Last Updated on 2026 年 3 月 31 日 by 総合編集組
Oral Cancer New Drugs and Treatments 2025-2026: Pembrolizumab Perioperative Therapy, Bispecific Antibodies, and ADC Breakthroughs
Summary of Key Advances in Head and Neck Squamous Cell Carcinoma (HNSCC) Treatment
Head and neck squamous cell carcinoma, including oral cancer, remains one of the most challenging malignancies worldwide, accounting for approximately 4.5% of all cancer cases. Despite improvements in surgery, radiotherapy, and chemotherapy, the five-year survival rate has hovered around 60% for decades. However, 2025 and 2026 have witnessed a paradigm shift with the integration of immunotherapy into earlier treatment settings, the rise of bispecific antibodies, and the maturation of antibody-drug conjugates (ADCs).
Perioperative Immunotherapy: Expanding from Local Control to Systemic Protection
Traditionally, resectable locally advanced HNSCC was managed with upfront surgery followed by risk-adapted adjuvant chemoradiotherapy. This approach has reached a plateau in preventing distant metastases and improving long-term survival. The most significant advancement in 2025 is the validation of perioperative immunotherapy, which combines neoadjuvant and adjuvant immune checkpoint inhibitors to enhance systemic immunity.
On June 12, 2025, the U.S. FDA approved pembrolizumab (Keytruda) for resectable locally advanced head and neck squamous cell carcinoma. This approval was based on the pivotal KEYNOTE-689 phase 3 trial. Patients in the experimental arm received two cycles of neoadjuvant pembrolizumab, followed by surgery, then adjuvant pembrolizumab combined with radiotherapy (with cisplatin added based on pathology risk), and up to 12 cycles of maintenance pembrolizumab.
Key efficacy results included:
- Median event-free survival (mEFS): 51.8 months in the perioperative pembrolizumab group versus 30.4 months in the standard-of-care group (HR 0.73).
- In patients with PD-L1 CPS ≥ 1: 59.7 months versus 26.9 months (HR 0.66).
- Three-year event-free survival rate: 57.6% versus 46.4%.
From an immunobiological perspective, administering a PD-1 inhibitor before surgery leverages the intact tumor as the largest source of tumor antigens. This allows antigen-presenting cells to prime a broader and more robust T-cell response, helping to eliminate micrometastases and reduce the risk of distant recurrence (HR 0.71 for distant recurrence in the pembrolizumab arm).
However, clinicians must remain cautious about disease progression during the neoadjuvant waiting period. In KEYNOTE-689, progression occurred in 12.4% of the pembrolizumab group compared to 1.2% in the control arm. Careful patient selection is essential for tumors with rapid growth kinetics.
For high-risk postoperative patients (those with extracapsular extension or positive margins), the NIVOPOSTOP (GORTEC 2018-01) phase 3 trial demonstrated benefit from adding nivolumab to postoperative radiotherapy. The three-year disease-free survival improved to 63.1% versus 52.5% in the standard chemoradiotherapy arm, with a 24% reduction in recurrence or death risk. The benefit was observed across PD-L1 expression levels and was particularly relevant for HPV-negative patients, who traditionally have poorer prognosis.
The Rise of Bispecific Antibodies: Targeting Multiple Oncogenic Pathways
The research focus has shifted from single-target agents to bispecific antibodies capable of simultaneously blocking two key signaling pathways, addressing resistance issues common with monotherapy.
Amivantamab (Rybrevant), a fully human bispecific antibody targeting EGFR and MET, showed promising activity in the OrigAMI-4 trial. In patients who progressed after platinum chemotherapy and PD-1 inhibitors, single-agent subcutaneous amivantamab achieved an objective response rate (ORR) of 45%. The subcutaneous formulation (Rybrevant Faspro) was approved in 2025, significantly shortening infusion time and reducing infusion-related reactions to 7%. When combined with pembrolizumab in the first-line setting, the ORR reached 56%, indicating strong synergy.
Another notable agent is petosemtamab (MCLA-158), which targets EGFR and the cancer stem cell marker LGR5. In a phase 2 study for PD-L1-positive recurrent/metastatic HNSCC, petosemtamab plus pembrolizumab as first-line therapy achieved an ORR of 63% (including 6 complete responses). Additional outcomes included a 12-month overall survival rate of 79% and median progression-free survival of 9 months. Two phase 3 trials (LiGeR-HN1 and LiGeR-HN2) are now underway to confirm these results.
Antibody-Drug Conjugates (ADCs): Precision Delivery of Cytotoxic Payloads
Third-generation ADCs have matured in 2025, featuring improved linkers and bystander effects that allow killing of neighboring cancer cells even if they do not express the target antigen. This is particularly valuable in heterogeneous tumors like HNSCC.
TROP2 is highly expressed in over 80% of HNSCC cases and correlates with aggressive behavior. Datopotamab deruxtecan (Dato-DXd) received accelerated FDA approval in June 2025, demonstrating meaningful progression-free survival benefit in EGFR-mutated or cetuximab-resistant lesions. SKB264 (Sacituzumab tirumotecan) reported an ORR of 45% in heavily pretreated patients at the 2025 ASCO meeting, with manageable safety. Telisotuzumab vedotin (Teliso-V) targeting c-Met was also granted accelerated approval in May 2025 for c-Met-overexpressing tumors.
Biomarker-Driven Treatment and NCCN 2025 Guidelines
Precise biomarker testing has become mandatory. PD-L1 Combined Positive Score (CPS) guides first-line therapy for recurrent or metastatic disease:
- CPS ≥ 1: Pembrolizumab monotherapy or pembrolizumab plus chemotherapy (platinum + 5-FU).
- CPS ≥ 20: Strongest responses to immunotherapy, moving toward chemo-free regimens.
- CPS < 1: EXTREME regimen or clinical trials recommended.
For salivary gland malignancies and rare subtypes, next-generation sequencing (NGS) is strongly recommended. Actionable alterations include androgen receptor (AR), HER2 amplification, NTRK fusions, BRAF V600E, and FGFR variants, each linked to specific targeted therapies per NCCN 2025 guidelines.
Real-World Patient Experiences and Toxicity Management
While trial data are encouraging, patient forums highlight practical challenges. Long-term immune-related adverse events from pembrolizumab may include permanent endocrine deficiencies requiring lifelong hormone replacement, joint pain affecting daily activities, and the need for regular liver function monitoring. Cetuximab frequently causes acneiform rash, which patients often manage with topical antibiotics and oral doxycycline. Taste alterations and dry mouth remain significant issues for oral cancer patients, making protein supplements helpful for maintaining weight and completing treatment.
Future Directions in Oral Cancer Care
Looking ahead, digital twin technology is expected to integrate pathology images, genomic data, and treatment plans to simulate individual responses and toxicities. Treatment strategies will further diverge between HPV-positive and HPV-negative diseases: de-escalation for HPV-positive oropharyngeal cancer to preserve organ function, and intensification with bispecific antibodies or ADCs for HPV-negative oral cancer. Multidisciplinary collaboration and logistical support for perioperative immunotherapy will be critical for broader implementation, especially in resource-limited settings.
In conclusion, oral cancer treatment is transitioning from the traditional three pillars to a four-pillar model incorporating immunotherapy, bispecific antibodies, ADCs, and precision biomarkers. These advances offer new hope for improved survival and quality of life when molecular information from each biopsy guides personalized decisions. Close communication with the medical team remains essential for optimal side-effect management.
