The ASCO 2026 Annual Meeting Features a Rich Landscape of New Research in Head and Neck Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  1. Perioperative Immunotherapy – KEYNOTE-689 Continues to Shape Practice:
    • The KEYNOTE-689 phase 3 trial:
      • Which led to the FDA approval of perioperative pembrolizumab (June 2025):
        • For resectable locally advanced HNSCC with PD-L1 CPS ≥ 1:
          • Remains a central focus
      • New ASCO 2026 exploratory analyses demonstrate that the EFS benefit of neoadjuvant / adjuvant pembrolizumab:
        • Persists across surgical outcome subgroups, including:
          • Patients with and without extranodal extension or positive margins
        • Notably, fewer patients in the pembrolizumab arm had ENE or positive margins post-surgery:
          • Suggesting neoadjuvant pembrolizumab contributes to pathologic downstaging
    • A pooled meta-analysis of three phase 3 trials (KEYNOTE-689, NIVOPOSTOP, and IMvoke010; n=1,786) presented at ASCO 2026:
      • Confirmed a significant improvement in event-free / disease-free survival with perioperative or adjuvant PD-1 / PD-L1 blockade (pooled HR 0.79, 95% CI 0.68–0.91):
        • With no meaningful increase in treatment-related deaths

The following figure from the KEYNOTE-689 trial illustrates the event-free survival benefit across PD-L1 subgroups:

  1. Neoadjuvant Bispecific Antibody Combinations: Ivonescimab Leads the Way:
    • Several ASCO 2026 abstracts highlight the emerging role of bispecific antibodies in the neoadjuvant setting:
      • Ivonescimab (PD-1 / VEGF bispecific) + nab-paclitaxel / cisplatin:
        • Achieved a remarkable 100% ORR:
          • 50% CR, 50% PR
        • Achieved a 50% pCR rate:
          • In 30 surgical patients with resectable LA-HNSCC
        • All patients with CPS >30 achieved pCR, and 100% laryngeal / pharyngeal preservation was achieved
    • A randomized phase II trial comparing ivonescimab (PD-1 / VEGF), cadonilimab (PD-1 /CTLA-4), and penpulimab (PD-1 alone), each combined with chemotherapy:
      • Showed the highest pCR rate with ivonescimab at 60%, compared to 42.1% with cadonilimab and 40% with single-agent PD-1
    • Adebrelimab (PD-L1 inhibitor) + chemotherapy demonstrated:
      • An 87.5% ORR and a 95.8% larynx preservation rate in resectable LA-HNSCC:
        • With all p16-positive and CPS ≥ 20 patients responding
    1. Novel Agents in Recurrent / Metastatic HNSCC:
      • Bispecific antibodies are generating significant excitement in the recurrent / metastatic setting:
        • Ficerafusp alfa (EGFR × TGF-β) + pembrolizumab:
          • Two-year follow-up data showed a confirmed ORR of 54% in HPV-negative R/M HNSCC (21% CR), with a median DOR of 21.7 months and median OS of 21.3 months
            • The phase 2 / 3 FORTIFI-HN01 trial is now actively enrolling
        • Petosemtamab (EGFR × LGR5) + pembrolizumab:
          • Updated phase 2 data showed a 60% ORR (including 5 CRs) in first-line PD-L1+ R/M HNSCC, with median DOR of 11 months
            • Two phase 3 trials (LiGeR-HN1 and LiGeR-HN2) are recruiting
        • CRB-701 (Nectin-4 ADC):
          • A phase 1 / 2 study in heavily pretreated R/M HNSCC (85% refractory to immunotherapy and platinum):
            • Showed a confirmed ORR of 33.3% at both 2.7 and 3.6 mg/kg doses, regardless of HPV status
        • Becotatug vedotin (EGFR ADC):
          • A new randomized phase II trial is evaluating neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors in resectable LA-HNSCC
      1. HPV-Directed Immunotherapy and De-escalation:
        • The TARGET-HPV trial presented at ASCO 2026:
          • Evaluated neoadjuvant HB200 (HPV16-specific viral immunotherapy) + carboplatin / paclitaxel in HPV16+ oropharyngeal SCC:
            • The deep response rate was 87.9%, with 86% of patients receiving de-escalated definitive therapy
            • At 23 months median follow-up, 2-year PFS was 86% and OS was 100%
            • Circulating tumor HPV-DNA was significantly associated with recurrence
      1. Evolving First-Line R / M HNSCC Pipeline:
        • A landscape analysis presented at ASCO 2026 identified 145 active regimens (111 unique assets) in the first-line R / M HNSCC pipeline
        • Key trends include a shift toward chemotherapy-free combinations alongside PD-1 blockade:
          • With bispecific antibodies (10.8%), ADCs (10.8%), and cancer vaccines (9.0%) representing the most common novel modalities
        • Eight key phase 3 trials are underway:
          • All incorporating PD-1 as a target, with pembrolizumab as the backbone in 7 of 8
      • Overall, ASCO 2026 highlights a transformative period in head and neck oncology:
        • With perioperative immunotherapy now established as a new standard, bispecific antibodies and ADCs showing compelling early efficacy, and biomarker-driven strategies (PD-L1 CPS, HPV status, ctHPV-DNA, MRD) increasingly guiding treatment selection

