. They were also required to have acceptable hepatic, renal, and hematologic function. Those with prior systemic therapy for R/M disease were excluded; prior platinum, anti-EGFR, or anti–PD-1 treatment for locoregionally advanced disease completed more than 6 months before enrollment was permitted.
Patients received pembrolizumab at 200 mg intravenously on day 1 and ficerafusp alfa at 1500 mg intravenously on days 1, 8, and 15 of 21-day cycles until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal. The primary end point was safety and tolerability; secondary end points included ORR, CBR, DOR, PFS, and OS.
Between February 2022 and April 2023, 42 patients received at least 1 dose (safety set), and 39 were efficacy evaluable. In the HPV-negative cohort (n = 30), the median patient age was 63 years (range, 31-84). More than half of patients were male (63%), and most were White (80%); 63% of patients had an ECOG performance status of 1. Primary disease sites included oral cavity (47%), oropharynx (27%), hypopharynx (13%), and larynx (13%). Half of the patients had a CPS of 1 to 19, and the other half had a CPS of 20 or higher.
Among the 15 HPV-negative responders, 12 (80%) had at least 80% target lesion shrinkage. The probability of maintained response was 65% (95% CI, 40%-90%) at 12 months and 57% (95% CI, 32%-83%) at 18 months.1 The median time to response was 1.4 months (95% CI, 1.4-4.7), and 56% of responses occurred by the first imaging assessment at 6 weeks. Responses were observed across PD-L1 levels: confirmed ORRs were 54% (95% CI, 25%-81%) in patients with a CPS ranging from 1 to 19 (n = 13) and 53% (95% CI, 25%-81%) in those with a CPS of 20 or higher (n = 15).
In the HPV-positive subgroup (n = 11), the confirmed ORR was 27% (95% CI, 6%-61%), with a CR in 18%; the CBR was 55% (95% CI, 23%-83%). The median PFS was 2.0 months (95% CI, 1.0-10.0), and the median OS was 16.4 months (95% CI, 2.6-25.7).
A subsequent April 2025 assessment showed 24-month OS rates of 46% (95% CI, 23%-65%) in the HPV-negative subgroup and 27% (95% CI, 1.0%-53.6%) in the HPV-positive subgroup. Pharmacodynamic analyses showed complete plasma neutralization of TGF-β1 with minimal effect on TGF-β2, and significant downregulation of intratumoral pSMAD2 after treatment, particularly in HPV-negative tumors.
Among 42 treated patients, 40 (95%) experienced a treatment-related adverse effect (TRAE). Grade 3 TRAEs occurred in 19 patients (45%), and one patient (2%) had a grade 4 TRAE; no fatal TRAEs were reported.
The most common grade 3 or higher TRAEs were anemia (14%) and acneiform dermatitis (12%), with all other grade 3 or higher TRAEs occurring in 3 or fewer patients. The most frequent any-grade TRAEs were acneiform dermatitis (76%), fatigue (45%), and pruritus (43%).
TRAEs led to ficerafusp alfa discontinuation in 5 patients (12%), with no single TRAE causing discontinuation in more than one patient. Investigators reported that infusion-related reactions and mucosal bleeding were generally mild and rarely required dose interruption.
The authors noted limitations such as the single-arm design, which precludes isolating the contribution of individual components; limited geographic scope; and the absence of patient-reported outcomes.
“Additionally, information on subsequent treatment after study discontinuation was not collected routinely and could not be analyzed,” the study authors wrote.
A randomized phase 2/3 global trial of first-line ficerafusp alfa plus pembrolizumab vs pembrolizumab monotherapy in PD-L1–positive, HPV-negative R/M HNSCC has been initiated (FORTIFI-HN01; NCT06788990).
