ESMO 2025 to Showcase Breakthrough Immunotherapy Trials in Head and Neck and Endocrine Cancers
Key Insights
The ESMO 2025 Congress will feature groundbreaking immunotherapy studies focusing on head and neck squamous cell carcinoma (HNSCC) and neuroendocrine carcinomas, exploring innovative combinations beyond traditional PD-1 (search) inhibitors.
KEYNOTE-689 trial demonstrates significant clinical impact with pembrolizumab plus standard care achieving 59.8% vs 45.9% three-year event-free survival in PD-L1 (search) positive patients (HR 0.66, p=0.004).
Novel therapeutic approaches include ZG006 trispecific T-cell engager showing 33.3% objective response rate in platinum-refractory neuroendocrine carcinoma and combination checkpoint inhibitor strategies targeting LAG-3 (search) and TIM-3 (search) pathways.
The ESMO 2025 Congress is poised to present pivotal immunotherapy trials that could reshape treatment paradigms for head and neck squamous cell carcinoma (HNSCC) and endocrine tumors. These studies move beyond traditional checkpoint inhibitors to explore innovative therapeutic combinations and novel immune targets, offering new hope for patients with difficult-to-treat cancers.
Perioperative Immunotherapy Shows Promise in Resectable Disease
The KEYNOTE-689 trial represents a landmark achievement in perioperative immunotherapy for locally advanced HNSCC. This phase 3 study demonstrated that adding pembrolizumab (2 cycles neoadjuvant plus 15 cycles adjuvant) to standard care significantly improved patient outcomes. Three-year event-free survival reached 59.8% versus 45.9% in patients with PD-L1 (search) CPS ≥10 (HR 0.66, 95% CI 0.49–0.88; p=0.004) and 57.6% versus 46.4% in the total population (HR 0.73, 95% CI 0.58–0.92; p=0.008).
Major pathologic response occurred in approximately 9% of patients receiving pembrolizumab compared to 0% with standard of care alone. Safety profiles remained consistent with prior PD-1 (search) experience, with grade ≥3 treatment-related adverse events occurring in 44.6% versus 42.9% of patients. Patient-reported outcomes suggested improved quality-of-life recovery post-surgery, highlighting the potential of perioperative PD-1 blockade to meaningfully alter disease trajectory.
Novel T-Cell Engager Targets Refractory Neuroendocrine Carcinoma
ZG006, a trispecific T-cell engager targeting DLL3 (search), represents a significant advancement for patients with platinum-refractory neuroendocrine carcinoma (NEC). This innovative therapy engages both DLL3 and CD3 to enhance T-cell cytotoxicity against DLL3-expressing tumor cells, addressing a patient population typically resistant to standard chemotherapy and immune checkpoint inhibitors.
Preliminary results from the phase 2 trial demonstrated a 33.3% objective response rate and 66.7% disease control rate, with manageable treatment-related adverse events including pyrexia and cytokine release syndrome. The study continues to assess objective response rates and progression-free survival as key endpoints in this challenging patient population.
Combination Checkpoint Inhibition Expands Treatment Options
Several trials are exploring dual checkpoint inhibition strategies to overcome resistance mechanisms. The retifanlimab study combines anti-PD-1 (search) therapy with anti-LAG-3 (search) and anti-TIM-3 (search) antibodies in PD-L1 (search)+ recurrent/metastatic HNSCC. This double-blind, randomized phase 2 trial targets co-inhibitory receptors that suppress immune responses, aiming to enhance the immune system's ability to target cancer cells.
Early findings from ASCO 2025 demonstrated numerically longer median progression-free survival (approximately 5-6 months) versus PD-1 (search) monotherapy (approximately 3 months), supporting enhanced activity of concurrent checkpoint inhibition in PD-L1 (search)+ squamous cell carcinoma of the head and neck.
The SKYSCRAPER-09 trial evaluates tiragolumab, a TIGIT (search) inhibitor, in combination with atezolizumab in recurrent/metastatic disease. TIGIT downregulates T-cell function, and targeting it alongside PD-L1 (search) inhibition could enhance anti-tumor immunity. Preliminary data suggests TIGIT blockade may significantly enhance response rates compared to PD-L1 monotherapy alone.
Advanced Therapeutic Modalities Show Clinical Promise
Antibody-drug conjugates are emerging as powerful treatment options for heavily pretreated patients. The EV-202 trial tests enfortumab vedotin, which targets Nectin-4 (search), combined with pembrolizumab as first-line treatment in PD-L1 (search)+ HNSCC. This approach delivers potent cytotoxic payloads directly to tumor cells expressing Nectin-4, with preliminary findings suggesting good response rates and manageable toxicity.
The ongoing EV-202 recurrent/metastatic HNSCC cohort is testing this combination in patients with CPS ≥1, with interim analysis requiring ≥5/20 responders and promising results at ≥14/40 total responders. This is contextualized by enfortumab vedotin monotherapy achieving 23.9% objective response rate and KEYNOTE-048 first-line pembrolizumab median overall survival of 12.3 months.
Amivantamab, an EGFR (search)/MET bispecific antibody, addresses resistance mechanisms in HNSCC that has progressed after checkpoint inhibition and chemotherapy. Preliminary findings suggest this therapy can induce objective responses in patients with EGFR/MET-driven resistance while maintaining a favorable safety profile.
Neoadjuvant Approaches Gain Momentum
The CompARE phase III trial investigates durvalumab, a PD-L1 (search) inhibitor, combined with chemoradiotherapy in intermediate- to high-risk oropharyngeal cancer. This study focuses on high-risk patients, particularly those with HPV-negative tumors who traditionally have poorer outcomes with standard chemoradiotherapy alone. Early results suggest improved event-free survival with durvalumab addition, though final overall survival benefits await confirmation.
The CAMORAL phase II study evaluates camrelizumab, a PD-1 (search) inhibitor, combined with chemotherapy as perioperative treatment for locally advanced HNSCC. Preliminary data suggests encouraging rates of major pathological response with low-grade toxicities, exploring how adding immunotherapy before and after surgery might enhance tumor immunogenicity and reduce recurrence.
Radiotherapy Combinations Explore Immune Activation
The KEYNOTE-717 trial combines hypofractionated radiotherapy with pembrolizumab in recurrent/metastatic HNSCC, testing whether radiotherapy-induced immune activation can improve PD-1 (search) therapy efficacy. The study's primary endpoint assesses systemic response rates, with additional endpoints evaluating the abscopal effect where local tumor irradiation induces immune responses in distant metastases.
These trials collectively represent the next frontier of immunotherapy for head and neck cancers and endocrine tumors, offering promising strategies to expand treatment options for patients with challenging malignancies. The diversity of approaches—from checkpoint inhibitors to T-cell engagers and antibody-drug conjugates—demonstrates the field's evolution toward more sophisticated, targeted therapeutic interventions.