      References

      1. Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer. Uppaluri R, Haddad RI, Tao Y, et al. The New England Journal of Medicine. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434.
      2. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma | FDA. Food and Drug Administration. 2025-06-13.
      3. Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) for resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Efficacy by surgical outcomes in the phase 3 KEYNOTE-689 trial.. Adkins D, Haddad R, Tao Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6057. doi:10.1200/JCO.2026.44.16_suppl.6057.
      4. Perioperative or adjuvant PD-1/PD-L1 blockade with curative-intent multimodality therapy for locally advanced head and neck squamous cell carcinoma: A systematic review and meta-analysis of randomized trials.. Daher S, Daher H, Altal H, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):e18074. doi:10.1200/JCO.2026.44.16_suppl.e18074.
      5. Neoadjuvant ivonescimab (AK112, a PD-1/VEGF bispecific antibody) combined with nab-paclitaxel and cisplatin (AP) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): An exploratory phase II study.. Kunyu Yang, Xiaomeng Zhang and Lu Wen. Journal of Clinical Oncology. 2026;44(Suppl 16):6014. doi:10.1200/JCO.2026.44.16_suppl.6014.
      6. Neoadjuvant immunotherapy in combination with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma: Updated efficacy and safety data from a randomized phase II trial.. Liu L, Chen F, Li Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6091. doi:10.1200/JCO.2026.44.16_suppl.6091.
      7. Neoadjuvant adebrelimab plus chemotherapy in untreated locally advanced head and neck squamous cell carcinoma: Efficacy and biomarker insights from a single-arm phase 2 trial.. Fang R, Lei W, Huang B, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6106. doi:10.1200/JCO.2026.44.16_suppl.6106.
      8. Ficerafusp Alfa (BCA101) With Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Two-Year Results of an Expansion Cohort of a Phase I/Ib Trial. Hanna GJ, Zandberg DP, Wong DJ, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2026;:JCO2502027. doi:10.1200/JCO-25-02027.
      9. A multicenter, randomized, double-blind, phase 2/3 study of ficerafusp alfa (BCA101) or placebo in combination with pembrolizumab for first-line treatment of HPV-negative, PD-L1–positive, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): FORTIFI-HN01.. Ferrarotto R, Kaczmar J, Spigel D, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):TPS6129. doi:10.1200/JCO.2026.44.16_suppl.TPS6129.
      10. Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of PD-L1+ recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 trial. Herpen C, Daste A, Arrazubi V, et al. Journal of Clinical Oncology. 2025;43(Suppl 16):6024. doi:10.1200/JCO.2025.43.16_suppl.6024.
      11. LiGeR-HN Phase III Trials of Petosemtamab + Pembrolizumab and Petosemtamab Monotherapy in Recurrent or Metastatic HNSCC. Machiels JP, Fayette J, Haddad R, et al. Future Oncology (London, England). 2025;21(16):2007-2016. doi:10.1080/14796694.2025.2511470.
      12. A phase 1/2 study of the next-generation nectin-4–targeting antibody-drug conjugate CRB-701 (SYS6002) in patients with recurrent or metastatic head and neck squamous cell carcinoma.. Mantia C, Hanna G, Loriot Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6062. doi:10.1200/JCO.2026.44.16_suppl.6062.
      13. A randomized, non-comparative, multicenter phase II trial of neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors (penpulimab/ivonescimab) in resectable locally advanced head and neck squamous cell carcinoma.. Wei X, Xiang Z, Zeng Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):TPS6135. doi:10.1200/JCO.2026.44.16_suppl.TPS6135.
      14. Neoadjuvant HPV16-specific viral immunotherapy (HB200) plus chemotherapy with response-adapted de-escalation in HPV16+ oropharyngeal squamous cell carcinoma: TARGET-HPV trial.. Rosenberg A, Juloori A, Cursio J, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6097. doi:10.1200/JCO.2026.44.16_suppl.6097.
      15. Emerging trends in research strategies in the first-line recurrent or metastatic head and neck cancer (R/M SCCHN) landscape: A top-level analysis by Oncofocus.. Shukla A, Keeshara V, Chamaria M, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):e18029. doi:10.1200/JCO.2026.44.16_suppl.e18029.
      16. Recent Highlights and Breakthroughs in Immunotherapy for Head and Neck Cancers. Vuille JA, Szturz P. Current Opinion in Oncology. 2026;38(3):201-211. doi:10.1097/CCO.0000000000001211.
      17. Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: The Current Status and Future Outlook. Köylü B, Selçukbiricik F, Aksoy S, Güven DC. Critical Reviews in Oncology/Hematology. 2026;:105145. doi:10.1016/j.critrevonc.2026.105145.
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      Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

      My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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