The addition of the STAT3 anti-sense oligonucleotide danvatirsen (AZD9150) to pembrolizumab (Keytruda) did not improve objective response rate (ORR) compared with pembrolizumab alone in patients with previously untreated, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to findings from the phase 2 PEMDA-HN trial (NCT05814666) presented at the 2026 Multidisciplinary Head and Neck Cancers Symposium.1
In patients with a PD-L1 combined positive score (CPS) of at least 1, the confirmed ORR was 15.6% (90% CI, 7.5-27.2) in the combination arm (n = 45) compared with 14.3% (90% CI, 4-32.9) in the pembrolizumab monotherapy arm (n = 21). Among patients with high PD-L1 expression (CPS ≥20), the ORR was 18.2% with the combination vs 21.4% with pembrolizumab alone.
“Although the first interim analysis did pass futility, the study was halted early after a second interim analysis,” Deborah J. Wong, MD, PhD, stated in a presentation of the data. “The ORR of pembrolizumab monotherapy was consistent with that seen in the phase 3 KEYNOTE-048 trial [NCT02358031].”
Wong is a head and neck medical oncologist at UCLA Health in Los Angeles, California.
What was the rationale for combining danvatirsen with pembrolizumab in HNSCC?
STAT3 is a transcription factor that promotes tumor cell proliferation, angiogenesis, and the activity of immunosuppressive cells, such as M2 macrophages and myeloid-derived suppressor cells. Conversely, STAT3 inhibits the maturation of dendritic cells and the activity of natural killer cells and effector T cells. Preclinical data have indicated that knocking down STAT3 with an anti-sense oligonucleotide could inhibit tumor growth and synergize with anti–PD-1 therapy.
Furthermore, previously reported data from the phase 1/2 SCORES study (NCT02499328) evaluating danvatirsen plus durvalumab (Imfinzi) in patients with immunotherapy-naive HNSCC showed promising activity with the combination, particularly in patients with PD-L1–positive disease. Data presented at the 2018 ESMO Congress showed an ORR of 23%, including a CR rate of 7%.2 Based on these signals, the PEMDA-HN investigators sought to evaluate danvatirsen in combination with pembrolizumab, which is the standard of care in the frontline recurrent/metastatic HNSCC setting.1
What was the design of the PEMDA-HN trial?
This randomized, open-label, controlled study enrolled patients with recurrent or metastatic (non-nasopharyngeal) HNSCC who had not received prior systemic therapy for advanced disease. Eligible patients were required to have PD-L1–positive disease (CPS ≥1), be naive to immunotherapy, and have at least 1 measurable lesion per RECIST 1.1 criteria.
PEMDA-HN Trial: Key Takeaways
- The PEMDA-HN trial found that adding the STAT3 anti-sense oligonucleotide danvatirsen to pembrolizumab did not improve ORR compared with pembrolizumab alone in patients with previously untreated, recurrent or metastatic HNSCC.
- The study was halted early after the second interim analysis because the combination failed to show a significant efficacy benefit vs pembrolizumab monotherapy.
- Although the safety profile of danvatirsen plus pembrolizumab was considered manageable, patients in the combination arm experienced a higher incidence of certain AEs, compared with those in the control arm.
Patients were randomly assigned 2:1 to receive:
- danvatirsen plus pembrolizumab
- pembrolizumab monotherapy
ORR per RECIST 1.1 criteria served as the primary end point. Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival, and pharmacokinetics.
What were the baseline characteristics of the PEMDA-HN study population?
Between January 2024 and May 2025, 69 patients were randomly assigned. The overall mean age was 64.7 years, and most patients were male (77.3%) and White (63.6%). Regarding clinical status, 66.7% of patients had an ECOG performance status of 1, and 43.9% of patients had stage IVC disease. Additionally, 71.2% of the total patient population had a PD-L1 CPS of 20 or higher. The most common primary tumor locations were the oral cavity (43.9%) and the oropharynx (33.3%).
“PEMDA-HN did enroll a diverse, global population of patients with recurrent and metastatic HNSCC,” Wong noted.
What additional efficacy data were reported from the PEMDA-HN trial?
The median PFS was 3.52 months (95% CI, 1.48-6.83) in the combination arm compared with 2.92 months (95% CI, 1.41-not reached) in the monotherapy arm. The median duration of treatment was nearly identical between the groups, at 2.98 months with the combination and 2.83 months with pembrolizumab.
What was the safety profile of danvatirsen plus pembrolizumab in recurrent/metastatic HNSCC?
The safety analysis included 66 patients. Treatment-emergent adverse effects (TEAEs) of any grade occurred in 97.8% of patients in the combination arm and 85.7% of those in the control arm. The toxicity profile of the combination was described as manageable and consistent with data from prior studies investigating these agents.
The combination arm showed a higher incidence of certain laboratory abnormalities and systemic AEs compared with the control arm, respectively, including:
- Increased alanine aminotransferase levels: 42.2% vs 0%
- Increased aspartate aminotransferase levels: 35.6% vs 0%
- Anemia: 31.1% vs 19.0%
- Nausea: 22.2% vs 4.8%
- Arthralgia: 17.8% vs 0%
Other common TEAEs, such as fatigue (37.8% vs 38.1%) and diarrhea (20.0% vs 19.0%), occurred at similar frequencies across both treatment groups.
“The toxicity of the combination was manageable and consistent with that seen in prior studies,” Wong concluded. “Future directions should explore tissue biomarkers, including STAT3 knockdown, that may inform treatment response.”
Disclosures: Wong reported receiving grant or institutional research support from A2 Biotherapeutics, AstraZeneca, Bicara Therapeutics, Merck, TopAlliance, GSK, Eli Lilly, Johnson & Johnson, BioNTech, Sensei Therapeutics, TEMPUS, Aveo, and Pyxis; as well as performing consulting or advisory roles with Coherus, Merck, Bicara Therapeutics, Merus, and Regeneron.
References
- Wong DJ, Harrington K, Neupane P, et al. Danvatirsen plus pembrolizumab versus pembrolizumab as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (PEMDA-HN): final results of a randomized phase 2 trial. Presented at: 2026 Multidisciplinary Head and Neck Cancers Symposium. February 19-21, 2026; Palm Desert, CA. Abstract 5.
- Phase 1b/2 data of durvalumab plus danvatirsen presented at European Society for Medical Oncology. News release. Ionis Pharmaceuticals, Inc. October 22, 2018. Accessed May 7, 2026. https://ir.ionis.com/news-releases/news-release-details/phase-1b2-data-durvalumab-plus-danvatirsen-presented-european
