The 2026 European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain. During the Head and Neck Cancer Oral Presentation Session, the Phase II results of the HexAgon-HN study (LBA42) were presented. The study evaluated the efficacy and safety of the hexavalent OX40 agonist INBRX-106 plus pembrolizumab (P) versus pembrolizumab monotherapy as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with a PD-L1 combined positive score (CPS) ≥20. The results showed that the objective response rate (ORR) in the combination group reached 48.3%, representing an absolute improvement of 21.8 percentage points over the monotherapy group (26.5%). The benefit was particularly pronounced in the HPV-positive subgroup (80.0% vs. 33.3%). This also represents the first positive proof-of-concept result from a randomized controlled trial of an OX40 costimulatory pathway agonist in cancer immunotherapy.At the congress, Oncology Frontier invited Professor Jong Chul Park of the Head and Neck Cancer Center at Massachusetts General Hospital Cancer Center to discuss the study design, efficacy findings, drug mechanism, and future development strategy. The following is an edited summary of the interview.
Study Overview
Background
Pembrolizumab (P) is one of the standard first-line treatment options for R/M HNSCC. However, its objective response rate as monotherapy remains suboptimal, and a substantial proportion of patients fail to achieve durable responses with currently available immunotherapies. INBRX-106 (106) is an engineered hexavalent OX40 agonist designed to promote higher-order clustering of the OX40 receptor, thereby more fully activating the OX40 costimulatory pathway. Combining INBRX-106 with pembrolizumab may amplify and prolong antitumor immune responses, potentially improving the efficacy of first-line treatment.
Study Design
HexAgon-HN (NCT06295731) is an open-label, randomized, controlled Phase II/III study. The Phase II portion enrolled patients with R/M HNSCC and a PD-L1 CPS ≥20 who had not previously received systemic therapy. Patients were randomized 1:1 to receive 106+P or pembrolizumab monotherapy. The primary endpoint was confirmed ORR assessed by investigators according to RECIST v1.1. The prespecified success criterion was an observed ΔORR ≥8 percentage points in favor of the 106+P group. Key secondary endpoints included progression-free survival (PFS) and safety.
Key Results
As of the data cutoff date of August 19, 2026, a total of 68 patients had been randomized, with a median follow-up of 7.0 months. The median patient age was 64.5 years; 85.3% were male, 57.4% had distant metastatic disease, and 27.9% had HPV-positive disease.
Among the 63 patients evaluable for efficacy, the ORR was 48.3% (95% CI: 29.4–67.5) in the 106+P group (n=29), compared with 26.5% (95% CI: 12.9–44.4) in the P group (n=34), representing an absolute ΔORR of 21.8 percentage points. The benefit was even more pronounced among patients with HPV-positive disease: the ORR reached 80.0% in the 106+P group (n=10; 3 complete responses [CRs] and 5 partial responses [PRs]), compared with 33.3% in the P group (n=9; 3 PRs), representing a ΔORR of 46.7 percentage points. Preliminary PFS analysis suggested a marked improvement in the 106+P group, with updated results to be reported at a later date.
Regarding safety (n=65), the incidence of treatment-emergent adverse events (TEAEs) of any grade was 100% in the 106+P group and 85.3% in the P group. The incidence of grade ≥3 TEAEs was 58.1% and 47.1%, respectively, while serious adverse events (SAEs) occurred in 38.7% and 35.3%, respectively. The most common treatment-related adverse events in the 106+P group (any grade/grade ≥3) were rash (32.3%/3.2%), maculopapular rash (32.3%/9.7%), diarrhea (29.0%/9.7%), and fatigue (29.0%/3.2%). Infusion-related reactions (22.6%/3.2%) were generally manageable and occurred primarily with the first dose.
Study Conclusions
Among patients with R/M HNSCC and a PD-L1 CPS ≥20, first-line 106+P significantly improved ORR compared with pembrolizumab monotherapy and showed preliminary evidence of a PFS benefit, with no new safety signals observed. The benefit was particularly pronounced in the prespecified HPV-positive subgroup, warranting further investigation. These positive randomized Phase II results provide clinical proof of concept for the use of OX40 agonists in cancer immunotherapy.
Insights from the Investigator
We presented the randomized controlled data from the Phase II portion of the HexAgon-HN study during the Head and Neck Cancer Oral Presentation Session. The study compared INBRX-106 plus pembrolizumab with pembrolizumab monotherapy as first-line treatment for R/M HNSCC. The results showed that the combination achieved a significantly higher objective response rate than monotherapy. At the time of the data cutoff, however, the 6-month PFS rate, median PFS, and duration of response had not yet matured.
We conducted subgroup analyses based on stratification factors, including ECOG performance status, disease status, and HPV status. These analyses showed that the HPV-positive subgroup derived the greatest benefit from combination treatment. Specifically, in the overall population, the ORR was nearly 50% in the combination group, compared with approximately 26% in the pembrolizumab monotherapy group, representing an absolute difference of more than 20 percentage points. In the HPV-positive subgroup, although the sample size was small and the findings should therefore be interpreted with caution, 8 of the 10 patients in the combination group achieved an objective response, compared with 3 of the 9 patients in the control group (80.0% vs. 33.3%).
A key feature of INBRX-106 is its hexavalent structure. The drug contains six OX40 receptor-binding domains, whereas conventional bivalent monoclonal antibodies have only two. By promoting higher-order clustering of OX40 receptors, this design is theoretically capable of generating stronger downstream signaling, potentially overcoming the limitations of earlier bivalent OX40 agonists, which had limited receptor clustering and suboptimal agonistic activity.
Based on the strong efficacy signal observed in the HPV-positive subgroup, we plan to conduct a Phase II expansion cohort involving approximately 50 patients with HPV-positive oropharyngeal cancer to further validate this finding. This strategy also reflects the evolving landscape of first-line treatment for head and neck cancer. EGFR bispecific antibodies currently in development are primarily focused on HPV-negative disease, leaving an unmet therapeutic need among patients with HPV-positive disease. In the expansion cohort, we will broaden the CPS eligibility criterion from the previously reported threshold of ≥20 to ≥1. Given the strength of the efficacy signal we have observed, we believe that a CPS ≥20 threshold may not be necessary for this subgroup. Data from the expansion cohort will help us define the target population for subsequent Phase III studies. If this efficacy signal is confirmed in this population, it could provide patients with HPV-positive disease with a chemotherapy-free treatment option offering greater durability.
